Ontario Cancer Institute : Successes and Reverses at Sherbourne Street [1 ed.] 9780773570948, 9780773525252

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The Ontario Cancer Institute

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mcgill-queen’s associated medical services ( h a n n a h i n s t i t u t e ) st u d i e s i n t h e h i s to ry o f m e d i c i n e , health, and society Series Editors: S.O. Freedman and J.T.H. Connor Volumes in this series have financial support from Associated Medical Services, Inc., through the Hannah Institute for the History of Medicine program. 1 Home Medicine John K. Crellin 2 A Long Way from Home The Tuberculosis Epidemic among the Inuit Pat Sandiford Grygier 3 Labrador Odyssey The Journal and Photographs of Eliot Curwen on the Second Voyage of Wilfred Grenfell, 1893 Edited by Ronald Rompkey 4 Architecture in the Family Way Doctors, Houses, and Women, 1870–1900 Annmarie Adams 5 Local Hospitals in Ancien Régime France Rationalization, Resistance, Renewal, 1530–1789 Daniel Hickey 6 Foisted upon the Government? State Responsibilities, Family Obligations, and the Care of the Dependant Aged in NineteenthCentury Ontario Edgar-André Montigny 7 A Young Man’s Benefit The Independent Order of Odd Fellows and Sickness Insurance in the United States and Canada, 1860–1929 George Emery and J.C. Herbert Emery 8 The Weariness, the Fever, and the Fret The Campaign against Tuberculosis in Canada, 1900–1950 Katherine McCuaig 9 The War Diary of Clare Gass, 1915–1918 Edited by Susan Mann

10 Committed to the State Asylum Insanity and Society in NineteenthCentury Quebec and Ontario James E. Moran 11 Jessie Luther at the Grenfell Mission Edited by Ronald Rompkey 12 Negotiating Disease Power and Cancer Care, 1900–1950 Barbara Clow 13 For Patients of Moderate Means A Social History of the Voluntary Public General Hospital in Canada, 1890–1950 David Gagan and Rosemary Gagan 14 Into the House of Old A History of Residential Care in BC Megan J. Davies 15 St Mary’s The History of a London Teaching Hospital E.A. Heaman 16 Women, Health, and Nation Canada and the United States since 1945 Georgina Feldberg, Molly Ladd-Taylor, Alison Li, and Kathryn McPherson, editors 17 The Labrador Memoir of Dr Henry Paddon, 1912–1938 Edited by Ronald Rompkey 18 J.B. Collip A Life in Medical Research Alison Li 19 The Ontario Cancer Institute Successes and Reverses at Sherbourne Street E.A. McCulloch

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The Ontario Cancer Institute Successes and Reverses at Sherbourne Street e.a. m c culloch

McGill-Queen’s University Press Montreal & Kingston · London · Ithaca

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© McGill-Queen’s University Press 2003 isbn 0-7735-2525-4 Legal deposit second quarter 2003 Bibliothèque nationale du Québec Printed in Canada on acid-free paper that is 100% ancient forest free (100% post-consumer recycled), processed chlorine free. McGill-Queen’s University Press acknowledges the support of the Canada Council for the Arts for our publishing program. We also acknowledge the financial support of the Government of Canada through the Book Publishing Industry Development Program (bpidp ) for our publishing activities.

National Library of Canada Cataloguing in Publication McCulloch, Ernest A., 1926– The Ontario Cancer Institute: successes and reverses at Sherbourne Street/Ernest A. McCulloch. (McGill-Queen’s Associated Medical Services (Hannah Institute) Studies in the history of medicine, health, and society, no. 19) Includes bibliographical references and index. isbn 0-7735-2525-4 1. Ontario Cancer Institute – History. 2. Cancer – Research – Ontario – Toronto – History – 20th century. i. Title. rc279.c3m332 2003 c2002-905129-0

616.99’4’00720713541

Typeset in Palatino 10/12 by Caractéra inc., Quebec City

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This work is dedicated to my wife Ona, whose constant love and support made possible my contributions to the Ontario Cancer Institute

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Contents

Preface

ix

Beginnings 3 First Research Programs 21 Leadership and Style 32 Normal and Malignant Stem Cells 46 Growth and Change 61 Immunology and Hematology Using Cell Culture Methods 71 Physics and Radiation Therapy 85 The Middle Years, 1971–1981

98

Interface Research 110 The Style of Ray Bush as Director 123 Response to the Crisis of Space and Equipment 141 Preparing to Move 155 Last Days on Sherbourne Street 160 Glossary 175 Index 179

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Preface

Many of the beliefs and values that gave Ontario Cancer Institute/ Princess Margaret Hospital a platform for success were diluted or even lost after it moved from its original site on Sherbourne Street to a new and much larger building on University Avenue. With time, fewer people remembered the past. Those who did were sometimes considered to be backward-looking rather than supporting a forward vision. I began to chronicle the history of the oci /pmh on Sherbourne Street because I believed strongly that the past achievements should not be forgotten. My concerned was shared by my senior colleagues, who gave personal support to the project. I began work with the help of a complete set of oci /pmh annual reports. These had been carefully preserved by Michael Rauth, who lent me his collection for as long as I needed. Dr Don Cowan made available a copy of an unpublished history of the Ontario Cancer Treatment and Research Foundation, written by Dr Broughton and Dr Sellars. This book was particularly useful for its account of the planning of the Ontario Cancer Institute. My colleagues provided me with copies of their cv s and lists of their publications. Ray Bush died before the move. His cv and bibliography came from departmental records. Ronnie Buick, who was the first vice-president research, lost his life in 1996 in an accident before I began to write. I have also found helpful theses by graduate students in the Department of Medical Biophysics, the Department of Immunology and the Institute of Medical Science who worked at the oci .

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The reports of studies of the Ontario Cancer Institute and the Ontario Cancer Treatment and Research Foundation, conducted in 1972 and 1985, and the following implementation documents, provided much information, especially the minutes of the Joint Committee. I am grateful to Ms Ani Orchanian, who gave me access to these papers in the library archives. Most of the photographs came from the files of the hospital photography department. I am very grateful to the department staff, and particularly Alan Connors and Keith Oxley, who searched them out for me and often made new prints. With these materials I worked on the manuscript until I considered that I had a presentable draft. Then I asked for help from my colleagues. Lou Siminovitch and Jim Till read the whole manuscript. I sent section describing their work and careers to Gordon Whitmore, Arthur Axelrad, Bob Bruce, Mike Rauth, Tak Mak, Vic Ling, and Don Carlow, who provided thoughtful reviews and important corrections. Their contributions gave me confidence that my own memories were not dominating the chronicle. The comments of these colleagues were the major force behind a further extensive revision of the manuscript. At this stage I approached the Hannah Institute for the History of Medicine for advice on how the book might be published. The recommendation was to approach McGill Queen’s University Press. The editor of the press, Philip Cercone, initiated a review of the manuscript. Three experts read the work and submitted reports. I am grateful for their many constructive suggestions. An important idea was that an account be provided of the development of cancer centres in provinces other than Ontario. Dr Charles Hayter and Dr Don Carlow provided insight into such cancer centres as they have developed before or during the founding and growth of the oci /pmh . Together with these additions, the reports of the referees were used in preparing a final revision. I thank Joan McGilvray and Diane Mew, together with the staff of McGill-Queen’s University Press, for their help and encouragement. I am grateful to the Ontario Cancer Institute/Princess Margaret Hospital for support during the writing of this book. I thank Ms Janet Wong for excellent secretarial assistance. It is my hope that the book will keep alive the achievements of the oci /pmh during its stay on Sherbourne Street. There it achieved international stature for cancer care. Its scientists made important contributions to basic and applied knowledge. These are described in the book, along with some of the real problems that had to be faced along the way.

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The Ontario Cancer Institute

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Beginnings

Cancer is an ancient, often fatal disease, affecting most multi-cellular animals. For many humans, the thought of cancer is particularly distressing. When cancer is diagnosed the patient’s response may be not only fear but despair. The facts support a different view. Often cancer can be cured by surgery, radiotherapy, drug treatments, or other methods. Even when the disease is not controllable, many of its manifestations, including pain, can be managed effectively. It follows that cancer treatment facilities are highly prized. Cancer treatment is based firmly on research results obtained over the last century. The disease begins as a genetic change in a single cell. The cell becomes less responsive to normal mechanisms that restrain growth. The result is a population derived from a single cell (a clonal population), all of whose members carry the genetic change that began the process. The clone may remain localized long enough to grow into a recognizable tumour, but invasion of adjacent tissues usually occurs. Early or late in its history the cancerous clone gains access to the blood system; cells then migrate to distant organs, where cells initiate new subclones, called metastases. Some tumours, particularly those of the blood and lymph systems, are almost always widely spread when the disease is sufficiently advanced to allow for diagnosis. As long as the malignant clone remains localized, it can be removed surgically or the growth capacity of the cancer cells can be destroyed by radiation. When the tumour has spread, systemic treatment is needed, usually with chemotherapeutic drugs. Cancer treatment methods

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4 The Ontario Cancer Institute

require special skill; for radiation therapy, machines are used that can deliver high-energy ionizing radiation under carefully controlled conditions. The special physical requirements for treatment with radiation provided a compelling reason for establishing facilities devoted to cancer care.* The Ontario Cancer Institute (oci ) opened officially in the spring of 1958, although its research divisions had begun work a year earlier. The origins of the institute can be traced to events of the previous three decades. The discovery of radium in 1898 and its first use in cancer treatment in 1901 had a lasting effect on how patients were treated. Prior to the use of radium, treatment had been almost entirely surgical and, with few exceptions, ineffective. Radium was seen to be useful in certain cancers. However, it was expensive and special knowledge and equipment were needed for its use. Expense led to the demand that governments or hospitals buy the radium. The need for experts suggested that treatment should be centralized. In 1922 the government of Quebec spent $100,000 for the purchase of radium and established a special institute for its use. In 1925 the government of Nova Scotia and the board of the Halifax Visiting Dispensary purchased 200 milligrams of radium. Both these initiatives were hindered by jurisdictional disputes between hospitals; the beginning of the specialty of radiotherapy encountered opposition from surgeons and doctors in private practice. These felt that they would loose patients and the money they earned from patient care.† Saskatchewan proved that it was feasible to establish a provincial cancer agency. The province established a Cancer Commission in 1930, with the objects of providing public education, the acquisition of radium, and the delivery of treatment at central clinics. In spite of some opposition from the medical profession, the commission provided care for about half of the cancer patients in the province. Manitoba soon followed, establishing its Cancer Relief and Research Institute. Ontario was slow to move towards centralized cancer treatment. Perhaps embarrassed by the progress in the west, in 1931 the provin-

** A excellent and clear general account of cancer can be found in: Cancer – The Evolutionary Legacy, by Mel Greaves, published by Oxford University Press, 2000. *† Charles R.R. Hayter, “‘To the relief of malignant diseases of the poor.’ The acquisition of radium for Halifax, 1916–1926,” Journal of the Royal Nova Scotia Historical Society 1 (1988), 130–43.

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cial government established a royal commission to study the issue, with the president of the University of Toronto, H.J. Cody, as chairman. The Royal Commission visited many other jurisdictions, seeking ideas from experts. It was soon clear that opinion was polarized. As in other parts of the country, private doctors wished to retain a decentralized system where they could care for patients close to their homes. Cancer specialists urged the creation of a centralized system, that could use radium, keep records, and support research. It took years before action was taken, perhaps because of poor economic conditions and the beginning of the Second World War. At last, in 1943, the Ontario Cancer Treatment and Research Foundation (octrf) was established by provincial legislation.* The octrf was given a broad mandate to provide cancer treatment and to support conferences and research. The foundation’s clinical role centred on radiation therapy, whose large machines required special resources of money and infrastructure. octrf established regional clinics in association with major hospitals at Kingston, London, and Hamilton. These regional centres was largely out-patient facilities, with radiation therapy machines and radium. Regular conferences served to bring radiation therapists together to share their experiences. In Toronto, cancer treatment was provided at the Ontario Institute of Radiotherapy, located at the Dunlop Building of the Toronto General Hospital (tgh). The institute was a part of the tgh, the largest and most influential of the teaching hospitals of the University of Toronto’s Faculty of Medicine. Its immediate neighbour to the south on University Avenue was the Hospital for Sick Children, Canada’s major pediatric centre. Two major University buildings, the Banting Institute and the Best Institute were just to the north, across College Street and connected to the tgh by a tunnel. The main St George Campus of the university was within easy walking distance, just north of College Street and east of Queen’s Park. This put radiotherapy in the middle of a major hospital concentration, closely tied to the university and influenced by traditions and policies of a large health centre. In the early 1950s this arrangement had obvious advantages and disadvantages. Cancer patients had the support of the medical and surgical specialists of the Toronto General Hospital. Radiation therapy ** The information about Saskatchewan was provided by Dr Charles Hayter, in the form of a preprint, “Compromising on Cancer: The Saskatchewan Cancer Commission and the medical Profession, 1930–1940.” Early Ontario experience is described in his paper “Medicalizing Malignancy: The Uneasy Origins of Ontario’s Cancer Program, 1919–34,” Canadian Bulletin of Medical History 14 (1997), 195–213.

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6 The Ontario Cancer Institute

1. oci/pmh, Sherbourne Street site 2. Wellesley Hospital 3. Toronto General Hospital 4. Sick Children’s Hospital 5. Mount Sinai Hospital 6. oci/pmh, University Avenue site

was a treatment success in the management of local tumours, yet radiotherapy did not flourish. Academically, it was linked with diagnostic radiology in a single university department. There was little exposure of medical students to the specialty. Interns saw only patients at the beginning of their treatment or when therapy failed; such patients were sick and often difficult. They did not attend the out-patient clinics, where cured patients came for follow-up. These circumstances provided little incentive for young doctors to chose a career in cancer care. In 1951 the Ontario premier, Leslie Frost, responded to advice from a committee of octrf by announcing funding for a free-standing cancer hospital, to be situated on Sherbourne Street, next to the Wellesley

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7 Beginnings

Hospital a few blocks west of the Toronto General.* The new hospital would be called the Ontario Cancer Institute. This was a bold step, since no dedicated cancer hospital existed elsewhere in the country. The oci remained unique until the Cross Hospital was established in Edmonton in 1968. Conflicts with private doctors, and particularly surgeons, were avoided by making the provision of radiation therapy the principal function of the new establishment. Academic ties with the University of Toronto were maintained through the Department of Radiology. When the oci began to receive patients in 1958, most of them were treated as out-patients. Only those requiring extensive medical or social support occupied the in-patient beds. It soon was seen that patients did not like being admitted to a “Cancer Institute”; they much preferred a hospital. When the issue of finding an name for the inpatient facilities became urgent, Princess Margaret happened to be passing through Toronto, so her name was adopted for the hospital. The whole operation was called the Ontario Cancer Institute, incorporating the Princess Margaret Hospital, or oci/pmh. Clinicians usually preferred the hospital name, while the scientists used oci. A novel clinical feature of the hospital was a special ward for the treatment of children with cancer. The first pediatrician was John Darte. Fully trained in pediatrics, Darte spent two years in Manchester, learning radiation therapy. He was a remarkable man; huge in stature, he was gentle in manner. Highly skilled, he was also forward-looking. He readily formed collaborative links with research. With the help of McCulloch he performed three marrow transplants as a treatment for leukemia in children. These were certainly the first human transplants in Canada and may have been the first in the world. One temporary remission was obtained. Unfortunately, the early experience was discouraging and was reported only orally at a meeting. Darte left the oci to go to Newfoundland, and soon after the pediatric ward was closed. In Toronto’s early days the neighbourhood, north of Wellesley and between Jarvis and Sherbourne Streets, had been home to many wealthy families, such as the Masseys. By the time the new Cancer ** The Wellesley Hospital itself had a varied existence. Founded by a prominent Toronto surgeon, Dr Herbert Bruce, as a place where he could treat his wealthy patients it had matured into a general hospital where many private doctors continued practice as staff members. For a while it was administered as department of Toronto General Hospital. Later it became an independent public teaching hospital, with its own board. Such was its status during the time that the Ontario Cancer Institute was its immediate neighbour on Sherbourne Street. Joan Hollobon has written an entertaining history of the Wellesley Hospital, The Lion’s Tail, a History of the Wellesley Hospital, 1912–1987 (Toronto: Irving, 1987).

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Clifford Ash, the founding director of oci/pmh.

Institute built there, the area had decayed greatly. Many former mansions were rooming houses. Prostitution was obvious at night. The ambience was strikingly different from that the university and its adjacent teaching hospitals. The new Ontario Cancer Institute would replace the Ontario Institute of Radiation Therapy while providing a better structure for the work of its excellent leaders. Gordon Richards, the founder of the Ontario Institute and its first head, had died of aplastic anemia, possibly the result of exposure to radiation incurred in the work that established the specialty in Toronto. He was succeeded by Clifford Ash, who was to become the first director of the Ontario Cancer Institute. Vera Peters was already pioneering the radical treatment of Hodgkin disease that was to establish her international reputation. The esteem she earned greatly helped the oci to achieve recognition by the profession. Her fame helped Ash recruit radiation therapists to join the new institute. The Ontario Cancer Institute was established formally in 1952 by an act of the legislature. Under the terms of the act the Board of Trustees, called members, represented the octrf, the University of Toronto, the Toronto General Hospital, St Michael’s Hospital, and the Toronto Western Hospital. The board was clearly intended to insure links between the new institute and the established medical community.

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9 Beginnings

However, the composition of the board did concern the staff of the institute. They feared that representatives of other hospitals might favour competing interests. By the terms of the act, the chairman of Board of Trustees of the Toronto General Hospital was also the chairman of the oci board. To overcome this problem, oci board chairmen were subsequently appointed by the provincial government, thus giving the oci a certain amont of autonomy, enabling it to preserve its integrity and promote its objectives. The first chairman of the oci board was Norman Urquart. Allward and Gouinlock were appointed architects for the building and construction began in 1954. The initial estimate was for $5 million, but the province soon needed to add a further $2 million – an example of the provincial support given to the oci easily and generously in its early days. As the building approached completion in 1957, the province revised the Cancer Act and established the relationship between the octrf and oci. At about the same time Wallace McCutcheon replaced Norman Urquart as chairman of the board. Mr McCutcheon was to have a profound and positive influence as the new institute started its life.

planning and construction It is widely believed that the original plans called for a five-storey building, with its principle functions the delivery of radiation treatment, the provision of in-patient facilities, and long-term follow-up of patients. It is said that the premier, Leslie Frost, looked at these plans, disapproved of the absence of any research component, and arbitrarily added two research floors. One floor was for research into the biology of cancer; this was a priority since it was widely thought that new treatment or prevention strategies might come from a better understanding of how normal cells became cancer. The other floor was for physics research, since knowledge of the physical basis of radiation was essential for safe and effective treatment. The completed building was a long narrow structure, fronting on Sherbourne Street and occupying almost half of the block between Sherbourne and Jarvis Streets. A short south wing connected the building with the Wellesley Hospital; the angle between the major part of the building and the south wing provided space for a circular drive for cars coming in from Sherbourne or exiting back to it. This driveway was immediately adjacent to the ambulance entrance for the Wellesley Hospital. An oci ambulance entrance was situated off Wellesley Lane, which ran along the north side of the main building. The oci building was eight stories high over most of its extent. At the west end only the first four floors were built; the roof of these floors was

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10 The Ontario Cancer Institute

The Ontario Cancer Institute/Princess Margaret Hospital, as seen from Sherbourne Street, shortly after it opened. Many attempts have been made to photograph oci/pmh. Regardless of the artistic talent of the photographer, the pictures, like this one, show only an uninteresting red brick building.

equipped as a tennis court, a feature that led the staff to unfounded expectations of leisure and games. The physical link between the oci/pmh and the Wellesley was a clinical necessity. The new cancer institute was never intended to have many of the services essential for a general hospital. A major example was the policy to exclude all but the most minor surgery. Only one small operating room was used for biopsies or such radiation therapy procedures as the insertion of radium. The oci/pmh had no emergency department; unexpected needs of patients required the adjacent Wellesley emergency. Seriously-ill cancer patients might need to be transferred to the critical care unit at the Wellesley. Other special consultation services were also supplied by the neighbouring general hospital. The new building was well equipped with modern devices for delivering radiation to cancer patients. Standard therapy machines were in place, operating at energy levels from 50kv to 270 kv. Isotope machines, using cobalt 60 or Cesium 137 were either purchased or constructed in the oci machine shop. These, with their easily calculated dose outputs, were to be the mainstay of the radiation oncology department for many

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Premier Frost, front left, speaks at the opening ceremony. He is watched by the first chairman of the board, Wallace McCutcheon (front right), John Law (right middle), and Cliff Ash (right back). Dr Cosbie, the head of the octr stands behind Mr Frost.

years. The most energetic machine was a 24 Mev betatron, whose beam could deposit large amounts of energy in tumors deep in the body. Adequate amounts of radium were to hand for implant treatments.

appointments The major officers of the new cancer institute had been recruited while the building was under construction. Cliff Ash, already in charge at the Dunlop Building site, was the first director and personally in charge of radiation therapy. He had two important English-trained recruits; William Rider was not only an expert clinician but also a sparkling personality. William Ault, professionally Rider’s equal, was quieter by nature. Perhaps the most important appointment was made from the staff of the board that planned the hospital. John Law had been the board’s secretary, and he was the natural choice for administrator. He understood that administration is there to help and support treatment and research, not to govern them. He knew how to foster an environment of creativity. He was always available personally and gave good advice to many members of the staff, advice that might be personal as well as professional. Without John Law, the oci would never have grown to world-class stature. Nor would it have been the happy work

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environment that was enjoyed by all, from cleaners to doctors and senior scientists.

the department of medicine Radiation oncology was the dominant clinical department at the oci. Yet patients with cancer have medical problems, sometimes related to their tumours or treatment, but often part of an important unrelated disease. The oci needed a Department of Medicine. The first chief physician was Harold Warwick, recruited from his post as medical director of the National Cancer Institute of Canada. Like other oci leaders, his appointment was made before the building was complete. He spent the interval as a staff physician at the Toronto General Hospital. His cheerful personality and administrative skill insured the success of his oci department. The idea was taking shape that the medical care of cancer patients might require a new specialty in internal medicine, medical oncology. The first physicians with a special interest in cancer were usually trained as hematologists. The link with hematology was natural because certain cancers arose as malignant transformation in cells of the blood-forming or lymphatic systems. Cancer of the marrow, where normal blood cells are produced, are leukemias. These are disseminated at the time of diagnosis. When the oci was founded the treatment of leukemia with chemotherapy was just beginning. Since radiation was not usually part of the management of leukemia, the oci had little to offer such patients that they could not find in the hematology services of general hospitals. In contrast, cancers of the lymphoid system, the lymphomas, often presented as a single enlarged lymph node that could be treated appropriately with radiation. When lymphomas were spread through many lymphatic spaces, either when first diagnosed or as the disease evolved, treatment with both drugs and radiation was usually needed. It followed that patients with lymphoma would often be treated at the oci and that the staff of its Department of Medicine would have an essential role in their management. Warwick was a hematologist. He needed to recruit physicians who could treat not only leukemia and lymphoma but also common diseases such as diabetes. Cancer-related problems, such as infection or disturbed metabolism, required special medical care. For the first year Warwick had to rely on his own work with help from consultants with primary appointments at other hospitals. His first active medical staff appointment was made in 1960, when Dr William Meakin, a young endocrinologist, came to help in the treatment of cancers whose growth was known to be influenced by hormones, such as cancer of the breast

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13 Beginnings

and prostate. Later that year, Dr Warwick was appointed dean of the Faculty of Medicine at the University of Western Ontario. He was replaced at the oci by Dr Mac Whitelaw, a distinguished physician from British Columbia. Whitelaw was soon joined by Dr Richard Hasselback, one the first Canadian hemato-oncologists. The Department of Medicine included an eight-bed ward with the special features needed for metabolic studies in man. Here it was possible to measure metabolic changes as they occurred in patients either after treatment or as their diseases progressed. Dr Allan BruceRobertson, a clinical investigator trained in metabolic studies, used the facilities to document changes in protein metabolism in patients after irradiation. Patient care depends not only on front-line doctors but also on ancillary services, such as pathology and diagnostic radiology. In octrf clinics these tools were usually supplied by the host hospital. The oci had, from the beginning, a small diagnostic radiology service, with its own dedicated machines. At first, only a single part-time radiologist was on staff, although soon this number grew to three, still only part-time. Pathology is central to cancer treatment, since accurate tissue diagnosis is a requirement for deciding that a cancer is present; the pathological diagnosis is usually a major determinant of each patient’s management plan. The chief of pathology at the oci was Tom Brown, a distinguished cancer expert, with a special skill in the classification of lymphomas. But Brown was also chief of pathology at the Wellesley Hospital and this arrangement, similar to those found at the octrf regional centres, may have hindered the development of pathology at the oci. Everything was now in place to provide exemplary care to cancer patients. Along with the resources, there was an attitude of caring and prompt but unhurried service. Volunteers from the Canadian Cancer Society contributed greatly to the atmosphere, giving support to people who were having to dealing with a serious and potentially lethal disease. Together, the volunteers, the professionals, and the support staff, provided a service that earned a high level of patient satisfaction and loyalty. The good will and generosity of cancer patients would remain a major source of strength to the oci throughout its Sherbourne Street days.

research As the construction on Sherbourne Street was nearing completion, an urgent priority was to recruit the research leaders. Harold Johns, the inventor of the “cobalt bomb” for radiation treatment was the obvious

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14 The Ontario Cancer Institute

choice to lead physics; fortunately, he accepted the post in 1956. The search committee for a biology head was chaired by Arthur Ham, the Professor of Histology at the University of Toronto and a leading Canadian cancer scientist. Ham was very active in the newly founded National Cancer Institute (nci), the research funding arm of the Canadian Cancer Society and was well acquainted with those in the field of Canadian cancer research. When he failed to recruit Professor Charles Leblond, the chairman of Histology at McGill, Ham took the post himself. Both Johns and Ham were in position to recruit young investigators to begin independent research careers in the new oci. Johns’s most promising students were just finishing post-doctoral training. Gordon Whitmore and Jim Till joined in 1956 after each finished his Ph.D at Yale. Both began work at the Connaught Labs in Toronto while waiting for the oci facilities to be completed.* John Hunt was ready soon after, while Robert Bruce, with both a physics Ph.D and a Chicago md, came a year later in 1958. Johns knew that he needed practical help to support radiation therapy; for this, his most important recruit was Jack Cunningham. As computers became available, Cunningham wrote the programs that were necessary for patient treatment, based on careful measurements of radiation dose delivered at different depth in tissues. Both Bob Baker and J. Cederlund added strength to the clinical physics work. Whitmore, Till, Hunt and Bruce knew how to use the oci radiation facilities to learn more about the biological effects of radiation. Their studies contributed greatly to radiation therapy. One of the most accomplished of Ham’s recruits was Lou Siminovitch.† After his Ph.D in chemistry at McGill, he did five years post-doctoral work at the Pasteur Institute in Paris. When Ham approached him, he was at the Connaught Laboratories, where, in collaboration with Angus Graham, he described the semi-conservative model of the replication of dna in animal cells. Ham had already attracted Allan Howatson, a Scottish electron microscopist to the Anatomy Department in Toronto. He was persuaded to quit the established academic environment for the new oci. ** The research was conducted at a renovated farm at Steeles and Dufferin, a site then outside the city. The atmosphere was exciting, with Angus Graham and Lou Siminovitch doing fundamental studies on dna replication in cultured cells. *† The phage group, of which Siminovitch was a member, had a remarkable organization, modelled on the Roman Catholic Church. One member (Max Delbruck) was considered the pope. Others were cardinals. The effect of the organization was to recognize an “in group” where materials (special mutant phages) and information were freely shared; all others were “out” and lacked the church resources. The church also had clear moral doctrines. Siminovitch was a “cardinal”; as such he brought many of the church principles to the oci.

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15 Beginnings

Arthur Axelrad, with both the md and Ph.D from McGill, was trained in histology, cytology, and genetics. Ham persuaded him to come to Toronto. He was on staff for a year before the building opened, developing his research program in the Department of Anatomy’s laboratories. Ernest McCulloch was a physician who had a special interest in hematology. A year’s laboratory experience at the Lister Institute in London had introduced him to the pleasures of research. His interest in blood cells led to a collaboration with Howatson, who used electron microscopy to examine marrow specimens provided by McCulloch. Ham recruted Ed Goranson, an established biochemist at the University of British Columbia, together with Christopher Helleiner, a recent Ph.D in biochemistry. Siminovitch was directly responsible for recruiting two others. In 1958 he introduced Dr Bernhard (Hardi) Cinader to his Toronto colleagues. In England, Cinader had already established a reputation as an immunochemist. Siminovitch persuaded Ham that immunology was a discipline that was needed in cancer research. Later, in 1961, Clarence Fuerst brought his expert knowledge of bacterial viruses (bacteriophage) to strengthen Siminovitch’s program in genetics. The group in biological research was much more heterogenous than that in physics. Unlike physics staff, the biologists did not start with a direct link to the clinical programs at the oci. Rather, they were free to seek the inspiration for their research from the world around them. Three major fields became oci priorities. First, genetics was in rapid expansion, based on the discovery that dna and rna were the biochemical repositories of genetic information. Much progress in the understanding of their function and regulation was emerging from studies of bacterial viruses. Here Siminovitch had his major influence. He championed the hypothesis that the genetic changes that transformed normal cells into cancer cells might be similar to the events in bacteria, where virus could alter both phenotype and genotype. Regardless of the fate of that hypothesis, he insisted on the primacy of genetics in the understanding of biological phenomena. Second, cell biology was undergoing a revolution based on the introduction of techniques for isolating, in culture, populations of cells derived from single progenitors. These populations, called clones, could be recognized by their capacity to form colonies, when cultures were seeded at low cell density. The method, first developed by Theodore Puck and his collaborators in Denver, had been used to challenge the basis on which ionizing radiation was thought to be an effective treatment for cancer. Before clonogenic assays, it was believed that cancer cells were more sensitive to radiation than their normal counterparts. This sensitivity was considered to be the basis of the capacity of radiation treatments to destroy tumours while sparing normal tissue. Clonal methods allowed a test of this view; it made it possible to

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construct quantitative radiation dose-response curves for the survival of cells with the capacity to form clones. When clonogenic capacity was used as a criterion of viability, radiation dose response curves for normal and tumour cells were found to be very similar. Not surprisingly, radiation therapists were not immediately ready to abandon their long-held views. Both biologists and physicists saw that testing the new model of radiation sensitivity was an important task. Clonal analysis of mammalian cells was also an important tool in genetics. As such, it was a good fit with the research championed by Siminovitch. Third, the link between medical practice and mechanisms of disease was becoming stronger. Replacement therapy in hormone-deficient diseases, such as diabetes or hypothyroidism, always depended on measuring both the defect and the response to treatment. The value of rational therapy in infectious disease was obvious, as antibiotics were chosen on the basis of the sensitivity of pathogens. It was natural to seek a similar reason to select which drug should be used to treat each patient’s cancer. This concept had motivated McCulloch to attempt to culture bone marrow cells in the hope that a cell culture assay for drug sensitivity could be developed. His clinical mentors persuaded Raymond Parker to make a place for him to work. Parker had learned tissue culture from Alexis Carrel, the founder of the method. Parker’s laboratory in the Hygiene Building of the university continued to be a centre for cell culture, using Carrel’s methods. The Hygiene Department had structural links with the Connaught Labs. Siminovitch met McCulloch there and introduced him to the new cloning methods. In the strange way science happens, a cell culture artefact was at the centre of collaboration between oci scientists. When cultures were newly established, for example from human marrow in McCulloch’s experiments, slowly growing cells were seen for many days. Then, quite suddenly, rapidly growing cells appeared and quickly dominated the cultures. Parker considered these findings to mean that cells in culture could undergo transformation spontaneously and acquire properties like those of cancer. This was an exciting idea. Siminovitch saw the appearance of rapidly growing cells and wanted to study what appeared to be cell transformation using genetic methods. Both Whitmore and Till were brought into the search for an explanation of Parker’s “transformed” cells. Arthur Axelrad was also intrigued and agreed to collaborate. Siminovitch reasoned that insight could be obtained by comparing the chromosomes of the slowly growing and rapidly growing cells. The result was startling; a complete difference in chromosome number and appearance was seen between the two cell types. Mouse, monkey, and human cells were grown in the same laboratory, using methods that allowed pipettes to enter culture

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dishes repeatedly. The chromosomes of the putative transformed cells and cells of a continuous mouse fibroblast line, called “L” cells, were found to be very similar. Cell contamination had occurred. The excitement associated with transformation went away, but the personal links remained. One practical outcome was that cell culture became a common tool at the oci, where scientists in both the Physics and Biology divisions used methods that avoided cell contamination.

the university department of medical biophysics The research staff at the oci all had academic backgrounds. They expected and intended that the research divisions would resemble university departments. The original plan was straightforward: each staff member would seek and obtain an appointment in the appropriate basic science department of the University of Toronto and his students would work for their degrees through that department. This plan failed almost at once because the chairmen of the university departments, and particularly Professor Fisher of Zoology and Hanes of Biochemistry, refused to make the necessary appointments. Their stated reasons were not that the candidates lacked merit, although they may have resented the fact that they had not been consulted in the recruitment. Rather, they could not accept that an institute removed some blocks from the main campus of the University of Toronto could provide an appropriate environment for graduate studies. Correctly, they saw that students at the oci would interact together rather than with students in the same department at the university. They may also have been convinced that the untried oci, with its major role in radiation therapy, would support only applied research and would not be a proper organization for research in the basic sciences upon which most graduate programs were founded.* The oci research divisions had to find a new route to graduate education. A second option was founded upon the links that were developing between the staff in physics and biology. They soon saw that physical methods were powerful tools for probing problems in biology. At a practical level, radiation was a useful way to perturb biological systems, without the pharmacological complications associated with drugs. At a conceptual level, the quantitative methods fundamental to physics proved valuable in evaluating biological processes. ** At the time it was not polite to make a point about money; though not stated, professors at the university may have resented provincial funds going to research at the oci rather than to their own established departments.

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It was an easy step to propose a new department, based on the union of physics and biology, a department that would be called Biophysics. This plan needed the cooperation of the University of Toronto. Like cross-appointments, a Department of Biophysics met opposition. The issue of distance from the main campus was reintroduced as a powerful objection. Some science departments also considered that the physical approach to biology was already in their domain. As a result of this opposition, the Faculty of Arts and Science rejected setting up a Department of Biophysics. A third solution proved successful. Arthur Ham had a long and distinguished association with the Faculty of Medicine. His course in histology and his textbook were major sources of pride to the faculty and satisfaction to generations of medical students. He was able to convince it to found a new department, to be called Medical Biophysics. The arguments against the oci used by Arts and Science were less impressive to Medicine, since medical students regularly received instruction at teaching hospitals that might be well removed from the St George campus. Perhaps more important, the research at the oci was certain to be focused heavily on the problem of cancer. This disease-orientation made the new department a logical part of the structure of the medical faculty. It was in place and working by 1960. The difficulties encountered in founding the Department of Medical Biophysics may have contributed to its success. Scientists united in a single department at one geographic location were much stronger than they might have been if fragmented among several university departments. The new department was free to develop its own identity and procedures which made it attractive to potential students. The high standards set by Harold Johns were supported by regulations that brought biologists and physicists together, as these worked on committees that supervised and assessed student programs. As success became obvious, the unified department was recognized as important both nationally and internationally. The oci scientists were lucky that the university did not immediately embrace them and force them into its established modes. Arthur Ham was the first chairman of Medical Biophysics. Students were selected carefully by an admissions committee on the basis of academic record and personal interviews with many staff members. This often required that candidate-students travel to Toronto with their expenses covered by oci funds. When admitted, each student was insured of a minimal financial support. Each student was assigned to a supervisor. A program committee, consisting of two to three other faculty members met with the student and supervisor at least twice a year to review progress and plans. This system insured that students

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had a broad access to the faculty, and it also provided a disputeresolution mechanism if student and supervisor disagreed. It was an effective early-warning system if a student was in difficulty. A key to all the student-related activities was the graduate secretary. The faculty member holding this office served as the general administrative officer for admissions and student programs. He or she worked directly with the chairman to implement departmental policies, as these were established at faculty meetings. The annual rotation of the office among the faculty insured that each was fully conversant with the graduate program, including those procedures that governed the relationship between the department and the University’s School of Graduate Studies (sgs). It was departmental policy that the program would include both biology and physics. Students had to take at least one graduate course in the discipline not included in their undergraduate work. That is, students with a physics background took a biology course while those from biology were enrolled in a physics course. At the final departmental examination, students were expected to demonstrate knowledge of both physics and biology. These practices were not only the underpinnings of the graduate programs, but also brought together the staff in the two oci research divisions. The individual graduate programs in Medical Biophysics were based on research. The student was required to complete research projects. These became more challenging as the student progressed while, concurrently, faculty supervision was decreased. Although it was expected that each doctoral student at graduation would be prepared for independent work, departmental policy was to urge graduates to take postdoctoral work at another institution. Supervisors, with the help of other faculty, often arranged for such post-doctoral experience. As a result oci graduates now populate most of the cancer research programs in Canada.

emerging philosophy A distinct set of values and standards began to emerge at the oci, greatly encouraged by John Law, who made all staff feel that his administration, and indeed the corporate oci, was intent upon helping each member obtain his or her professional goals. The institute succeeded in part because the links between the chairman Wallace McCutcheon, and the provincial government insured generous financial support. The senior provincial agency, the octrf was also helpful. The formation of the Department of Medical Biophysics fostered a research climate

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The founding administrator of the oci/pmh; John Law at his desk. His wise practices laid the foundation of oci/pmh success.

characterized by a firm intention to make a contribution to cancer research at a world level. The interaction between clinicians and scientists was cordial, often based on the need of radiotherapists to improve understanding of their treatment modality. These internal strengths provided a sense of unity and confidence. The negative attitude of the university insured that the scientific staff saw their allegiance to the oci rather than the university disciplinary departments. The Faculty of Medicine was supportive, although the university and the major teaching hospitals did not expect much of the oci. Benign neglect was a major reason why the oci scientists were able to be innovative, since their priorities were not of concern to their older, more powerful neighbours. The result was a sense of pride in the oci and a determination to succeed as judged by international standards.

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First Research Programs

The staff in the two research divisions began work in 1957, as soon as they had unpacked their apparatus and assembled supplies. Their first programs reflected both the ideas they brought to the oci and the priorities flowing from its goals.

research in physics The work in the Physics Division followed two lines. Clinical physics was closely linked to radiation oncology. Isotope-based radiation therapy machines were just coming into common use, based on Harold Johns’s discovery that 60Co could be engineered into apparatus suitable for clinical use – the “cobalt bomb” of popular language. His personal research was directed toward a further exploitation of the isotope approach to therapy. The spectrum of 60Co has two distinct energy peaks. Johns was attracted to radioactive cesium because it has a single spectral energy peak. In the well-equipped machine shop of the Physics Division Johns and his staff constructed isotope machines using either 60 Co or 137Ce. These proved powerful tools to increase the ability of the oci to attract both more therapists and more cancer patients. Johns also maintained a strong interest in Jack Cunningham’s dosimetry experiments. Laboratory constructs (phantoms) were made that mimicked the radio-densities of parts of the human body. Cunningham used these to make maps of the distribution of energy deposited from

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Harold Johns, taken shortly after the oci/pmh opened.

a variety of sources, including 60Co and x-rays (iso-dose curves). With the help of the therapists, these were supplemented with maps showing the distributions of the biological effects of the radiation doses (iso-effect curves). The construction and application of the iso-dose and iso-effect curves were a major early oci contribution to clinical cancer research, since it improved both the efficacy and safety of radiation therapy. A parallel line of basic physics research was the study of the biological effects of radiation (radiobiology). The new clonogenic assays allowed Whitmore and Till to evaluate radiation effects using as an endpoint survival of cells with proliferative capacity as assessed by colony-formation in culture. Since proliferation is the property of cancer cells that allows then to grow progressively, the clonogenic assays provided clinically relevant data. Whitmore and Till showed that radiation dose response curves for x-rays or gamma rays had common features, regardless of the cell culture line examined. These dose-response curves, usually called radiation survival curves, were prepared by plotting the number of surviving clonogenic cells as a fraction of an unirradiated control on graph paper with arithmetic horizontal and logarithmic vertical scales (semilog paper). Radiation dose was plotted on the arithmetic scale and fractional survival on the

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logarithmic scale. With semilog paper, when survival decreases exponentially, it is depicted as a straight line with a negative slope. Radiation survival curves were found to have two components – an initial shoulder, followed by exponential decline in survival with increasing dose. It was seen that radiation survival curves were similar when measured in culture for very different cell lines. These observations had major consequences for the use of radiation in cancer treatment. Much work and thought were given to the mechanisms underlying radiation survival curves. The shoulder was studied by comparing survival after a single radiation dose with that seen when the same dose was delivered as two fractions, separated in time. This “splitdose” experimental design, devised originally by Mortimer Elkind, showed that a larger fractionated dose was needed to achieve the same cell kill as radiation given as single exposure. This meant that some of the radiation damage could be repaired, using mechanisms inherent in the cells. Since radiation therapy was almost always given as a series of fractions, these observations had clinical importance. Repair of sublethal damage was an explanation for the failure to achieve significant tumour kill in some patients. The slope of the exponential component a radiation survival curve is determined both by the size of the critical target or targets and of the rate at which energy is deposited. For example, neutron beams, which are densely ionizing, give survival curves with much steeper exponential components than those obtained with gamma rays. The slope on the exponential component can be used to estimate the size of the critical target, where the deposition of energy leads to cell death. Such estimates give values of the target size, indicating that radiation damage to dna is lethal to mammalian cells. Altering density of ionization is not the only way in which sensitivity can be changed. Radiation has long been observed to be less damaging when given in the absence of oxygen (anoxic conditions). Radiation damage can also be reduced by giving certain chemicals, particularly sulphur-containing compounds such as methionine. These compounds prevent the interaction of oxygen with the damage in dna caused by radiation-induced radicals. The oci physicists confirmed the effects of oxygen and protective compounds using clonogenic assays. This work provided a basis for tests of the clinical use of oxygen under pressure (hyperbaric oxygen) and radio- sensitizing chemicals, a further example of the close link between physics research and radiation oncology. Their use of clonogenic assays placed Whitmore and Till at the forefront of the international radiation biology research community.

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Whitmore collaborated with Mortimer Elkind on a major reference book, The Radiobiology of Cultured Mammalian Cells, published in 1967.*

research in biology When the Division of Biological Research moved into its new quarters at Sherbourne Street in 1957, a single problem dominated the research program: are viruses often the cause of cancer? The viral etiology of cancer was then very controversial. Forty years had elapsed since Peyton Rous had demonstrated that a virus could cause leukemia in chickens. This virus was studied in many laboratories over the years, but the only mammalian example was a virus that caused a benign tumour in rabbits. Discovered by Shope in 1933, it was found that the tumour sometimes progressed to malignant carcinoma. It was thought widely then that the viral-induced leukemia might be common in chickens but was rare in other animals. For mammals, genetic studies in mice provided an attractive alternative hypothesis. Mice had been bred carefully for use in cancer research since the 1920s, and now the objective was to produce large numbers of genetically-identical animals. The goal was reached by brother-sister breeding over at least twenty generations, when tumours arising in one animal could be successfully transplanted into others of the same strain. This also provided an understanding of the genetic basis of tissue transplantation. Each of the strains of inbred mice had been selected because of desirable phenotypic characteristics. Since cancer frequency and site appeared to be linked to the genetics of the animals, it was easy to propose that genetic predisposition was a major contributor to cancer causation. As soon as the oci opened, Arthur Axelrad started an animal colony, housing several strains of inbred mice in an environment that protected them from external diseases. Neither he nor his colleagues considered that the tumours arising in inbred mice could be explained only by Mendelian genetics. It seemed plausible that one or more viruses could be transmitted from parent to offspring and explain cancer incidence. Lou Siminovitch’s experience with bacterial viruses provided the oci group with a powerful and undisputed precedent for the viral etiology of tumours. At the Pasteur Institute he had learned that the dna of some bacterial viruses could be integrated into the genomes of host

** M.M. Elkind and G.F. Whitmore, The Radiobiology of Cultured Mammalian cells. Gordon and Breach, Science Publishers, Inc., New York, N.Y., 1967.

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Alan Howatson, seen with his electron microscope.

cells where the viral dna could replicate as part of the host dna without producing infectious particles. When bacteria with integrated virus were exposed to certain agents, such as ultra violet light, the viral genes became active, particles were produced, and the bacterial cells destroyed. This bacterial phenomenon, called lysogeny, was compelling evidence that viruses could cause genetic changes in host cells. Siminovitch argued that a similar mechanism could exist in mammalian cells and provide an explanation for viral-induced cancer. Arthur Ham found this hypothesis attractive. He provided the leadership that brought Siminovitch, Axelrad, Howatson, and McCulloch into active collaboration. Each had a special skill to offer the group: Siminovitch provided knowledge of the newly emerging molecular

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genetics that was derived from the lysogeny experiments. Axelrad was an expert in mouse immunogenetics. Howatson, the electron microscopist, knew how to visualize virus particles and classify them on the basis of their morphology. McCulloch had studied human leukemia and was qualified to detect the murine disease. He also shared with his colleagues the cell culture experience he had obtained in Parker’s laboratory at the University. Ham himself had many years’ experience in cancer research. The viral theory of cancer received an important impetus in the 1950s. Ludwig Gross, working by himself in New York, took advantage of inbred mice to look for a virus causation of leukemia. He made cell-free extracts of leukemic tissue from an inbred mouse strain called akr. Almost 100 percent of akr mice died of thymus lymphoma and lymphatic leukemia. Gross injected his extracts into newborn mice of strain c3h, where leukemia was almost never seen. Many of these mice developed leukemia or other tumours. Extracts of these tumors were positive when tested for capacity to produce leukemia in other newborn c3h mice, strong support for their viral etiology. Nevertheless, the Gross experiments were not readily reproduced in other laboratories and many doubted their validity. The importance of the Gross findings was obvious to the five researchers at oci; a trip to the Gross laboratory in New York was essential. This visit convinced them that Gross had, in fact, demonstrated a viral etiology for leukemia and perhaps other cancers as well. Subsequent events proved that this conclusion was correct.* The failure of other laboratories to repeat Gross’s findings was traced to the specific substrains of c3h mice used as recipients of tissue extracts. Only some strains were susceptible to the agent that is now known as the Gross leukemia virus. Gross was not a sophisticated scientist; rather, he had a single important idea and the determination to test it. He was a keen observer, hard working, and prepared to repeat experiments many times. His example showed the young oci group that knowledge by itself was not enough. Laboratory work proceeded in parallel with the discussions and visits. The most successful experiments began with electron microscopic observations. Howatson found virus-like particles in the cytoplasm of a transplantable mouse mammary cancer. McCulloch added ** When Ludwig Gross visited the National Cancer Institute, part of the National Institutes of Health in Bethesda, md, Loyd Law, a prominent investigator of mouse leukemia, refused to shake his hand. This uncivilized behaviour was not typical of Law; it shows how a challenge to established science (Gross’s evidence for viral leukemia) can bring out strong emotions.

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extracts of this tumour to cultures of mouse kidney cells. These cells subsequently became degenerate, a response known to occur in virusinfected cultures. When supernatants of the degenerating cultures were added to newly-prepared mouse kidney cell cultures, these also soon showed the characteristic response. Repeated similar passages provided evidence of a virus. The important issue, then, was to see if the virus was novel and if it was capable of causing tumours. A test in animals was clearly needed. The decision to undertake such a test was difficult, since it required the introduction of a virus into the carefully controlled mouse colony and a potentially lethal virus could devastate this important oci resource. It was finally decided to test the virus outside the colony in non-inbred Swiss mice. After about three months, tumours in several organs appeared in these animals. In the interval Dr Stewart and Dr Bernice Eddy of the American National Institutes of Health (nih) had reported the isolation in tissue culture of a virus that caused several types of tumours in mice, rats, and hamsters. They called their isolate polyoma virus. It seemed likely that the virus isolated in Toronto from a mouse mammary tumour was also polyoma. With this news, the oci group injected cell culture fluid containing the virus into newborn hamsters. The newborns began to die after eight to ten days. When examined just before death, the young hamsters were seen to have large hard tumours in both kidneys and hemorrhagic lesions of the liver. This unusually rapid induction of tumours was a feature of the Toronto strain of polyoma. The five oci collaborators used light and electron microscopy to follow the cellular events in the few days between infection and diffuse cancer of the kidney. Light microscopy showed cell death in renal cells beginning soon after virus injection and reaching a peak after about a week. Electron microscopy identified virus particles in tight arrays in the nuclei of infected cells. The potency of the virus was measured by injecting various dilutions of tissue extracts from infected hamster kidneys into newborn animals. The incidence and distribution of tumours in these secondarily-infected animals showed that the virus in kidney increased rapidly after injection and then disappeared when tumours were dominant. These events were, of course, reminiscent of lysogeny, in that the virus was able to both reproduce itself and kill cells. Also, the virus could transform the cells into rapidly-growing cancer. The analogy between polyoma and lysogenic bacterial virus was not complete. Virus could not be recovered from tumours with treatment using agents that induced virus in lysogenic bacteria. Any account of the work with the Toronto strain of polyoma needs to include a description of a control experiment. The collaborators

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asked if the isolation of the virus could be repeated and if the virus was present widely among mice. They were also concerned that the virus, which was known to be hardy, might be passed accidently during laboratory experiments. They borrowed space in the Best Institute, where no virus work was in progress. There, polyoma was again successfully isolated from tumours. The new isolate was tested in hamsters at the oci but outside the animal colony. As well as the putative virus, two control solutions were tested, each designed to detect an artefact. One control was supernatants from uninfected mouse cell cultures. If positive, this control would show unintended infection of sensitive cells. The second control was supernatant from monkey kidney cell cultures, known not to support polyoma virus growth. If this control were positive, viral contamination was happening by some route other than the cells. The results disappointed the investigators. While the virus-injected animals had large numbers of tumours, some cancers were seen in both control groups. The obvious conclusion was that viral contamination had occurred, in spite of the special efforts made to prevent it. But that conclusion was wrong, at least in the instance of the hamsters injected with monkey kidney culture supernatants. Later, Bernice Eddy showed convincingly that such cultures sometimes contained a monkey virus (sv40) that caused tumours in hamsters. Others at nih tried to show that Eddy’s findings were artefacts, but in time, her observations were confirmed repeatedly. The Toronto group failed to grasp the opportunity presented by their unexpected positive controls. Had they done so, they might have discovered sv40. These studies were widely reported in peer-reviewed papers and presentations at meetings. The reports gave the new cancer institute recognition by mainstream investigators. Yet, the collaboration among the five oci scientists did not remain active, although they continued as friends and often worked together in twos or threes on other projects. It is not certain why the work on polyoma came to a stuttering halt in 1961. Jim Till, not one of the original group, maintained an interest through his student Cliff Stanners. His Ph.D thesis was on the effects of polyoma on fibroblasts in culture. Arthur Axelrad continued to work on Friend Leukemia Virus (flv). dna tumour viruses other than polyoma, such as certain adenoviruses, were shown to be carcinogenic under experimental conditions, although they caused only febrile diseases in nature. It was a worry that carcinogenesis by dna-containing viruses might be only a laboratory phenomenon. Subsequent events showed that dna tumour viruses had much to teach about viral integration and function. Notable were the studies of viral antigens as these were expressed in host cells. The important

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tumour-suppressor oncogene p53 was discovered in such work. Studies of its mechanism are now considered to be central to understanding how tumours start, grow, progress, and die. Important research in these areas was done at the oci, but only after more than twenty years had passed since the isolation of the Toronto strain of polyoma.

joint biology-physics research in hematology Ernest McCulloch came to the oci to study the function of bone marrow by transplanting marrow cells into irradiated hosts and needed the institue’s facilities to irradiate mice. Dr Johns, determined to maintain the quality of the use of radiation at the oci, insisted that any member of the Biological Research Division wishing to use radiation must do so in collaboration with a member of the Physics Division. Jim Till volunteered to oversee the radiation experiments. This started an important partnership, for Till was not content to insure that the radiation doses were accurate. Rather, he entered into a vigorous participation in the short and long term planning of the research program. The first Till and McCulloch experiments asked if the mechanism by which gamma rays interacted with tissue had an effect on the survival of irradiated mice. The measurements of radiation sensitivity is a function of the irradiation and the material in which the energy is deposited. Two mechanisms of radiation absorption are important in biological material. In the first, photoelectric scattering, the atomic composition of the radiation-absorbing material is an important determinant of the amount of damage. In the second mechanism, Compton scattering, damage is almost independent of the substance in which the energy is deposited. Absorption of energy from a 250 kv x-ray machine is likely to be photo-electric, while a cobalt source yields photons that are absorbed by Compton scattering. Photons absorbed in bone by photo-electron scattering are more likely to cause damage to adjacent marrow than those absorbed in soft tissue. No such difference would be expected for radiation from 60Co. Blood formation in the mouse occurs principally in two anatomic sites, bone marrow and spleen. The hypothesis was that 250 kv electrons would do more damage to blood forming cells close to bone than photons from 60Co. Any effect of such increased damage would not be detected because a similar differential would not occur in spleen. This problem could be overcome simply by removing the spleens from animals. When the effects of 250 kv and 60Co photons were compared in animals without spleens, the 250 kv x-rays should, if the hypothesis was correct, prove to be more lethal than 60Co photons.

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The experiments were tried. Initial inspection of the results appeared to support the hypothesis. However, Till, the careful physicist, looked in more detail at the radiation measurements. He found that the small effect on animal survival could be traced to the different techniques used to measure the 250 kv and the 60Co irradiation. The hypothesis was not supported, but the experience convinced both collaborators that they could work together happily. They also set down rules for their partnership. For example, they determined that when publishable results were obtained, the order of authorship would alternate between them. The first paper would be by McCulloch and Till, the second by Till and McCulloch. This rotation would continue for subsequent publications. The plan insured them against arguments about priority that could well sour their cordial relationship. The next Till and McCulloch project was more ambitious. The tissue culture cell cloning methods challenged the prevalent view that radiation therapy was successful because malignant cells were more radiosensitive than normal cells. Those who championed this model criticized the cell culture evidence as artificial, not representative of events in vivo. Hewitt, working in England, had used limiting dilution techniques to measure the radiation sensitivity of a transplantable tumor. His work provided the only available in vivo data. While the radiation survival curves he obtained were similar to those constructed using clonogenic cultures his result, with transplantable tumours, could be attacked as a special case. The oci scientists determined to measure the radiation sensitivity of a critical normal tissue, bone marrow, and to measure it in vivo. The devised a viability assay for marrow based on its capacity to engraft and protect mice from the lethal effects of radiation. When groups of ten to twenty mice were irradiated with a lethal dose and then a carefully measured number of isogenic marrow cells were injected into each animal, the number of mice surviving after thirty days was related to the number of marrow cells injected. The same effect could be obtained by injecting each animal with a marrow cell number known to be just sufficient to give 100 percent survival but where the cells were irradiated prior to injection. A linear relationship was seen between recipient survival and dose of radiation to the transplanted marrow cells. Till and McCulloch compared the curve relating number of unirradiated marrow cells to survival with that obtained by injecting one marrow cell number that was irradiated with different doses. This comparison allowed then to calculate the degree which each dose of irradiation reduced the capacity of marrow to protect mice from radiation death. From these data, it was straightforward to construct a radiation dose response curve for proliferation of normal marrow. The method was cumbersome, time-consuming, and yielded results with a wide statistical spread.

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Nonetheless, the radiation survival curve obtained by the mouse protection assay was similar in form and parameters to those based on clonogenic assays. Although the sensitivity of normal mouse marrow was at the low end of the tissue culture-based values, it was evident that this critical tissue had a response to radiation similar to that of malignant tumors. The experiment answered the criticism directed at the cell culture results by showing that a similar radiation response could be measured in vivo and for a normal tissue.*

individual and clinical research Individual scientists started their own projects. For example, Cliff Stanners, a master’s student working with Jim Till, was measuring the phases of the cell cycle with the view of relating the time spent in preparing for mitosis and division to radiation sensitivity. Ed Goranson was measuring the effects of whole body radiation on the serum proteins of mice. These individual projects and the larger collaborative programs were started as soon as the laboratories that housed them were ready. For the clinical departments, initiating research was not so easy. They properly gave first priority to patient care. Patterns of practice had to be established and the new environment moulded to its major function. Clinical research, since it often involves voluntary participation by patients, usually requires more preparation than laboratory work, where a fault in design can readily be corrected in a replicated experiment. In the first years at Sherbourne Street, the medical staff was not large enough for its own research programs. The physicians participated eagerly in the arguments and discussions of their scientist colleagues. All of this was preparation for the stem cell model of cancer that was soon to emerge from the two research divisions.

** See E.A. McCulloch and J.E. Till, “The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice,” Radiation Research 13 (1960), 115–25. This publication was the first result of the collaboration between McCulloch and Till.

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Leadership and Style

The Ontario Cancer Institute was not a democracy. Its leaders were given great powers in such important areas as appointments, review, space allocation, and salaries. The management style was not that of an oligarchy; instead, individual staff members in both research and clinical services felt that they were in control of their own destinies. Without being stated, each understood that success would be rewarded and failure tolerated only within narrow limits. The director, Cliff Ash, concentrated his attention on his own area, radiation oncology. The chiefs of departments and divisions were given only very general direction. They conferred either one-on- one or in small groups, often stimulated by John Law, whose low-key manner had a positive influence. Although the style was permissive, the major figures under Ash moulded the development of the oci. Four men were key; three of them – Arthur Ham, Lou Siminovitch, and Daniel Bergsagel – came or went from the 1957 to 1965. The fourth, Harold Johns, was a constant presence for more than thirty years. Bergsagel, joining in 1964, also stayed until retirement in 1990.

arthur ham Arthur Ham’s knowledge and diplomacy made him a guiding force in establishing the structures that would prove the foundation of oci success. His background was that of a successful university teacher of histology. He was convinced that if he himself could understand any biological process, he could explain it to medical students. His personal

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Arthur Ham, founder and first chief of the Division of Biological Research.

research was closely linked to his teaching goals. His interest in cancer research always had a teaching element. He correctly perceived that many Canadians attempting cancer research lacked the knowledge and skills required for the work. He would explain in detail to biochemists that their measurements of enzymes in tissue homogenates were meaningless if they did not consider variation in cellular composition in different parts of an organ. He gave much thought to the proper controls for tumour cell populations. His histological studies showed that cells from a normal organ were not adequate for comparison with cancer cells in growing in that organ. He thought that it was preferable to compare cancer to embryonic cells. He also emphasized the need to understand the genetics of the inbred mouse strains used in cancer research, often as hosts for transplantable tumours. He never tired of explaining the differences between “isologous” (now isogeneic), homologous (now allogeneic) and heterologous transplants.* As a member

** Isologous refers to the relationship of cells of different animals from the same inbred strain; homologous is the word for cells from different animals of the same species; heterologous refers to cells from animals of different species.

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of the Research Advisory Group of the National Cancer Institute, he saw the “teaching” of cancer research as an important goal. The provincial government supported the oci generously, paying for the construction of the building. Ham knew that the province could not be the only source of support for research, although clinical care continued to be its responsibility, particularly after the federal and the provincial governments instituted universal publically funded health care. Two other cancer agencies were available to support oci research. The Ontario Cancer Treatment and Research Foundation (octrf) had served as a sponsoring parent to the oci during its planning and construction and continued its support. A block grant to the research divisions paid the salaries of the scientists, thus providing them with personal security that was a recompense for their lack of university tenure. The National Cancer Institute of Canada (nci(c)) was the second major source of support. It had been established by the Canadian Cancer Society as its vehicle to support basic cancer research on a national basis. Ham’s strong association with nci(c) was helpful in obtaining a block grant which funded the individual research of oci scientists. Before receiving the grant, the institute was evaluated at a large site visit, where established investigators from the United States and Europe, together with some Canadians, came to the institute, heard presentations, and were able to ask questions. The block grant idea was based on the concept that a group of collaborating scientists would make a greater contribution to the solution of the cancer problem than individuals working by themselves. These nci(c) block grants were usually provided for a three-year term. The preparation for the site visit was a major undertaking. Investigators had to explain their plans to their colleagues. A document had to be prepared that was acceptable to all. Ham’s writing style was dominant in the preparations from his division’s grant application. He was fond of the typewriter and composed on it using two fingers. Sections of prose were often cut out and joined together with paste. All this contrasted with the more austere style of the physicists. After the proposal was completed, there were many rehearsals of the presentations to be made to the reviewers, with colleagues serving as each others’ severe critics. The site visits to the oci were always successful. The grants were made, although not without informed criticism. The process itself reinforced the close relationships between oci scientists in both divisions, and certainly improved the quality of the research. Ham and other experienced scientists were aware of other grant sources that were in place or being developed. These were not designed specifically to support cancer research. oci science was able to attract support on the basis of its intrinsic merit. For example, the early Till

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35 Leadership and Style

and McCulloch work on protection from radiation death was supported for years by grants from the Defence Research Board (drb). The board was interested in the work because of its perception that nuclear weapons might be used in wartime. The Medical Research council (mrc) was being established in the early 1960s as a federal granting agency separate from the National Research Council (nrc). The oci scientists were usually successful applicants for mrc funding, including support for students. Applications were even made to the American nih. For a time, oci had an nih training program that supported many students in Medical Biophysics. Unfortunately, the rules changed and later in the decade it became much more difficult to attract American money. This funding structure provided three important elements for research success. First, the investigators had a degree of personal security which permitted them to undertake important projects where success was not assured on the basis of previous findings. Second, the nci block grants provided the research stability needed for long-term goals, while encouraging collaboration. Third, individual grants allowed each scientist to express his own research style in pursuit of goals that he himself had set. The value of the funding structure is evident from its survival until the late 1980s, although with modifications. For example, the nci(c) soon made separate grants to the Biology and Physics divisions rather than a single block for both. The site visits became more formal. At first, visitors met with investigators in their own labs and had direct interactions. Later, the visit consisted of presentations made in a single conference room. The granting agency environment changed. The Defence Research Board ceased to make grants, while the mrc became steadily more important, not only as a source of funds but also as a national standard of research excellence. Arthur Ham’s happy disposition contributed much to the atmosphere at the oci. His hospitality was legendary. He did not like to go out in the evening, so, he and his wife gave evening parties. An excellent dinner was usually followed by discussion of research and planning. Particularly in the early days, these gatherings were influential in setting research directions. It was at one of these parties that discussions of measuring radiation damage to mouse bone marrow led to the collaboration between Till and McCulloch. It was clear from the first that Ham had no wish for personal fame. Perhaps, for him, his membership in the 1926 Canadian Davis Cup team was the highpoint of his ambition. As head of Biology, he enjoyed the polyoma work, but saw that the credit went to his young staff members. His door was open; he was always eager to hear and applaud the latest result. He had peculiarities. He would not fly and did his best

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to prevent his staff from travelling by air. He took a train from Toronto to Vancouver when he needed to maintain his fellowship in the Royal Society by attending a meeting. Many an overnight trip by rail was taken to attend cancer meetings in Atlantic City. Sadly, this idiosyncrasy would not be possible today. After a time, it was noticed that Ham was less active. The quantitative graphs used to display results were not his style. He liked a picture, an image in his microscope that told him a story. He continued to get major satisfaction from revising his textbook, often using the insights he obtained from his oci colleagues. Yet he seemed unsatisfied. Perhaps the loss, at different times, of his son and his daughter may have weighed on him. It was certain that he was very concerned about the possibility of nuclear war. He moved from his house close to the university and bought a suburban estate near Markham, where he built a shelter. He continued to give parties and he obviously enjoyed the role of a market gardener, often bringing fresh vegetables in for the staff. He retired in 1963, at the age of sixty-three, although he continued to be an active scholar. He often sought the opinions of his oci colleagues, but his major contribution had been made and he did not attempt to influence policy after he had resigned.

harold johns and lou siminovitch Lou Siminovitch became head of Biological Research after Arthur Ham retired, while Harold Johns replaced Ham as chairman of Medical Biophysics. These two were the major leaders of oci research until Siminovitch resigned in 1969 to become founding chairman of the Department of Medical Cell Biology (later Medical Genetics) in the Faculty of Medicine. Although very different in personality and scientific interest, Johns and Siminovitch worked well together. Johns was an enthusiastic advocate of the idea that graduate students in Medical Biophysics should have understanding and competence in both basic disciplines. He recognized that students came with a background in either biology or physics, but seldom both. He himself gave a course in radiation physics to the staff, including the biologists. The department mounted graduate courses in biology for physicists and in physics for biologists. While the content of these courses was considered elementary, it was presented with a research prospective that qualified the courses as “graduate.” It was a firm rule that neither biologists nor physicists could take the graduate course in their first discipline. Johns, with the agreement of his colleagues, also demanded considerable mathematical accomplishment. The departmental graduate

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37 Leadership and Style

Harold Johns replacing by hand the radioactive source of a cobalt 60 irradiator. He is helped by Jack Cunningham (foreground) and John Hunt at the read. Jan Cerderland looks on.

course called Mathematical Biophysics was a challenging exercise in statistics and probability. Each graduate student was required to present an annual formal seminar to the department. A faculty committee met with the speaker after each seminar to point out weaknesses in the presentation, and perhaps, occasionally, to offer praise. Because the student seminar program was so prominent, the graduate supervisor was on display as much as the student. As a result an oci seminar style developed. The program helped to insure that both staff and students were aware of all research programs in the institute. The skill the students acquired in public presentation increased their likelihood of finding a suitable academic post in which to pursue their own research after training was completed. Harold Johns used scientific retreats to increase the cohesion among members of the Department of Medical Biophysics. Harold and several of his family owned summer cottages on Boshkung Lake in Haliburton. He would invite his colleagues there for a few days in the early fall, for relaxation and discussion. The relaxation was vigorous, for Harold was a great believer in physical, almost violent, activity. Water skiing was always part of the agenda; even non-athletes, such as Siminovitch

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The members of the Department of Medical Biophysics at a retreat held at Harold Johns’s summer cottage on Lake Boshkung. The front line, from left to right, is Lou Siminovitch, Ernest McCulloch, Rose Sheinin, John Hunt Arthur Axelrad, and Harold Johns. The middle row, is Jack Cunningham, Mike Rauth, Allan Howatson, Gordon Whitmore and John Wright. At the back, Clarence Fuerst, with his face parially shadowed by leaves, Bob Baker, Don Parsons, and Jim Till.

and McCulloch, were urged to attempt it.* Discussion was almost as strenuous. Each member presented at the blackboard. Interruptions were frequent but new ideas or challenges of ten emerged. The atmosphere was informal, the participant were expected to cook and wash the dishes, following a roster prepared by Harold. Memories lingered, often of private conversations while walking in the woods. The retreats at Boshkung, and Harold Johns’s hospitality, added greatly to the strength of the staff. The unity of Medical Biophysics and its attachment to the oci grew as the staff members in Physics and Biology became friends. Lou Siminovitch was as successful as a division leader as Harold Johns, but in a very different way. Wisely, he allowed his faculty full choice of research direction and supported that choice loyally. He saw no need to duplicate the Medical Biophysics programs or hold, retreats. Instead, he made full use of his many connections in the developing ** Harold Hewitt, a visitor from England, described his experience at Johns’s cottage. He successfully rode water skis, which, he claimed, was quite an accomplishment since he did not know how to swim.

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field of molecular biology. His work at the Pasteur Institute made him a prominent member of the phage group there, which including Luria and Delbruck. Seymour Benzer and Sidney Brenner were long-time friends. Francis Crick, on a visit to the oci, spent much time discussing the work, which led to the deciphering of the genetic leave the code and the emerging concepts of its regulation. Through these and many other contacts, Siminovitch insured that the oci scientists were wellinformed about the most exciting aspects of rapidly changing biology. He also made it possible for his colleagues to meet many scientific leaders. His policy strengthened the determination of oci staff to work at the forefront of their field and to play a role in international research. Ample travel funds allowed Siminovitch to encourage his staff to attend meetings of such scientific societies as the American Society of Hematology (ash), the American Association for Cancer Research (aacr), and the Federation of American Societies for Experimental Biology (faseb). Smaller meetings were arranged by research institutions. Presence at these was by invitation, and often oci scientists were invited to make presentations. There were also Canadian research conferences. The nci(c) sponsored a national cancer research meeting every second year, held at Honey Harbour on Georgian Bay. Excellent invited speakers as well as Canadian grantees of nci(c) gave research papers. The proceedings were published and remain valuable reference volumes. While the oci participated, it was not a sponsor. The 1960s were not a time of great publicity for science. The institute was well known by fellow scientists as a centre for excellent graduate education but the general public knew little of its research accomplishments. In contrast, the public was well aware of the fine clinical care the Princess Margaret Hospital provided for cancer patients. Lou Siminovitch had some unusual personal traits. For example, he never wore a tie, and his example insured an informal atmosphere on the research floors. Of much greater importance, he set the style for research presentations. He did not allow speakers, either internal or invited, to use slides or other visual aids; the medium was chalk on the backboard. Particular emphasis was placed on explanations that were readily understood by both biologists and physicists. The result was an oci presentation style that was highly adaptable. Even when slides were needed at major meetings, the clarity characteristic of the “chalk talk” persisted. Siminovitch was an excellent collaborator. He made significant contributions to the polyoma tumour virus program, but genetics remained his true vocation. Toward the end of his stay at the oci he initiated a new program in somatic cell genetics. He knew that genetic concepts had a major impact on the recent explosion of knowledge of

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In 1985 nci(c) sponsored a symposium in honour of Lou Siminovitch’s sixtyfifth birthday. The meeting was held at Honey Harbour, a favourite site for such gatherings. The potograph shows a gathering on the steps of the main building of the Delawana Inn. Chan Park, from Korea, who did his Ph.D with Bergsagel, is at the far left. Next to him, Siminovitch is an imposing figure. Yoshi Niho from Japan, who spent several years in McCulloch’s lab is at Lou’s right. At Yoshi’s right are four smiling figures. Jim Till is in front opposite his former past-doctoral student, Connie Eavies. The face between the two is Carlos Izzaguire. He, and Bertie Aye from Burma, seen at the right of Connie, were both Ph.D sudents in McCulloch’s lab. Two others are recognizable to the rear. The curly head between Siminovitch and Niho belons to David Houseman, a scientist in the Division of Biological Research. Alan Bernstein is next to him.

bacteria and viruses. He felt that if the same methodologies could be developed for somatic cells, it would have similar effects on knowledge of function for somatic cells. The basic methodology of genetics was to obtain mutants. Such an approach had not received much attention in somatic cells because it was felt that most mutations would be recessive. It followed two mutations would be needed, rather than one (as in haploid microorganisms) to observe a change in function. Siminovitch was aware that “L” cells were highly aneuploid. He reasoned that some genes might be present as only one copy in such cells. If such were the case a single mutation might be adequate. The decision to look for ways to apply genetic methods to mammalian cells took Siminovitch into new territory. If the project failed, he

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and his collaborators would see their reputations diminish, along with their ability to win competitive grants from major agencies. Siminovitch could afford to gamble for two reasons. First, he was carrying out a very successful program in λ bacteriophage genetics funded by mrc. He could undertake a new venture simultaneously with his established work. Second, he was able to convince Till and Whitmore, and two of their postdoctoral fellows, that somatic cell genetics provided an exciting opportunity. These postdocs, together with one in Siminovitch’s laboratory, also “took a chance.” The gamble was successful. Mutants were obtained and characterized. The validity of a somatic cell genetics program was established. Somatic cell genetics eventually attracted staff members both from other university departments and at the oci. The program was probably the first inter-institutional cooperative endeavour at the University of Toronto, since it involved the oci, the departments of Medical Genetics and Banting and Best, as well as the Hospital for Sick Children. The program became recognized internationally, giving prestige to its participants and their institutions. Harold Johns also understood the value of collaboration. He often sought help from colleagues, especially Chris Helleiner, in Biological Research, who was a skilled biochemist. Chris was a soft-spoken, mild man, whose major outside interest was music. He was a marked contrast to the physically active Johns. Communication between them may have been difficult. It is also possible that Johns, lacking chemical training himself, had expectations of success that were beyond the technology of the time. Other oci scientists found Helleiner very helpful when biochemical advice was sought. But it was Johns, by position and temperament, who was in a dominant position. Chris Helleiner left the oci in 1995 to join the Biochemistry Department at Dalhousie, where he was successful and later became chairman. The relationship with Helleiner proved to be an example of a general problem. It seemed that the oci made chemists unwelcome. Ed Goranson succeeded in some collaborative research, based on his interest in the effects of radiation on serum proteins, but he returned to British Columbia after a short oci stay. Later, Murray Fraser, a senior and accomplished biochemist, joined Biological Research. His stay also was short. Rose Sheinen was recruited to Biological Research in 1967. She was a microbiologist with a special interest in the biochemistry of virus infection. Rose maintained a research program in this area during her oci career, which lasted until 1975, when she returned to the university as chairman of the Department of Microbiology. Both Johns and Siminovitch preferred to recruit from the ranks of those who had been trained at oci. Their abilities were known, and

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their experience insured a good relationship with the senior staff. Johns appointed Mike Rauth to the staff in Physics. He proved to be a pillar of strength to the whole institute for the rest of his career. Siminovitch chose Clifford Stanners, who had earned his Ph.D in medical biophysics under Jim Till’s supervision. Since biochemistry was already weak at the oci, it was unlikely that its own graduates would strengthen the discipline. Insufficient biochemistry proved a real handicap to the institute as the revolution in molecular biology began to unfold. Its techniques, including enzymology, molecular separation by a number of procedures, and nucleic acid and protein chemistry, were developed out of biochemistry.

leadership in medicine Harold Warwick was head of Medicine only from 1958 to 1960. In those two years he had time only to begin the task of insuring that patients received comprehensive care, and that his department had a research mandate. Mac Whitelaw, the second head of the department, was an expert physician, who did his best to improve the quality of medical care at the oci. His direct approach brought him into conflict with the easy-going Cliff Ash. Ash, as director and head of Radiation Therapy, did not take kindly to Whitelaw’s assertion that changes were needed if cancer patients were to receive optimal care. A personality conflict developed between the two men. Since Ash had the power, it was probably inevitable that Whitelaw would leave. His departure back to British Columbia was much regretted by the research staff, who had had no difficulty either with his standards or the way in which he stated his views. In 1964 the institute recruited Dr Daniel E. Bergsagel from the M.D. Anderson Hospital in Texas to be the chief of Medicine. In a career of over thirty years, he would make many changes in his department, to the benefit of the whole institution. Bergsagel was originally from Winnipeg. After graduating from Medicine at the University of Manitoba, followed by internships at Winnipeg and Salt Lake City, he was funded by the National Research Council to study at Oxford, where he obtained a D.Phil. He returned to North America as a staff physician at the M.D. Anderson Hospital, a major cancer centre. There Bergsagel learned to be a medical oncologist. For the first time, the oci Department of Medicine would be led by a doctor specially trained in the medical aspects of cancer care. Bergsagel had a clear objective: medical management of cancer would complement the treatment provided by radiotherapy. He knew that his department needed excellent research programs if it was to accomplish

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Harold Warwick (left) and John Darte (right) find a common subject to interest them.

its goals. He expected to benefit from the hematopoiesis program in Biological Research and Robert Bruce’s quantitative studies of chemotherapy. He planned to participate in these programs and use the results to guide the medical treatment of patients. Cliff Ash correctly perceived that Bergsagel’s medical program strengthened radiation therapy and did not compete with it. Accordingly, unlike Mac Whitelaw, Bergsagel had support from the director. He also had an easy personality, which helped him to work together with both clinical and research colleagues. The community of medical oncologists was not large in 1964, and most of its members were known to Bergsagel. Hematological malignancies were their principal choice as a model system. Since the leukemias were usually quickly fatal, it was ethical to propose novel treatments for them. Leaders in the field were at the Clinical Centre at the American National Institutes of Health. The team around Emil Frei iii (Tom Frei, as he was always called) and Emil J. Freireich had pioneered methods of assessing drug response. Bergsagel knew that Tom Frei was about to move to Houston to become head of Medical Oncology there and Freireich was debating whether to go with him. Bergsagel tried to recruit Freireich to Toronto. He arranged a recruiting seminar where several medical oncologists came at the same time. Over

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Mac Whitelaw, the second head of Medicine.

a two-day period the visitors and oci scientists gave talks. There was also a lavish dinner at the York Club. The seminar brought no new staff to oci but nonetheless it was a success, since it introduced the oci to the clinical investigators who were laying the foundation of rational cancer treatment with drugs.*

the success of leadership Ham, Johns, and Siminovitch made the research divisions of the oci unique international centres of cancer research. The early successful research in polyoma virus and experimental hematology is a testament to the skill with which they built broadly-based research in a narrow radiation cancer treatment hospital. Bergsagel provided a direct link between this research and clinical practice, as he worked diligently to make a Department of Medicine that would be an equal partner with the research divisions and with radiation oncology. The major and

** A noteworthy example of this benefit was a personal friendship between McCulloch and Freireich that was to prove stimulating and useful in the coming years.

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increasing workload was still carried by the radiotherapists. Where possible, these also worked on improving their practice through careful follow-up of patients and clinical trials. By the end of its first decade, the oci had earned a place among the major cancer centres of the world that it was to maintain and expand throughout its time on Sherbourne Street.

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Normal and Malignant Stem Cells

From 1960 on stem cells became a major research theme at the Ontario Cancer Institute. Stem cells are important because many adult tissues consist principally of short-lived cells that must be replaced continuously. Stem cells are long-lived and their growth capacity allows them to be the source of new functional cells with limited life spans. A stem cell may divide, giving rise to two new stem cells. Alternatively, stem cells may undergo a change that results in reduced growth potential and the initiation of the series of events that lead to functional cells. This change is called differentiation. Blood cell formation and epithelial surfaces, such as those of the skin and intestines, are examples of tissues where stem cells are needed to maintain mature functional but non-dividing cells. These are called obligatory renewal systems. Cells of other organs, such as the liver, do not normally divide, but are able to do so in response to injury. Such organs are conditional renewal systems. Tumour populations are always obligatory renewal systems. Cancer stem cells are the targets for therapy with x-rays or chemotherapeutic drugs. Work on stem cells was, therefore, of immediate interest not only to scientists but also to radiation and medical oncologists.

colonies in the spleen The first experimental work on stem cells was an unexpected outcome from McCulloch and Till’s indirect measurement of the radiation sensitivity of normal mouse marrow. They noted that their sensitivity

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value for marrow was lower than most sensitivities reported for mammalian cells. They wondered if their marrow transplantation assay, based on measurements of the survival of heavily irradiated mice, depended not only on the proliferation of the transplanted cells, but also on their differentiation. If this hypothesis was correct, normal marrow and irradiated marrow, both growing after transplantation, should be different when examined microscopically. An altered growth pattern of differentiation would be recognized readily, since much was known about changes that led from very early hematopoietic progenitors to fully functional cells. If differentiation was radiation-sensitive, transplanted irradiated marrow would be seen to be aberrant as compared to controls. The hypothesis was attractive, since irradiation was known to be a cause of leukemia, where differentiation is often reduced, with a preponderance of cells with immature appearance. The dose ranges for survival of irradiated mice transplanted with diluted or irradiated marrow were known from the earlier work. These numbers were used to design an experiment in which intact or irradiated marrow was transplanted into recipient mice at cell numbers that gave approximately the same animal survival value. Then, the number of cells initiating differentiation would be comparable for intact and irradiated transplants. Since differentiation is a time-related function, the experiential design included a plan to kill recipient mice at various intervals after transplantation. Marrow or spleen from these animals would then be prepared for morphological examination. The experiment was successful in that the hypothesis on which it was based was disproved. No morphological difference was observed between intact and irradiated marrow; differentiation was not highly radiation-sensitive. The major finding, however, was not related to the hypothesis. The design called for groups of the irradiated mice that had been given various small marrow cell numbers to be killed ten days after marrow transplantation. By chance day ten fell on a Sunday. When McCulloch came to the institute in the afternoon to kill the animals and collect the specimens he saw that the spleens of the animals were irregular because nodules were embedded in their structure. The recent development of tissue culture cloning methods was very familiar to McCulloch. He was struck with the possibility that the nodules were hematopoietic clones. It was obvious that there was a numerical relationship between the appearance of the spleens and the dose of marrow that the animals had received. He was able to count the nodules. Back in his office, he attempted several kinds of plots to demonstrate the relationship between nodules and the marrow cell dose injected into the animals. It was soon clear that the relationship was linear and the fit of the curve was very good. At least, enumeration

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of nodules in the spleens of irradiated mouse marrow recipients was a quantitative assay for a transplantable entity in the marrow. Moreover, the entity was rare since the plot showed that about ten thousand marrow cells had to be injected for each nodule observed. The next day McCulloch showed the plot to Till, who immediately suggested that the assay be used to obtain a much better measurement of the radiation sensitivity of mouse marrow than had been achieved by the indirect method. Using the spleen colony assay, a radiation sensitivity for normal marrow was measured. The value obtained was close to that found in the previous experiments but now with acceptably low error. In addition to counting colonies, sections were prepared for microscopic study. Examination of these confirmed that the nodules consisted of growing and differentiating hematopoietic cells. When spleens were collected over a ten-to-fourteen day period after injection of marrow cells into irradiated recipients, the complexity of the cellular colonies increased. At early times, many colonies contained only one or two kinds of differentiating cells, while at later times granulocytes, red cell precursors, and platelet precursors (megakaryocytes) could be found in most colonies. An important byproduct of the histological examination came from the use of Bouin’s fixative, which is known to be useful for the preparation of hematopoietic cells for sectioning. When the spleens were fixed in Bouin’s solution, the colonies became much more distinct. A paper describing the spleen colonies and the radiation survival curve for normal mouse marrow was published in Radiation Research.* At the oci the spleen colony provoked much discussion, centred mainly on the nature of the entity that gave rise to each colony. The line relating number of cells injected to the number of colonies observed extrapolated back to zero. This is the plot that would be expected if only one thing gave rise to each nodule. A judgment on the issue was avoided for a time by coining a functional descriptive term, ColonyForming Unit or cfu. cfu remains in use today; with prefixes or suffixes, it is the name given to the cells of origin of hematopoietic colonies. The value of the spleen colony method depended on determining if a cfu was a single cell or several cells acting together. The institute seminar program contributed to the solution of the problem. Charles Ford of Harwell, England, was the cytogeneticist who first showed that

** J.E. Till and E.A. McCulloch, “A direct measurement of the radiation sensitivity of normal mouse bone marrow cells,” Radiation Research 14 (1961), 213–22.

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marrow protected heavily irradiated mice by engraftment. In a seminar given at oci he described experiments where clones of hematopoietic cells were identified in sublethally-irradiated mice because the cells had abnormal chromosomes. These abnormalities were the result of radiation damage compatible with continuing proliferation. The abnormal chromosomes served as markers to identify cells belonging to a clone even when dispersed throughout an animal. At once, Till and McCulloch realized that spleen colonies derived from irradiated marrow might contain chromosomally-marked cells. If this was the case, the distribution of the marker would reveal the origin of the colony. If all the dividing cells had the same marker, this would be strong evidence of a single cell of origin. It would mean that all the cells in the colony were derived from a progenitor in which radiation damage had resulted in a unique, random, non-lethal abnormality. Alternatively, if a colony contained mixtures of cells with abnormal and normal chromosomes, or two distinct markers, it would be highly probable that more than one cell was needed for colony formation. The concept of the experiment was simple enough. The data were at hand from the previous work to irradiate marrow with a sufficient dose to generate both markers and colonies in recipient mice. All that was needed was to examine the chromosomes from cells of a sufficiently large number of colonies. If a marker was present, the data would show whether it was in all the dividing cells. Both McCulloch and Till had made cell preparations where chromosomes could be studied, but it would be much more difficult to examine cells taken from spleen colonies. Here the oci graduate program in Medical Biophysics came into play. It was attracting students of great ability, one of whom, Andrew Becker, had a md, but wished to make a career in research. Through his medical connection, he knew McCulloch, who recognized his intellectual and technical capacity, Becker became Till’s Ph.D student. He was assigned the problem of determining whether one or more cells were required for spleen colony formation. Becker tested various experimental conditions to find how to procure dividing cells from spleen colonies in which he might find chromosomal markers. His persistence was finally rewarded. He was able to make suitable preparations of dividing cells so that he could identify colonies with markers. When markers were present, they were found in all of the dividing cells of the colony. It followed that a single marrow cell was able to form a macroscopic colony containing differentiating blood cells. The convincing demonstration that the cfu was a single cell established the validity of the spleen colony assay. oci scientists discussed at length how the cell represented by cfu would fit into the known differentiation of hematopoiesis. The cells recognized morphologically

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were ordered in a series of parent-progeny relationships, called lineages, and marked by increased specialization at each step. The nature of cells earlier than those identified by microscopic appearance was, at the time, highly controversial. Primitive precursors lacked the functional structures by which their descendants were recognized. Microscopy, therefore, was not useful for their study. In the absence of data, some hematologists postulated that each lineage, ending in red cells (erythropoiesis), granular leukocytes (granulopoietic), and platelets (megakaryocytopoiesis) was headed by its own stem cell. Others held that a common stem cell was the ancestor of all three lineages. The spleen colony assay provided the missing information, since it was evident that each cfu could give rise to red cells, granular leukocytes, and platelets. Dr Ham had spent frustrating years teaching medical students the various hypotheses about lineages and stem cells. He was quick to embrace the concept that the cell giving rise to spleen colonies was a pluripotent hematopoietic stem cell. This view was amply confirmed when cfu were found in cells taken individual spleen colonies. The result was evidence that the spleen clonogenic cell, in addition to differentiation, could give rise to new stem cells. Self-renewal, together with capacity for differentiation, was proposed by the oci scientists as the defining characteristics of stem cells. The spleen colony assay detected and measured hematopoietic stem cells capable of at least trilineage differentiation. The method provided the first proof that such a cell existed and could be studied experimentally.

the impact of the spleen colony method The discovery of the spleen colony assay led to five years of intense research. The method was applied to radiobiology, transplantation biology, the origins of hematopoietic lineages, and the regulation of differentiation. It attracted to the two original investigators collaboration with others, particularly Siminovitch and Bruce. The radiobiological work led to the conclusion that cfu was the cell required for hemopoietic repopulation and survival in heavily-irradiated mice. The regulation of hematopoiesis was an attractive issue for Siminovitch because he saw a genetic approach to the problem. The numbers of each blood cell type remained constant in health but respond promptly and appropriately to challenges such as infection or bleeding. Most hematologists interpreted this behaviour as a manifestation of precise and highly specific control. A quite different view emerged from examination of the cellular composition of spleen colonies. Spleen colonies are highly variable in such important characteristics as size and content

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of the hematopoietic lineages. A genetic approach to the origin of this variation required that it be known whether or not the phenotypes of individual colonies bred true on re-transplantation. Individual colonies developing ten to fourteen days after injection of marrow into irradiated recipients were dissected from spleen, and their cells made into suspensions. These were injected into new recipients, so that each animal was engrafted with most of the cells from a single colony. A few cells were retained to determine the phenotype of the donor colony. The result was both unexpected and perplexing. Few of the spleens of secondary recipients of day ten colonies had colonies, but, when colonies were present, they were plentiful. cfu were almost always found in colonies that had been allowed to develop for up to fourteen days after cell injection; but the same huge variation in cfu per colony was seen. It was clear that, while spleen colonies might contain new cfu, the number of such cells varied greatly from colony to colony. Control of self-renewal of colony-forming cells was not tight. Therefore the conventional teaching was not supported by evidence, nor was the anticipated evidence of genetic regulation found, for colonies did not “breed-true.” Rather, when looked at by clonal analysis, the regulation of hematopoiesis was seen to be lax. Till had long been interested in statistics. He applied his knowledge to an examination of the data from the re-transplantation of single colonies. His first task was to determine the nature of the distribution of new cfu among spleen colonies. After testing several distributions, Till determined that the skewed distribution could be well fitted, by a know distribution called gama. He then searched for biologically plausible mechanisms that might yield this distribution. Finally he found a book in the library of the Physics Department that excited him.* He began to look into the theory of stochastic processes. When events happen by chance, ordered only by definite probabilities, they can be described using stochastic models. Perhaps a stochastic program was followed during the development of individual hematopoietic clones expanding in the spleens of recipient mice. Such a program was considered to contain two possibilities: first, individual cfu might undergo ** The book, by Niels Arley, was entitled On the Theory of Stochastic Processes and their Application to the Theory of Cosmic Radiation (New York: Wiley, 1943). It introduced Till to the theory of stochastic processes, and subsequently led him to another work, by William Feller, An Introduction to Probability Theory and its Applications (New York: Wiley, 1957). This book contained a section on stochastic birth and death processes, presented as a realistic model of changes in the size of populations whose members can be born, or die, or drop out. Computer simulations confirmed that such a stochastic model could yield skewed distributions remarkably similar to those observed experimentally.

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self-renewal, giving rise to daughters that retained stem properties. This option was termed “birth.” Alternatively, a cfu might pass through a determination step, giving rise to a cell committed to differentiation in a specific lineage. Such a cell would not retain stem properties but rather gain the capacity to give rise to functional descendants through a limited number of terminal divisions. In contrast to “birth,” this option was called “death,” since its result was the loss of a stem cell. The stochastic model of spleen colony growth was tested by computer simulation and the results obtained were in agreement with the experimental findings. While the analysis of the composition of spleen colonies did not lead to a genetic approach to regulation, the idea that the cell of origin of spleen colonies might be responsible for recovery and survival after radiation was supported by genetic experiments. Inbred mice with single gene mutations affecting hematopoiesis were used. This approach, called physiological genetics, was pioneered by Elizabeth Russell and her collaborators at the Jackson Laboratory in Bar Harbor, Maine. There, in a centre for mouse genetics, animals were identified because they had blood abnormalities, usually anemia. Prominent among these were genetically anemic mice of genotypes W /W v and S l/S ld. These blackeyed white mice, in addition to severe anemia, were very sensitive to ionizing radiation. The theory that cfu were important in survival after radiation led to the prediction that these animals would have abnormalities affecting spleen colony formation. Elizabeth Russell supplied a small number of W /W v mice, along with their genetically normal littermate controls, to be tested with the spleen colony assay. Siminovitch, with his devotion to genetics, became an enthusiastic collaborator. Marrow from control animals formed colonies with the expected frequency, size, and cellular composition. In striking contrast, marrow from the genetically anemic mice formed no colonies at all, even when very large cell numbers were injected into irradiated recipients. The Bar Harbor group had demonstrated that the anemia of W /W v mice could be cured by transplanting normal marrow cells. This observation led the oci investigators to inject normal marrow into unirradiated W /W v mice; after ten to twelve days, colonies were seen in the spleens of the animals. Together, these observations showed that cfu in W /W v mice were abnormal, but that the hematopoietic environment of spleen and marrow was competent to support stem cell growth and differentiation. Defective cfu in highly radio-sensitive animals provided genetic evidence for the role of cfu in survival after irradiation. The Bar Harbor scientists then sent a very small number of S l/S ld mice to the oci. Both groups expected the results from these blackeyed white mice animals would differ only in degree from the findings

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in W /W v mice. Marrow from S l/S ld mice was injected into normal irradiated recipients. The surprise and excitement were great when these animals were killed at day ten, it was immediately obvious that the marrow cells from the S l/S ld mice were growing normally. Only one explanation seemed possible: that the hematopoietic environment in d S l/S l mice was defective. This conjecture was readily verified by showing that normal marrow did not form colonies when injected in irradiated S l/S ld mice. These experiments showed that gene products in stem cells or adjacent supporting cells were important and complementary growth regulators.* These genetic studies, combined with the skewed distribution of new cfu in spleen colonies, showed that the regulation of hematopoiesis was complex, with both genetic and stochastic components.

international response to spleen colonies The international research community quickly took notice of the spleen colony method and the way it was being applied by the oci scientists. In the early 1960s two categories of researchers were studying blood formation. First, traditional hematologists, usually members of the American Association for Hematology (ash), were working on the known lineages, and trying to push their cellular origins to more primitive cells. Much of the work was based on the regulation of red cell formation (erythropoiesis), since it was known that erythropoiesis was dependent on a circulating regulator with the classical features of a hormone. A feed-back loop had been identified between levels of this hormone, called erythropoietin (epo), and the number of circulating red cells. Lazlo Lajtha in England and Cliff Gurney in the United States developed protocols where red cell levels in mice were increased well above the normal by transfusion. In these animals, erythropoiesis was suppressed, as recognized by morphological examination of cells in marrow or spleen. When epo was injected into such animals, a wave of erythropoiesis could be observed and quantitated. Experiments using designs of this general form provided estimates of the parameters of the erythropoietic lineage, including the number of divisions need to make a red cell and the time spent at each stage. Bob Bruce, in the Physics Division of the oci, came to the institute from Chicago, where Eugene Goldwasser was actively purifying erythropoietin and studying ** Twenty years later the genes and their products were identified by molecular biology. The W locus specifies a membrane receptor, while the S l locus encodes its ligand. Binding of ligand to receptor initiates intracellular signalling specifying stem cell behaviour.

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its cellular effects. He brought the methods and thinking behind such experiments to Toronto, thus insuring that those using the spleen colony method were well aware of experimental erythropoiesis. Bruce collaborated with McCulloch in experiments that showed that the stem cell detected by spleen colony-formation was not sensitive to epo. Rather, cfu was a more primitive precursor, capable of giving rise to other lineages in addition to erythropoiesis. Eugene Cronkite and his colleagues at Brookhaven National Laboratory were developing a different way of measuring cellular parameters in known hematopoietic lineages. They used the newly available radio-isotopes, particularly thymidine labelled with radioactive tritium (3htdr), a precursor of dna, to measure the kinetics of blood-cell proliferation. Cells, in culture or in animals, were exposed to 3htdr; when the isotope was found in a cell’s nucleus, that cell was known to be making dna. The isotope was identified by a method called radioautography; in this technique cells were placed on top of a photographic emulsion and maintained there for periods of time. When the emulsion was developed, grains, made by exposing the emulsion to the radioactivity from the isotope, could be recognized within cells by microscopy. With this technique it was possible to describe the events that separate one cell division from the next. The cycle begins with a period of cellular inactivity, the first “gap” or g 1. The cell then begins to make dna, during s phase of the cycle. When the dna content is doubled, a second inactive phase, “gap 2” or g 2 is followed by mitosis, the m phase. Clinical investigators, particularly the groups around Fred Stohlman at St Elizabeth Hospital in Boston and Alvin Mauer at St Jude’s Childrens’ Research Hospital in Memphis, were applying radioisotopes and radioautography to the study of hematologic diseases, including malignancies. At the same time a second set of investigators was approaching hematopoiesis from a different starting point. Their interest was in the biological effects of radiation, and particularly protection against radiation damage. Their centre of activity was the National Laboratory at Oak Ridge, Tennessee. Marrow infusions were important because they promoted survival after irradiation. Charles Congdon of Oak Ridge was a major force in bringing together these radio-biologically orientated workers. At that time the Association of American Societies for Experimental Biology met each spring at Atlantic City, immediately following the meeting of the American Association for Cancer Research. Charlie Congdon always hired a hall at Atlantic City, where those interested in radiation protection assembled. Congdon had no formal agenda and no program was circulated in advance. Rather, he used his extensive knowledge of the field and the workers in it to call individual investigators to describe their recent findings.

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McCulloch usually stayed on after the cancer meetings and attended at Congdon’s hall. Once the spleen colony method had been described, he was often called upon to report oci research. This contact began to change the marrow transplantation/radiation protection field toward clonal analysis and quantitative biology. Later, Congdon’s informal meetings formed the basis of the Society for Experimental Hematology, which still aims to keep his informal and inclusive approach to reporting science. The spleen colony method formed a link between the hematologists and the radiobiologists, for it was a valuable tool for studying both hematopoiesis and radiation protection. Spleen colony formation was not widely accepted immediately. Early attempts to replicate the Toronto method failed because the mice used as irradiated recipients were not healthy enough to survive the ten to fourteen days required for spleen colony formation. When the technical requirements of the assay were met, other workers easily adapted the method to their own special requirements. Controversy is seldom avoided, particularly when a field moves quickly in response to a new method. Spleen colony formation was no exception. Many found the stochastic model unattractive. It was counter-intuitive to think that a survival-dependent function like bloodcell production could be based on a random choice between self-renewal and differentiation. John Trentin, a senior and respected radiobiologist from Baylor University, proposed a quite different mechanism to explain the development of spleen colonies, and, indeed, hematologic regulation in general. Trentin made histological observations as a function of time during colony growth. He interpreted what he saw as an effect of the immediate environment on the regeneration pattern of blood-producing cells. He called the regulatory stroma a “hematopoietic-inductive microenvironment” or him. He proposed that events during colony formation were determined by a direct message from their immediate cellular neighbours. This mechanism was the opposite of the random process postulated in the stochastic model. Till responded to Trentin’s him acronym by devising one for the stochastic model; he called it “hematopoiesis engendered randomly” or her. The proponents of each hypothesis pursued the controversy with vigour. A major point in favour of the stochastic model was its generality. Unexpectedly skewed distributions were found regularly when colonial growth was measured in other in vivo systems or in cell culture. The him model gathered support particularly from those who found chance an unhappy regulator of blood production. Its major disadvantage was the lack of specificity or detail in the nature of the supposed microenvironment inducers. It was not easy to devise a test based on modifying the microenvironment. With time, support for

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both models came from experiments in many different laboratories, including those at the oci. The him model needed to explain how environmental cells could influence the behaviour of hematopoietic precursors. Decades later, a way was found to explain how cells respond to environmental stimuli. In several systems, genetically-encoded receptors are found on cell surfaces. These could bind ligands, which might be produced in proximate cells. Ligand-binding initiating complex, protein-based signalling pathways, profoundly affecting cell behaviour. It became clear that activity in one cell set, perhaps stroma, could regulate adjacent cells, perhaps hematopoietic precursors. The mechanism was not inductive, since ligand-binding activated a genetically-determined program already in place. Nonetheless a role for environmental signals was established, even though that role was not as predicted from the him model.* An alternative to the stochastic mechanism was not forthcoming to explain the marked heterogeneity generated during the expansion of hematopoietic clones from single progenitors. The constant numbers of blood cells and their response to challenge – the reasons for postulating a rigid mechanism – could be explained within the stochastic model by postulating that the observations were averages of several clones. To physicists, an obvious analogy was radioactive decay; individual atoms decay at random but, as there are many atoms, the halflife of a radioactive element is constant. These arguments, and the lack of any viable alternative, increased support for the stochastic model. It remains today a powerful incentive for research.

clonogenic cells and cancer The link between clonogenic cells and cancer came from a particular challenge in stem cell biology. Stem cells are a minority population, much out-numbered by their differentiated descendants. Nor is there a specific morphological feature that allows stem cells to be identified by microscopy. Stem cell properties can be deduced by measuring and analysing clones derived from them; such methods are indirect, in that the cell of interest is lost as its descendants grow. The problem was to find ways to study stem cells directly. Radioautographic methods for measuring tritiated thymidine in dna are dependent on microscopic ** Definitive evidence against Trentin’s specific him model was found when culture methods were available for early committed progenitors of myelopoiesis and erythropoiesis. These were poorly correlated numerically with their morphologicallyidentified descendants; the methods used by Trentin were seen not to be reliable indicators of early differentiation events.

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examination of cells. Such methods are not useful in the study of stem cells which lack an identifying appearance so a different approach was needed. Radiobiology provided the clue; cells making dna might be identified, not by visualizing grains in radioautographs, but because sufficient radioactivity incorporated into the dna would destroy the cells’ capacity to form colonies. The plan seemed simple; again its execution was intrusted to Andrew Becker, the same Ph.D student who had proved the single-cell origin of spleen colonies. Becker devised a simple but elegant experiment. Rapidly proliferating cells, making dna, would be distinguished from resting hematopoietic populations because exposure to highly radioactive thymidine would kill the former but spare the latter. He chose two examples of tissues in which cfu would be dividing frequently: his first choice was fetal liver, the site of hematopoiesis during late embryogenesis; and second, spleens from irradiated animals that had received a marrow transplant six days earlier which would contain rapidly dividing blood progenitors. To contrast with these rapidly growing systems, stem cells might be in a resting state in marrow or spleens of mature, nonstressed mice. Cells from each of these sources were incubated for short times (fifteen to thirty minutes) with radioactive thymidine of increasing specific activity and then tested for cfu. A striking difference was observed between stem cells from the different sources. Rapidly growing blood progenitors in spleen or fetal liver showed a decrease in colony formation as the specific activity of the tritiated thymidine increased. The loss reached about 60 percent of controls and then no further decrease was seen as exposure to radio-isotope increased. In contrast, cfu from marrow or spleen were not killed even when incubated with maximum levels of radioactive thymidine. The initial loss of colony formation seen in suspensions from growing marrow meant that incorporation of radioactive thymidine into dna of cells in the s phase of the cycle was destroying their ability to grow and form colonies. The resistance to tritiated thymidine killing by cells from adult marrow and spleen was, by the same argument, evidence that the cfu from these sources were at rest. The experimental design came to be called “thymidine suicide” since cells killed themselves by incorporating radioactivity into dna. Becker’s maturing ability as a scientist was evident from the controls he added to his basic experimental design. First, cells were incubated with highly radioactive thymidine together with non-radioactive (“cold”) thymidine. This dilution of the radioactivity protected them from killing, providing proof that the radioactivity in 3htdr was the agent that was necessary for cell destruction. A second control was incubating

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the cells with a high concentration of non-radioactive thymidine. No cell kill was found, showing that it was radioactivity, not thymidine, that was responsible for cell death. The use of such controls makes the “thymidine suicide” experiment a continuing valuable way of measuring the percentage of stem cells in dna synthesis. These data broadened knowledge of normal stem cell physiology by showing that cells could alter their proliferative behaviour in response to demand for increased blood production. A more important meaning was perceived by Robert Bruce of the Physics Division. He saw that the ability to enter a low growth state provided normal hematopoietic stem cells with an advantage over their malignant counterparts. Many of the chemotherapeutic drugs then available for cancer treatment only killed cells that were making dna. Normal cells, not in dna synthesis, would be protected from such drugs. In leukemia and most cancers, the malignant cells are not able to enter a resting phase but must always continue to proliferate. More than half of such cells would be making dna and therefore be drug-sensitive. Bruce proposed that this difference between malignant and normal cells was the cellular basis for the success of certain chemotherapeutic drugs. Bruce quickly devised a system to test this hypothesis. He showed that suspensions from organs of leukemic mice would form spleen colonies consisting of malignant cells. He could compare the lethal effects of various known chemotherapeutic drugs on the survival of normal and leukemic stem cells. His work easily proved his hypothesis and led to a classification of chemotherapeutic drugs based on their effects on dna. His experimental systems also allowed him to examine combinations of drugs, looking for advantageous synergistic effects. Bruce and his students had a profound effect on medical oncology by providing a new rational for chemotherapy. Equally important, the results confirmed the view that tumours were self-renewing populations headed by stem cells. Stem cells were recognized as the targets for therapy, for if these were destroyed, the whole tumour would regress and not grow again. Medical oncologists saw the results Bruce was obtaining as a rational basis for chemotherapy, their major contribution to cancer care. Radiation oncologists could no longer explain the success of their methods as increased sensitivity of tumour cells compared to normal cells. Clonal assays provided a better way of understanding how tumours varied in their responses to radiation. Tumours were seen to be radiation-sensitive if they were maintained by small stem cell number and resistant if clonogenic cells were frequent. Further, analysis of the shoulder portion of radiation survival curves demonstrated that repair of radiation damage could occur. As radiation therapy was

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Robert Bruce, prominent member of the Physics Division, and, for a while, director of the Toronto Ludwig Institute.

usually delivered in a large number of doses, variation in capacity for repair provided an attractive explanation for different tumour responses. The importance of the Bruce findings, and the cancer model derived from them, was soon understood internationally. Bruce received a recognition equal to that of his colleagues Till and McCulloch. His background in both medicine and physics, combined with a modest manner, made him a great favourite. Both at the oci and in the international community, his ready flow of new and stimulating ideas made him an ideal collaborator. He was recognized by the American Society of Hematology by being chosen to be their first Stratton prize winner. The stem cell model of tumours is widely, although not universally, accepted today. The mechanism of chemotherapy proposed by Bruce continues to be used, although often with important modifications. Multiple steps separate initial contact of a cancer cell with drug and the fate of that cell as death or recovery from injury. Proteins, acting either as enzymes or energy transporters, form interacting networks that are activated when cells are injured. Given the complexity of these protein networks, it is not to be expected that any single model of chemotherapy will be universally satisfactory. Perhaps the greatest departure from the Bruce classification of drugs based on their intracellular targets is the suggestion

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that tumour stem cells, like normal stem cells, might be quiescent, and therefore resistant. Nonetheless, treatment strategies have been devised with the idea of recruiting resting cells into active proliferation, making them sensitive to drugs that attack dna. These treatments have not usually provided benefit in terms of tumour regression. It remains probable that tumour cells have lost the capacity to enter a resting state. The stem cell paradigm, as applied to both normal and malignant populations, was a unifying force for the oci. The discovery and implementation of the paradigm remains one of the institution’s major contributions to cell biology and cancer research.

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Growth and Change

From the beginning, the oci was successful in both patient care and research. But success always makes demands, and it was soon clear that the building was too small. The new cancer patients seen each year greatly exceeded the three thousand for which the facilities were planned. Success in the research divisions could only continue if more space was provided. In 1965 planning began for a major expansion that would increase in-patient beds by fifty-five, including fifteen for children and twelve for clinical investigation. Out-patient facilities were also to be enlarged. An expansion of research space would be funded by the Ontario Division of the Canadian Cancer Society. The new children’s ward was completed in 1967 and the other building projects followed soon after. When the expansion was completed, most of the needs appeared to have been met.

research space Research now had an opportunity to manage space for maximum value. New laboratories had been constructed at the west end of the building on the sixth and seventh floors. The additions were square in shape, with offices and conferences rooms at the periphery and common facilities in the middle. Laboratories and associated offices were also built on the sixth and seventh floors of the south wing, which joined the oci building to the Wellesley Hospital. On the fifth floor the new space was used for Department of Medicine offices and a large snack bar. These facilities made it possible to accommodate expanding programs in the research divisions.

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A unique feature of the research floors was the location of major equipment, such as centrifuges and very low temperature freezers. By placing them in the corridors, it was possible to share this expensive apparatus. It also meant that members of different research groups, particularly students and post-doctoral fellows, were brought into close contact as they used apparatus together. The result was a happy atmosphere, where ideas as well as equipment flowed easily between the scientists and their students. Often there were questions from the fire marshall who thought that in case of fire, corridors should not constricted by apparatus. The fire marshal came to tolerate equipment in corridors when he was assured that there was enough space to allow everyone to escape. Common facilities were set up to meet needs shared by many laboratories. For example, glass washing was centralized, insuring both cleanliness and sterility. Control of radio-active isotopes was also centralized to insure safety. A common laboratory was used to prepare culture media, fetal calf or horse serum, balanced salt solutions and other reagents required for cell culture. Material prepared in the culture laboratory was always pretested for sterility and activity. Very important was the testing of samples of large batches of serum for their capacity to support cells in culture. By selecting such batches, consistent results could be obtained over long periods of time. The oci never took the step of making its reagent-producing laboratories into commercial enterprises, although the later success of other institutions, notably the Terry Fox Laboratories in Vancouver, shows that making and selling specialized culture reagents would have been profitable.

the department of medicine The new space provided Daniel Bergsagel with an opportunity to build up his Department of Medicine. In addition to beds for investigation, space on the fifth floor was renovated to make laboratories for two new members of his department with interests in experimental work. One of these was occupied by Andy Becker, who had been on sabbatical in New York, learning the methods of molecular biology. Returning to the oci in Medicine, he embarked on a fundamental program in phage genetics. The encouragement given to this work was evidence of Bergsagel’s commitment to a full range of research in his department. The other laboratory made it possible to recruit David Osoba, a clinician who was already established as a research immunologist. The renewed research interest in Medicine was particularly attractive for McCulloch. As he acquired confidence as a graduate supervisor, he participated more in the activities of Medical Biophysics. One

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of his tasks was to give some of the lectures in the biology course designed for students with a physical background. Preparation for the lectures required a critical review of the recent literature in such topics as heterogeneity in tumour cell populations, experimental hematology, and immunology and tumour virology – all areas advancing rapidly. The teaching assignment brought him into conflict with some of the rigid aspects of Medical Biophysics under Johns’s chairmanship. McCulloch was supervisor of three Ph.D candidates, all of whom had come into the program with md degrees. Since, by definition, the md was considered a biological degree, these students were not permitted to take biology courses for credit. McCulloch knew that medical courses did not supply much of the material covered in his lectures and certainly it was not presented with a research perspective. The rule was firm; McCulloch found the rigidity discouraging. A change at the university was in a formative stage at about the same time. Dr J.C. Laidlaw (Jack), a prominent endocrinologist at the Toronto General Hospital, was concerned about the research training received by medical graduates. Often, a post-graduate medical education, in addition to clinical training, would include a year of research. Usually, this took the form of an apprenticeship in the laboratory of a clinician who was conducting patient-related studies. While this year might prove valuable, often there was little instruction in background knowledge or research methodology; sometimes the trainee was only an extra pair of hands to help in experiments. Laidlaw considered these failings in research education to be the result of a lack of structure and evaluation, both of mentors and programs proposed for their students. So he set up a small group of hospital-based clinician scientists to discuss the issue. McCulloch knew Laidlaw well as they had lived in the same residence (London House) in 1948–9 while Laidlaw was doing a Ph.D at the University of London and McCulloch was on a research fellowship at the Lister Institute. It was a natural evolution that Laidlaw began to include McCulloch in his discussions. Laidlaw’s group determined to establish a route by which medical graduates could take M.Sc or Ph.D programs with the rigour that such programs required. After much discussion and negotiation, in 1968, a new institute, called the Institute of Medical Science (ims), was established in the graduate school, with authority to conduct graduate programs. Laidlaw was the founding director and McCulloch the first graduate secretary. The ims could not serve as the home department for faculty, since it had neither the budget nor the mandate to make appointments directly. The graduate faculty in ims all had appointments in other university departments. Many held rank in clinical departments but could not supervise graduate students because they

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lacked affiliation with the School of Graduate Studies. The institute solved this problem because it had the authority to recommend its cross-appointed faculty for membership in the graduate school. McCulloch’s experience in Medical Biophysics proved useful in designing the policies and procedures of the ims. Three such, copied from Medical Biophysics, were designed to maintain high standards. First, appointments to graduate faculty in ims were made very carefully. Candidates whose primary affiliation were in clinical departments were required to show the same level of research experience and funding as investigators in basic science departments. Some basic scientists sought ims appointments. These were granted when it was evident both that the applicant wished to conduct medically relevant research and where the appointment would benefit ims. Second, students were admitted to graduate programs only if their credentials were of the same order as those demanded in established departments. Third, the programs proposed for accepted students were monitored. Each student had a supervisory committee whose members provided guidance by holding regular meetings with student and supervisor. Implementation of these procedures was not easy, particularly as they were foreign to the clinical departments. Jack Laidlaw as director of ims had such a high standing in the university Department of Medicine that he could insist on quality safeguards. At about the same time as the ims was starting in 1968, McCulloch’s role at the oci was changing. He was given the task of encouraging more clinically related research. His primary appointment was moved from Biological Research to Medicine, although he retained his association with the research division through a made-up title, Senior Research Associate. He had an office in the new space of the Medical Department, close to those of both Bergsagel and Bill Meakin. It was natural that, with this change, he accepted graduate students in the ims rather than Medical Biophysics, although he retained his graduate appointment there. It is a testament to the strength of the oci that graduate programs in the ims, conducted at the institute, were seen as positive, rather than as a weakening of Medical Biophysics. Many oci staff, including both Siminovitch and Till accepted cross-appointments to the ims, a clear sign of their support. Bergsagel’s strengthened Medical Department was a crucial beginning for important developments in oci programs. Clinically, medicine made it possible for the institute to accept and implement the policy of multi-modality treatment for cancer patients; that is, for each patient more than one kind of treatment might be considered. For example, chemotherapy could be added to surgery and radiation to improve the outcome of patients with breast cancer. In research, Medicine provided

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E. A. McCulloch

examples of work on patients or cells from patients that was as good as the basic studies conducted in the research divisions; it followed that oci scientists were able to include human studies in their research programs without compromising their standards. These initiatives, made possible by a good Department of Medicine, broadened the scope of the oci and improved its capacity to provide Canadian cancer patients with world-class care.

changes in the division of biological research In 1968, after almost ten years as head of Biological Research, Lou Siminovitch had a successful division. His own research in somatic cell genetics was going well. His collaborations spread well beyond biological research to physics and beyond the oci to scientists in other hospitals and university departments. Dr Laurie Chute, the dean of medicine at the university, had been examining the undergraduate medical curriculum and had identified important gaps in rapidly growing fields of basic science with medical relevance. These included genetics, cell biology, immunology, and biophysics. Chute knew that Siminovitch

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had either expert knowledge or excellent contacts in all of these areas. Chute proposed to start a new department, and offered the post of head to Siminovitch. The name of the department would be Medical Cell Biology and the scope would be broad. Chute committed himself to the funding for as many as twenty new tenure or tenure-stream appointments. Space was available in the Medical Science Building, which had just been constructed. The scientific strengths of the university would be close to hand. Siminovitch consulted with Harold Johns and John Law, the trusted administrator of the oci. With the exception of these two, the offer was kept confidential. A consensus developed that Siminovitch had a responsibility to the university and that the oci should assist him in meeting that responsibility. In 1969 Siminovitch accepted the chairmanship of the new department of Medical Cell Biology. The oci appointed Jim Till to be head of the Division of Biological Research. Siminovitch wanted to take some members of the oci staff with him. He needed Clarence Fuerst to provide the strength that his phage research would give to genetics. Marvin Gold, a Ph.D in Medical Biophysics, had just completed a sabbatical and had been appointed to the oci staff. His skill in biochemistry was important in the planning of the new department. Siminovitch decided to take Cinader because he was well known locally as an immunologist. Recruits outside the oci included such Medical Biophysics graduates as James Friesen and Mark Pearson. Jeremy Carver, an accomplished structural biologist, whom the oci wished to appoint, also agreed to go to the university department. As Siminovitch was reaching the staff complement he needed for his new department, Laurie Chute brought him bad news. University budget cuts made it impossible for the dean to honour completely his commitment to the new department. He could support only about ten new staff, rather than the more than twenty appointments promised in his letter of offer. Siminovitch saw that he was leaving Biological Research to head a new enterprise that would be the same size as the one he left. With only ten staff he doubted that he could fulfil the mandate of building genetics, immunology and biophysics. He asked whether the oci leadership would agree to his return as head of Biological Research and appoint to the division the non-oci scientists he had recruited. Ash and his chief advisors considered their commitment to Jim Till was firm. Siminovitch left as planned. The university had its new department, but Siminovitch resented his treatment by the oci. Fortunately a link was maintained between the university Department of Medical Cell Biology and the oci. Siminovitch knew that a

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successful graduate program was essential to the viability of his enterprise. He faced a long approval process if he were to establish a new program. In cooperation with Harold Johns, Siminovitch decided that his staff would be cross-appointed to Medical Biophysics and take their graduate students in the oci-based department. To make this arrangement work, the university department was given considerable autonomy which autonomy increased over the years. The happy result was that cooperation was maintained between the oci and Medical Cell Biology. Siminovitch also fostered his own relationships with the oci scientists. Although his direct influence was reduced, he continued to make an important contribution to the institute’s scientific development. He remained on the roster of the Division of Biological Research with the same title as McCulloch, Senior Research Associate. The Medical School had suffered a loss when Arthur Ham stopped teaching histology when he moved to the oci. The subject is so important to pathology and medicine that it had to be taught well. Arthur Axelrad was an obvious choice, not only because of his skill as a teacher, but also because he could bring an active research program to the Department of Anatomy at the university. In 1966 Axelrad decided to accept the appointment as Professor of Anatomy in charge of Histology. David McLeod, his associate at the oci, had already moved to the Anatomy Department, so the happy collaboration between the two was restored.

after the changes In 1970 Wallace McCutcheon retired as chairman of the board. The next chairman was Mr. P.S. Howson, the ceo of the Canadian branch of a large pharmaceutical company. Peter Howson remained in office for only a few months; he resigned when his company moved him to the United States. Mr. Robert Stevens, a prominent Bay Street lawyer with many good political connections, was appointed chairman. He served the oci well for sixteen years, providing strong support for both clinical and research activities. In 1971 Harold Johns, who had been head of Medical Biophysics since Ham’s retirement in 1962, stepped down as chairman. The university was beginning to establish policies limiting departmental chairmen to a ten-year term in office. Gordon Whitmore became the third chair of the department. Johns remained head of the Division of Physics until his own retirement in 1980. Cliff Ash, the director, John Law, the administrator, and Harold Johns were the only remaining members of the senior group that had led the oci at its foundation. John Law began his oci career in 1952, as secretary the original board. He was appointed administrator in

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Robert Stevens, chairman of the board, with Mrs Maclachlan, look at a portrait of Peter Mclachlan hanging in the lobby of the oci/pmh building. Peter Maclachlan was a long-time friend of Robert Stevens and served as vice chairman of the board until his death in 1981.

1954, years before the institute opened its doors. Perhaps more than any other single individual, John Law was responsible for creating the support structures and atmosphere that were essential for oci’s success. Law understood that the role of administration was to facilitate, not to direct. Under his broad direction, the support departments functioned well. Personnel, headed by Joanne Ratz, successfully recruited technicians for research and health care professionals for clinical services. The financial services saw that the money was properly and easily accounted for. Research was grateful, since investigators could access their grant funds with little paperwork and no administrative delays. The building was spotless, cafeteria friendly. An arrangement with a local community college allowed chefs-in-training to prepare meals. For this reason, and because of the ability of the oci food services staff, the food was the better than that available at any of the other Toronto hospitals. Even parking was easy; John Law negotiated an agreement with the Catholic church next door. In exchange for snow-clearing, oci staff could use their parking lot during the week. The attitude of the support services reflected Law’s own vision of the administrative role. He earned the respect and personal friendship

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Garth Hayley, first John Law’s assistant and then his successor.

of the staff and was included in discussion of any decisions that would affect the oci. No doubt his task was made much easier by an ample budget and the ability of successive board chairmen to contact the provincial government directly. He once stated his principle as follows: “any administrator can follow policy and enforce rules. My job is to change policy and know when to ignore rules.” When he retired in 1974 he was succeeded as administrator by his able assistant, Garth Hayley, an accountant by training. Hayley continued Law’s policies and these remained highly effective. Of the original staff in Biological Research, in addition to Ham, Siminovitch, Axelrad, Fuerst, and Goranson were gone. Only Alan Howatson and McCulloch remained. Alan continued as an active collaborator whenever electron microscopy was needed. McCulloch continued his research program but he was much occupied with his role in the Institute of Medical Science. The Physics Division was more stable; Johns retained all of his original appointments. Physics provided the new leadership, as Gordon Whitmore became chairman of Medical Biophysics and Till moved to the Biology Division as head. While Till inherited a Biological Research Division depleted of four of its founding members, its strength was maintained by Siminovitch’s appointments. By chance these had strong links to the new head. Cliff Stanners had been Till’s graduate student, while Rick Miller and Bob Phillips had both come to the oci as Till’s post-doctoral students.

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Importantly, Till had the resources both of space and budget to build the division further. Bergsagel’s Department of Medicine added clinical breadth to the oci’s capacity to treat patients with cancer. It also provided a link between service to patients and research. The changes that occurred in the late 1960s and early 1970s proved that the oci could evolve to meet new challenges. After its first decade the institute was different in all three of its major roles. In service to patients, it was no longer exclusively a radiation therapy facility; it was now beginning to offer multi-modality care. In education, it remained principally a graduate centre; but its programs were more diverse, as students with medical backgrounds were accepted through the Institute of Medical Science. Heterogeneity increased later when an Institute of Immunology was founded in the University School of Graduate Studies. Students enrolled in its programs were sometimes supervised at the oci. Finally, its research programs had matured; the spleen colony method had been honoured in 1969 by a Gairdner Foundation International Award to Till and McCulloch. New directions were emerging. Immunology was becoming a much more prominent part of the research effort, with a major emphasis on cellular events in lymphopoiesis. Other programs were added as Till built the Division of Biological Research and as Medicine continued to stress its role in investigation. The oci had earned its place as an internationally recognized cancer treatment and research centre. It was also an important part of academic strength to the university. Its challenge was to maintain its capacity for innovation and growth. It needed to show that it still merited its recognition as an international centre of excellence in cancer care and research.

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Immunology and Hematology Using Cell Culture Methods

Lou Siminovitch, while head of Biological Research, led his division at a time of dramatic change in science. His interest in genetics made it easy for him to understand the importance of the emerging concepts of biological information. His participation in the spleen colony work had convinced him of the value of the blood and lymphoid systems as models for probing such basic cell functions as growth and differentiation. His understanding was the basis for the priority given to immunology and hematology. When Till became head of Biological Research, he retained these priorities.

immunology Advances in molecular biology caused a revolution in immunology. Before the discovery that biological information is encoded in nucleic acid, it was widely thought that proteins, acting as antigens, instructed lymphocytes to make antibodies whose specificity was determined by the structure of the antigen. This “instruction” model became untenable when it was realized that the primary structure (the sequence of amino acids) of each protein was specified by the order of the bases thymine (t), adenine (a) guanine (g) and cytosine (c) that make up the backbone of dna. The need to find a model of the immune response that was compatible with the role of dna as the repository of biological information was the motivation for novel and important experiments and conjectures. The proof that the instructive model of antibody specificity was wrong was an important stimulus for much of the initial rapid growth

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of molecular biology. A major advance was made by MacFarlane Burnet, the director of the Walter and Eliza Hall Institute in Melbourne, Australia. He postulated that the protein structure that conferred antigenic specificity was established at the level of dna; protein encoded by this dna would then be present in immature lymphocytic cells. A cell with this protein, acting as a ligand at its surface, would bind antigen with complementary structure. Binding would lead to cell proliferation with the generation of a clone of cells producing specific antibody. In contrast with the instructive model, antigen selected cells rather than providing information.* Burnet’s “clonal selection” theory provided a link between the known genetic function of dna and antibody specificity. It raised a difficult question: how was the genetic diversity generated in dna to direct the synthesis of the large number (perhaps 10 million) different proteins needed to bind the many antigens that might be encountered in a lifetime? The answer came from two converging lines of research, one based on the structure of antibody protein, the other on the genes required for antibody specificity. Both relied heavily on a special cancer called myeloma. This tumour consists of malignant globulin-producing cells (plasma cells) that make a large amount of identical protein molecules; however, each clone of myeloma cells makes its own distinct protein. The proteins made by myeloma cells were homogeneous, so it was feasible to determine their sequences of amino acids. From analyses of proteins from many different myelomas, structures of the various classes of immunoglobulin became obvious. It was apparent that myeloma protein molecules (and antibody) were made up of a large protein (the heavy chain) tightly bound to a smaller chain (the light chain). Further, both chains contained stretches where the amino acid sequence was similar in molecules from different myelomas (the constant regions) and other regions that were different and unique (variable regions). Studies of dna from myeloma cells revealed single genes encoding the constant regions. Later, a novel mechanism was discovered as a source of the diversity that provided specificity through the variable regions. There were not a large number of different genes; a few genes could recombine in different ways, then be processed, so that many rna species were produced as sources of the variable, antigenbinding, regions of the protein. To obtain these results, new methods of nucleic acid and protein chemistry were developed. The ideas coming from understanding clonal selection and the generation of diversity ** It is not easy to distinguish between “instruction” and “induction.” Perhaps it was the influence of Burnet’s work that made it easy for oci scientists to reject Trentin’s “him” theory of the regulation of spleen colony clonal expansion.

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moulded much of the thinking in molecular biology. The technology became the basis from which modern genetic engineering has sprung. A fundamental immunological problem remained: how is it that the immune system can differentiate between “self” and foreign “non-self” proteins? Reaction to “self” would be destructive; it is seen only in certain serious diseases where there is an immune reaction against the patient’s own tissue. Reaction against foreign, “non-self” proteins is essential for mounting a protective immune response to bacteria or viruses. Recognition of “non-self” is a major reason that cells and tissues cannot readily be transplanted from one individual to another. Experiments by Peter Medawar and his colleagues in London were among the first to bring light to the issue. They worked with inbred mice in a transplantation model. Skin can readily be transplanted from one inbred mouse to another of the same strain, although graft is rejected when donor and recipient are not identical. Medawar developed an experimental design where cells from one inbred mouse strain were injected into animals of a different strain while the recipient animal was a late embryo or immediately after birth. The mouse injected with foreign cells was then allowed to mature. As an adult, the mouse was challenged by a skin graft from an inbred mouse of the strain that provided cells for neonatal injection. Often the foreign skin graft survived; dramatic pictures were published, showing a black mouse with a patch of transplanted white skin. The specificity of an animal’s ability to accept a foreign skin graft was shown by transplanting skin from an inbred mouse of a strain different from that providing the cells injected at or before the recipient’s birth. Such “third-party” grafts were always rejected. These findings were interpreted to mean that during the development of the immune system specific events occurred which made the system unresponsive to self-antigens. These events could be manipulated, making it possible to study their mechanisms. The state of non-responsiveness was called “tolerance” and the same term was applied to experimentallyinduced failure of antibody formation or graft rejection. The search was on at once to find out how the immune system becomes tolerant and how tolerance works. Many experiments were reported, almost as many theories were advanced. Even now, no single explanation is accepted. Tolerance appears to require precise cellular interactions, and these may vary depending on the circumstances of the experiment. None of these pioneering immunological advances was made at the oci. But the unfolding of new insights into immunity was followed avidly by oci scientists. It might have been expected that “Hardi” Cinader would have provided the necessary initiative, since he joined that staff of Biological Research with an established reputation as an

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immunologist. Unfortunately, Cinader did not choose to bring the molecular and cellular biology of immunology to the oci. Originally from Austria, Cinader was well read and appreciated art and music. In Canada he was to become an expert on native Indian painting. In social contact he was charming and affable. Cinader had a European concept of research organization, where the most senior scientist provided all the ideas and his juniors followed his instructions without question. He did not collaborate well, since he assumed he would be leader in any project. This was not the oci style, where question and debate were the norm. His technicians, students, and postdocs were frightened of him since they expected that, if they departed at all from his instructions, he would block their future advancement. All this might have been less important had Cinader made a major contribution to oci science. But he preferred to work in considerable secrecy, an attempt to work with Till and McCulloch lasted only a week. The senior oci scientists began to appreciate that his approach to science was not compatible with the philosophy of the institute. Cinader remained working in isolation until he left in 1969 to go with Siminovitch to the university Department of Medical Cell Biology.* Immunology research came to the oci in way that could not be predicted. The chairman of Medicine, K.J.R. Wightman, asked McCulloch to arrange research training for a young medical graduate, James Kennedy. At the time McCulloch was an assistant professor in the Department of Medical Biophysics and had no personal experience with graduate programs. He planned to depend on technicians to run his own lab, interacting with graduate students through collaboration with colleagues. McCulloch called a meeting with Siminovitch and Till to arrange supervision for Kennedy. The first step in the meeting surprised him. He was accustomed to the authoritarian style of Medicine, but his colleagues wished to begin by asking whether Kennedy had the necessary qualifications for entry into a graduate program. To McCulloch, Wightman’s recommendation was all the qualification Kennedy could need; he explained this view of the academic world forcefully to Siminovitch and Till. They responded by telling him that the question of graduate supervision was then also settled; McCulloch would have to be the supervisor. There was no escape; McCulloch’s research pattern was changed to the more usual oci mode of a laboratory centred on graduate students. ** Cinader was successful as an international organizer. He headed the committee that managed an International Immunological meeting in Toronto which gave him much prestige in the immunological community. He also served on the university’s governing council.

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75 Immunology and Hematology Using Cell Culture Methods

A few days after Kennedy joined the McCulloch lab, Hillary Koprowski came to visit. Koprowski, a virologist, was the director of the Wistar Institute in Philadelphia and one of Siminovitch’s many contacts. McCulloch described to him the recent spleen colony work. His new graduate student was there, and the conversation turned to assays for blood cells based on function. Koprowski described a technique that had recently come to his attention. Niels Jerne, a leading immunologist, had devised a simple assay for cells making antibodies to sheep red cells. The method was to take spleen cells from mice previously injected with sheep red cells, mix a small number of spleen cells with sheep red cells, and immobilize the mixture in agar in petri dishes. These were then incubated for a few hours. Simple inspection showed small clear areas visible against the red background of erythrocytes. Microscopic examination of these clear areas or plaques showed a nucleated cell at the centre of each. These nucleated cells were producing antibodies that caused the red cells in their vicinity to break up (lysis), leading to the production of the clear plaques. Plaques could be counted easily and their number was a measurement of the antibody-producing cells in the spleen suspension. Two days after this conversation Jim Kennedy walked into McCulloch’s office and showed him a petri dish with obvious plaques against the red background of sheep erythrocytes. On his own initiative, Kennedy had taken the brief description he had heard from Koprowski and turned it into a functional assay for antibody-producing cells. The achievement was a tribute to Kennedy; it also demonstrated clearly the great advantage of having graduate students in the laboratory. Kennedy’s graduate program was based on assays for antibodyproducing cells. Till and McCulloch viewed the work as a natural extension of stem cell studies to include lymphopoiesis. Indeed, many of the experimental approaches were either similar to or derived from the ongoing work on spleen colonies. The first step was to use the assay to measure the radiation sensitivity of the antigenic response to sheep red cells. The result was similar to that found when the radiation sensitivity of cfu was measured. This outcome was evidence that the production of antibody-producing cells required proliferation. Kennedy devised a transplantation assay for the cell in which the proliferation was initiated. He was able to detect foci of antibody-producing cells in the spleens of heavily-irradiated mice. He described the characteristics of the progenitor, in terms of its number in the spleen and its proliferative potential as indicated by the number of antibody-producing cells that each progenitor contributed to the immune response. These results fitted easily into the models that Till and McCulloch used to explain their spleen colony findings.

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The immune system soon proved to be more complex than the myelopoiesis seen in spleen colonies. Papers were appearing showing the essential role of the thymus in immunological development. These data were not readily accommodated by a simple lineage-based model. For the oci, the major importance of Kennedy’s work was that it started a novel kind of immunological research, based on functional analysis of cell systems. For immunology to flourish, a larger program was needed, one that was not wedded to the lineage models of hematopoiesis. Such a program became possible with Till’s recruitment in 1965 of two talented post-doctoral fellows, Rick Miller and Robert Phillips. They embraced the complexity of the system and worked toward developing cell separation techniques to permit the analysis of its interacting cellular components.

granulopoiesis in culture In 1965 a revolutionary change occurred in experimental hematology. Independently in Australia and Israel, Bradley and Metcalf* and Pluznik and Sachs described methods for growing clonogenic hematopoietic precursors in culture. Both groups identified two essential parts of the method: first, the cell had to be immobilized, either in agar or in methylcellulose; second, a source of biologic stimulus was required. This requirement was met initially by using a two-layer method. Feeder cells, often mouse renal tubules in agar or methyl cellulose, were in a bottom layer, while marrow cells were plated on top, again in an immobilizing medium. This clumsy method was later replaced by adding to single-layer cultures supernatants of cultures of kidney cells, peripheral blood leucocytes, or certain cancer cell lines. When mouse marrow cells were plated under these conditions, localized cellular colonies were formed. These colonies were found to consist of either granulocytes or macrophages or a mixture of the two. This was the first time that hematopoietic differentiation had been observed in cell culture. This discovery opened up many new avenues. A major challenge was to find the nature of the bioactive stimulators found in the conditioned medium. The first approach was to vary the stimulator and to observe the effect of such variation on the cellular composition of colonies. Later, attempts were made to identify the molecules required for colony formation. Fractions of conditioned media were obtained ** Donald Metcalf has recently described his experience in developing methods for studying hematopoietic cells in culture, with particular reference to the stimulating factors required for the growth. See Donald Metcalf, Summon up the Blood (Miamisburg, Ohio: AlphaMed Press, 2000).

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by biochemical methods. These were assayed for their potency, using number of colonies as an endpoint. The importance of the culture methodology was immediately obvious to the Toronto group. Early experiments used double-layer agar cultures, with mouse renal tubule cells as a source of stimulation. Soon it was found that methylcellulose was a more convenient immobilizing medium. The continuous line of mouse fibroblasts (l cells) was found to be an active source of stimulator. Cultures responding to l cell conditioned medium contained colonies consisting almost entirely of macrophages. Building on reports from Australia, where peripheral blood leukocytes were used as feeder cells, medium in which such blood cells were cultured (leukocyte conditioned mediumly or lcm) was tested. Marrow cultured in methylcellulose with the addition of lcm gave rise to colonies with both granulocytes and macrophages. Both culture conditions continued to be used, depending on the needs of specific experiments. The terminology developed for spleen colonies was extended to include clonogenic cells in culture. The cells that formed spleen colonies were called cfu-s. At first cells in vivo were called colony-forming units in culture or cfu-c. Later more meaningful terms were used, based on the cellular composition of the colonies. Thus, colonies of granulocytes were derived from a progenitor called cfu-g, colonies of macrophages from cfu-m, and colonies with a mixture of both types were the products cfu-gm. The oci hematopoiesis group defined two objectives arising from the new tissue culture observations. First, they asked if the cells of origin of colonies in culture were the same or different from cfu-s. If different, was there a lineage relationship? Second, could human marrow cells form colonies in culture using an adaption of the methods that worked for mouse marrow cells? If human calls formed colonies in culture, what was the effect of leukemia on such growth?

early cells in hematopoietic lineages The first question, the relationship of cfu-s to clonogenic cells in culture, was tackled by a Ph.D student, Alan Wu. Alan reached the oci in an unusual way. Harold Johns had decided that Medical Biophysics would accept at least one student from Asia. Alan Wu, a native of Taiwan with a md degree, had submitted an application that Johns found convincing. The department accepted him although, unlike most students, no one had met or interviewed him as part of the application process. Since none of the staff knew Alan, there was no obvious

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supervisor so the decision was made by a lottery. McCulloch won and time would show that he was lucky indeed. The first impression of Wu was worrisome, since he clearly could not speak English. Not a month had passed before he had established himself as highly intelligent, motivated, and unusually independent. He found his way through the formal admission procedures of the School of Graduate Studies with little help, in spite of his problem with the language. He had no difficulty in becoming thoroughly familiar with the concepts of stem cells and differentiation that were central to the work of the laboratory. He seemed to be able to work longer and harder than anyone else in the program, and his effort was always productive. Everyone he worked with liked him, and often depended on his remarkable abilities to help with research problems. His reputation remains as one of the best students to obtain a doctorate from Medical Biophysics. Sadly, his own independent career was cut short by his untimely death of a brain tumour, after he had obtained the rank of associate professor of anatomy in the University of Toronto. When methods for growing clonogenic myeloid cells in culture were reported, Alan Wu was well into his thesis research. His project was to use radiation-induced chromosomal markers to provide direct evidence for the differentiation capacity of cfu-s. He used the knowledge that mice of genotype W /W v could accept marrow grafts without previous irradiation. He knew that all such recipients would survive; they were ideal hosts for the rare but precious clones that had been shown to have radiation-induced markers. He was able to produce W /W v animals whose whole hematopoietic systems were repopulated by single chromosomally-marked clones. Such mice were used to prove conclusively that cfu-s could differentiate into the three myelopoietic lineages. Markers were also found in thymus and lymph node, evidence that cfu-s and lymphoid cells could belong to the same clone. Wu readily adapted his system to show that cfu-s and cfu-c could be members of the same clone; further that cfu-c could be recovered from well-isolated spleen colonies. Next Wu took advantage of previous data, showing a wide variation in the number of new cfu-s that could be recovered from individual spleen colonies. He argued that if cfu-s and cfu-c were identical, a nearly perfect correlation would be found when both were measured in spleen colonies. He obtained ninety-six colonies taken after fourteen days of growth; cell suspensions from these colonies were tested for both cfu-s and cfu-c. A strong but not perfect correlation was found between the results of each assay. Wu concluded that the most likely relationship between them was that cfu-s were the more primitive, and that cfu-c were very early descendants. The finding did not exclude the possibility that the in vivo and culture assays were measuring identical stem cells.

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79 Immunology and Hematology Using Cell Culture Methods

cell separation A satisfying resolution of the issue would be reached if cfu-s and cfu-c were shown to differ physically. Research was under way in Till’s laboratory, designed to separate and purify homogeneous populations from the complex mixture of cells in bone marrow. These experiments were based on the assumption that differences in such characteristics as size or density might exist and be used as a basis for separation. The goal of such experiments was not only to determine physical characteristics of specific marrow subpopulations but also to obtain cells that were sufficiently homogeneous to allow biochemical or genetic studies. Cell density was used as a basis for separation by placing cells on top of bovine serum albumen (bsa) that consisted of layers of protein with increasing concentrations; gentle centrifugation was then used to pull the cells into this “density gradient.” At equilibrium cells would settle in that density of bsa that corresponded to their own density. Fractions could be collected and both bsa density and cellular characteristics determined. Separation on the basis of size was obtained by allowing cells to sediment at unit gravity through a very shallow density gradient. The speed with which cells fall in the medium is a function of their size. This speed could be determined by measuring the position of cells in the medium after a fixed time of sedimentation, since this position was a function of their speed. The development of velocity sedimentation was the accomplishment of Rick Miller and Bob Phillips, whose talents were so obvious that they were both appointed senior scientists in Biological Research two years after they came to Till’s laboratory as post-doctoral fellows. Miller and Phillips devised an apparatus elegant in its simplicity, consisting of a glass funnel which contained the shallow gradient. Cells were layered on top, and after a fixed time were collected from the bottom of the funnel as fractions that contained cells that had fallen through the gradient at different speeds. The method was called “staput” in contrast with another development, “staflow” in which cells flowed through plastic tubes and were separated into drops for analysis using laser light. The staput method was a major oci approach to cell separation for at least a decade, until staflow was developed commercially into the flow cytometry method now in wide use for both analysis of cell populations and cell separation. While these methods had not been developed for the purpose of comparing cfu-s and cfu-c, Ron Worton, in a Ph.D program under Till’s supervision, made good use of both of them. With each he was able to separate cleanly cells forming colonies in culture from cfu-s.

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From all these results, Alan Wu’s initial conclusion was confirmed. A close parent-progeny relationship existed between the two classes of clonogenic cell, but cfu-s were earlier in the differentiation hierarchy than cfu-c.

erythropoiesis in culture While the cell culture methods were developed for granulopoietic progenitors, Arthur Axelrad and his group were continuing their work on leukemia viruses. They used Bob Bruce’s assay for leukemic stem cells to test the hypothesis that antiviral immunity could reduce leukemic cell growth. Mice were injected with several different known viruses, including the virus discovered by Charlotte Friend of Mount Sinai Hospital in New York (Friend Leukemia Virus or flv). The animals were then tested for leukemic spleen colony formation. The expectation was that colony number would be reduced in the virus-treated animals. As in other discoveries, the unexpected result was more important than the hypothesis. The spleens of mice infected with flv had many discrete foci that could be counted. A quantitative assay for the virus was to hand that proved useful in many studies. The foci Axelrad observed consisted of rapidly proliferating erythropoietic cells; he knew that the work would be greatly enhanced if a quantitative assay was available for erythropoiesis. John Stephenson, a Ph.D student in Axelrad’s lab, was given the problem of developing an assay. Reports were available in the literature showing that heme synthesis was increased in suspension cultures of hemopoietic cells when erythropoietin was added. Stephenson found that epo-induced increased heme synthesis in cultured mouse fetal liver cells was proportional to the number of cells in the cultures; this was then the basis for an assay. Stephenson and Axelrad used physical separation to prove that erythropoietin responsive cells were different from cfu-s. Axelrad’s senior collaborator, David McLeod, had developed a variation of the technique for growing granulocytic colonies; he used plasma clots for immobilization and medium conditioned by mouse renal tubules as a source of stimulation. McLeod’s method had the advantage that the plasma clots could readily be transferred to slides for histological study, including the use of special stains to identify cells of hematopoietic lineages. John Stephenson adapted McLeod’s method to mouse fetal liver cells cultured with erythropoietin. He observed the formation of colonies that could be identified as erythropoietic and was able to follow the differentiation of early erythroblasts into mature red cells. Similar observations were made with adult mouse marrow,

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although the erythropoietic colonies from marrow were neither as frequent nor as large as those found in fetal liver cultures. Following the terminology convention in place, erythropoietic colonies were called cfu-e. In elegant experiments, Stephenson demonstrated that cfu-e were regulated independently of cfu-c. Because the plasma clot method allowed him to identify colonies unambiguously, he showed that cfu-e only were seen in cultures with epo, while cultures with kidney tubule-conditioned medium contained exclusively granulocytes. When epo and conditioned medium were added together, erythropoietic and granulopoietic colonies were seen in the numbers expected from the results in cultures with only one source of stimulation. Thus, cfu-c and cfu-e were shown to be different progenitors, each responding to appropriate simulation with no evidence of interaction between them. The assay for erythropoietic colonies was readily adapted to the methylcellulose technique used for cfu-c. When epo concentration was increased in such cultures and the time of incubation prolonged, Axelrad observed that red cell colonies were not randomly distributed in the plates, but rather were grouped together; these aggregates of small red cell colonies, which he called “bursts,” were easily counted. The bursts were considered to be derived from a progenitor earlier in differentiation than cfu-e. This cell was given the name Burst-forming Unit, Erythroid or bfu-e. The relationship between hematopoietic progenitors was tested further by analysis of the cellular composition of spleen colonies. No correlation was found between granulopoietic or erythropoietic progenitors and their recognizable differentiated descendants, although cfu-e were more plentiful in highly erythropoietic spleen colonies than in others. In addition to the previously known correlation between cfu-s and cfu-c, bfu-e was significantly associated with both cfu-s and cfu-c. No correlation was found between cfu-s and cfu-e. These data were interpreted to mean than both cfu-c and bfu-e were early differentiated progeny of cfu-s, while cfu-e was further advanced in maturation. These conclusions led to hematopoietic lineage diagrams based on developmental assays, rather than the usual morphological criteria. Traditional hematologists were properly annoyed when the diagrams were shown at meetings, since they did not contain a lineage for platelets, although these were clearly derived from the same stem cells as the granulopoietic and erythropoietic lineages. The defect was subsequently corrected when colony assays for megakaryoctes were developed. Axelrad took his program in erythropoiesis to the university’s Department of Anatomy when he moved there in 1966 to be in charge of teaching histology to medical students.

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human hematopoietic cells in culture The oci investigators were eager to extend the culture assays to the characterization of human hematopoietic progenitors. This avenue was particularly attractive to those with a clinical background. John Senn, a hematologist on the staff of Sunnybrook Hospital, became first a visitor, and then a welcome co-worker in McCulloch’s lab. He undertook the first studies of human marrow, using an adaption of the methods that had been successful for mouse marrow. He soon was successful; his optimal system used methylcellulose to immobilize the cells and medium conditioned by human leukocytes as a source of stimulation. Following the laboratory tradition, he used the assay for human cfu-c to measure their sensitivity to ionizing radiation. The survival curve he obtained had parameters very similar to that for mouse cfu. This was the first measurement of the radiation sensitivity of a human cell population obtained directly from patients. The results showed that the concepts of radiation response developed in animal cells or continuous cell lines were applicable to man. More important, experimental hematology was extended to the study of human cells, both in health and disease. Axelrad’s assay for mouse cfu-e was adapted to human cells by a clinical fellow, attracted to the oci for a short research experience. Arnold Tepperman first used the plasma technique developed by Stephenson; he readily observed the formation of red cell colonies, although the time of incubation required was longer than the two-fourday period that was sufficient for mouse cells. He later adapted the method to methylcellulose; as in the case of mouse marrow, human marrow was shown to give rise to bursts of multiple cfu-e colonies, when the Epo concentration in the cultures was increased and the time of incubation prolonged.

an emerging program in cell biology Immunological work at the oci grew out of experimental hematology; problems of lineage, growth, differentiation, and their regulation were common to both. The leaders in cellular immunology, Miller and Phillips, both were former Till post-doctoral fellows; the cellular assay for antibody-producing cells had been developed by Kennedy, McCulloch’s student. It was easy and effective for hematology and immunology to remain closely related; often senior scientists would be engaged in both. Common interests and easy personal relationships provided a

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A group photograph of the members of biological research, taken at the McCulloch property near Thunder Bay Beach. Front row from left to right is Chris Page, Jim Till, Neil Miyamoto, Hillary Llewellyn Thomas, and Norman Iscove. Second row is Rick Miller, Hans Messner, Sal Minkin, David Tritchler, Alistair Cunningham, and Sam Benchimol.

secure basis for communication and collaboration. Scientists, postdoctoral fellows and students met together every Friday for presentations of recent results and discussions of future plans. The value of the Boshkung meetings led to their imitation by the hematology/immunology scientists. A suitable site was available; McCulloch and his wife had a country cottage near Thunder Bay Beach on Georgian Bay, an easy two-hour drive from Toronto. The group met there, usually for a day and a half, once in the winter and again in the spring. There was always a stated agenda of presentations, timed so as to free an afternoon for tennis at nearby courts or walks in the woods. Informal discussions were held both after each presentation or during the evening hours. These gatherings, isolated from the distractions of the institute, were very helpful in setting goals. The perspective on the work was broader than that provided at the weekly meetings in Toronto. Whether at Toronto or at Georgian Bay, the atmosphere was cordial. Two examples show the extent of warm personal relations. Allan Wu met his future wife Gill Edwards because she was Bob Phillip’s graduate

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student. It was obvious to most that Gill spent more time in the McCulloch lab than was required for scientific exchanges. Gill and Allan were married just before he left for his post-doctoral fellowship. A different Allan, Allan Eaves, a Ph. D student with Bob Bruce, was more discreet. He and Jim Till’s post-doctoral fellow, Connie Gregory, managed to progress from research colleagues to husband and wife without anyone in the group knowing about it until they announced their marriage.

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Physics and Radiation Therapy

The Division of Physics and Radiation Therapy (later called Radiation Oncology) enjoyed a synergistic partnership. The clinical physics group provided essential support for therapy by measuring doses, calibrating machines, and servicing equipment. Scientists in the Physics Division often found their research goals in the problems of the therapists; these, for their part, looked to research results as sources for clinical innovation. Harold Johns’s key faculty in Physics, Gordon Whitmore, Robert Bruce, John Hunt, Jack Cunningham and, after 1965, Mike Rauth, provided stability, since they spent their careers in the division, sometimes with interruptions. Jim Till, an original member, transferred to Biological Research, but he, like the others, stayed at the oci. Other scientists came for various times, did good work but went on to other jobs. More stable members were added as new research directions developed. Usually, these were former graduate students, who often came to continue work begun during their Ph.D programs. Johns’s own research was related to radiation and its use in diagnosis and treatment. Because of his strong personality, his research directions earned cooperation from his staff and attracted excellent graduate students. Johns was not a dictator. Members of his division were free to follow their own directions provided they were successful, as judged by research publications and approval at the periodic nci(c) site visits. Many of the senior scientists in Physics conducted research that supported the role of the division in providing research and development

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Harold Johns in one of his most effective roles, as a teacher of physics.

for radiotherapy. Many also had parallel research programs arising from their own interests and priorities. In many medical specialties most development and some research are contributed from within – that is by those trained or in training. Radiation therapists were few in number. As the oci began, therapists were largely occupied with their clinical work. Moreover, the dependence of the profession on physics made it difficult for many physicians to work at the forefront of their field. Radiation therapy needed the Physics Division.

harold johns and the key physics programs Harold Johns came to head the Division of Physics because of his remarkable achievements in the physics of radiation therapy. His most innovative achievements were in devising isotope-based techniques (cobalt and cesium) for delivering energetic radiation doses. These high-energy beams could reach deep tumours without damaging the skin. At the oci he developed the use of betatron radiation machines to treat deep tumours. Johns always gave radiation therapy a high priority and his personal attention. To meet this objective he established

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a large machine shop in the basement, with operators capable of fabricating complex apparatus. As a complementary facility, Johns established an electronics shop that made or modified the essential controllers for radiation machines and other apparatus. Because of these facilities, radiation therapists had several new isotope machines. Perhaps the most dramatic was a Co60 source mounted in a casing that was attached to a movable fitting in the ceiling of a therapy room. By sweeping this source across the ceiling, a uniform and precise dose of whole body irradiation could be delivered. This machine, colloquially called “the stripper,” was very useful in preparing patients for bone marrow transplantation. While the major tasks for both shops were to construct or modify radiation delivery machines, they were also able to make apparatus that scientists in both divisions needed for their experiments. The basement housed radiation sources for treatment and research. A huge room housed a Van de Graaf generator. This produced large streams of positively charged particles, useful in research by members of the university Physics Department. It is characteristic of Johns that he had no hesitation in scrapping the Van de Graaf when its use for oci research proved to be limited. Space was always at a premium and Harold did not maintain apparatus just because it was large and expensive. Safe and effective radiation therapy depends on the delivery of a precisely-known amount of energy to a defined physical location within a patient’s body. A major function of clinical physics was to calibrate therapy machines and measure the dose delivered at various depths within tissue. The Physics Division included responsibility for clinical physics. Mention has already been made of Jack Cunningham’s pioneering work in developing computer programs for therapy; the effort had to be ongoing as new delivery devices came into use. Graduate programs in clinical physics were very active since the Physics Division had the size, talent, and diversity required for training. Other institutions across the country relied on the division to provide them with clinical physicists.

radiation biology An understanding of the consequences of the absorption of ionizing radiation in cells and tissues provides the theoretical basis of radiation therapy. The discovery that the radiation sensitivity of normal and malignant cells is similar changed the way therapists considered how their treatments worked. The radiobiology studies of Whitmore and

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Till played a major role in forcing the paradigm shift.* As Till became more involved with hematopoiesis, including the radiobiology of cfu-s, Whitmore continued to work with continuous cell lines, especially mouse l cells. These were useful because they grew easily in suspension and formed colonies with a high plating efficiency. This latter property showed that the cell culture lines consisted almost entirely of cells with stem cell properties. Whitmore continued to concentrate on two problems in radiobiology: measurement of repair of radiation damage, and factors that influence the response of cells to radiation. Whitmore used the split dose method to measure the kinetics of repair, by varying the time periods that separated the two fractions. At the same time, cell cycle parameters were determined. In this way, he was able to relate repair of radiation damage to the dna synthetic phase of the cell cycle. Experimental modification of radiation sensitivity offered attractive possibilities for improving treatment. Oxygen concentration is a wellknown determinant of radiation damage. When oxygen is removed entirely from cells (anoxia), they become about three times less sensitive to ionizing radiation. Similar though less dramatic effects can be achieved by irradiating cells in the presence of compounds that compete with oxygen. Whitmore and his group used survival curves coupled with clonogenic assays to measure the oxygen effect. These studies provided strong support for the view that reactive oxygen radicals are important mediators of radiation damage. The oxygen effect was of great interest to radiation oncologists. They thought that some of their failures might be explained if a portion of tumour cells were anoxic and therefore resistant. In some centres, patients were irradiated at high oxygen tension in specially designed hyberbaric chambers. This approach was considered at the oci but rejected because the published reports were not encouraging. A more attractive idea was emerging in the mid-sixties at the Radiation Laboratories at Mount Vernon, England. There a group headed by Ged Adams was exploring chemical radiosensitizers. The international reputation of oci scientists had ensured contacts with these workers. Fortunately Adams and his colleagues were unselfish collaborators, who readily made promising compounds available to the oci investigators. Whitmore’s group, now much strengthened by collaboration with Mike Rauth, had an important contribution to make. They had ** The collaboration of Whitmore and Till extended beyond radiation biology. Both were avid participants in the game of curling. They worked together on experiments designed to show if sweeping the ice really had an effect on the final position of a rock. The controversy remains to this day.

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Bob Bruce’s successful adaption of the spleen colony method for the measurement of clonogenic tumour cells in vivo. With this method and the cell culture assays, they could compare a compound’s radiosensitizing effects in culture and in animals. Of course, in vivo activity was required if candidate compounds were to be useful clinically. Culture experiments were easy, since it was only necessary to measure radiation survival curves in the presence or absence of a putative radiosensitizer. The animal experiments were simple in design, though demanding in execution. Tumours were grown in recipient animals; these were either kept as controls or given compound. Then the tumourbearing mice were irradiated, the tumours removed, made into cell suspensions, and assayed for colony formation in recipient mice. A difference between survival in the presence of compound compared to controls was a measure of radiation sensitization. The initial results were not encouraging. The cell culture experiments readily repeated the Adams findings that identified the compounds as radio-sensitizers. In contrast, little or no in vivo activity was detected. Fortunately, Rauth persisted. Adams sent him Metronitazole (Flagyl), which was in clinical use to treat yeast infection. When this compound was tested in tumour-bearing mice, a sharp increase in radiation killing was easily seen. Clinical interest was immediate, particularly since Flagyl was already in use in humans. A clinical trial was undertaken, which unfortunately did not show improved outcome when Flagyl was used with radiation. However, research continued on the mechanism of action of Flagyl and on testing of other compounds with similar structures. John Hunt, a senior member of the Physics Division, contributed research on the chemical events that followed radiation. He used electron spin resonance to detect the radicals that were considered to be important mediators of damage. Later, he devised a novel apparatus for detecting short-lived chemical changes. Visible Cerenkov radiation is produced when a charged particle passes through a material at speeds greater than the speed of light in that material. Hunt’s idea was to use Cerenkov radiation as it was produced in irradiated material to detect events occurring very rapidly. The process, called pulse radiolysis, allowed Hunt to make measurements in the picosecond time scale. He was able to characterize radicals that were so transient that their very existence would escape other methods.

ultra violet light Radiation biology and chemistry were making useful contributions to an improved understanding of how radiation treatments worked.

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Harold Johns came to the conclusion that major progress required a new approach. He had many discussions with Siminovitch, his opposite number in Biological Research. These interchanges may have been the reason that Johns perceived the growing importance of molecular biology. Regardless, he knew that the interaction of energy and biologic targets needed to be understood at the molecular level. In 1961 he spent a sabbatical year in California, in the laboratory of Max Delbruck, a major figure in the world of bacteriophage genetics.* At the time Delbruck was interested in ultraviolet light. He made good use of Harold Johns’s ability to devise precise instruments for delivering radiation. Johns built an apparatus called a monochromator that produced high-intensity light waves at a single wave length in the uv spectrum. In California, Johns saw that studying the effects of uv light on the building blocks of dna was both a way into molecular biology and an approach to understanding how ionizing radiation affected large molecules inside cells. He decided that studies of uv damage was a good choice for the new approach he needed. When he returned to the oci, Johns quickly deployed the resources for a major program in uv photochemistry. At least twelve graduate students were given problems in the subject, several of whom later joined the staff. Mike Rauth was assigned to it when he came as a post-doctoral student in 1962. Garret Deboer was on the problem during his graduate program. Johns brought to the area important improvements, such as the use of uv at a defined wave length, and comparisons of the effects when different wave lengths were used to irradiate the same compounds. For these experiments, he used his California experience and the excellent oci workshop to construct a large uv monochromator. His work earned the respect and collaboration of major scientists in the field. The program came to an end, after more than a decade, perhaps because the well-defined changes seen in simple compounds, such as thymine, could not be easily observed in the large molecules of interest, such as dna and rna.

imaging Harold Johns took another sabbatical leave, in 1971, this time with his friend Jack Boag, at the Physics Department of the Institute for Cancer Research in Sutton, England. Again he returned with a new research direction. He was fascinated by the use of charged powders ** Delbruck was the pope of the phage church. Johns described an Easter Sunday breakfast at Delbruck’s home, attended by other scientists. A water fight was staged; the phage church had its own form of baptism.

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to produce images useful in diagnostic radiology. The process is called xeroradiography because of its similarity to the xerox procedure used to duplicate documents. Once again his energy, together with the resources of students and some faculty, was engaged in a major program. Unlike the uv photochemistry work, the imaging studies were of direct value to the radiation oncologists, since exact localization of a tumour is essential for radiation therapy. Many imaging modalities were investigated, including ultra-sound as well as techniques that depended on x-rays and nuclear magnetic resonance. While the new emerging techniques of computerized radiography (cat scanning) and Nuclear Magnetic Imaging (nmr imaging)were not invented at the oci, they were studied and improved in the Physics Division. The imaging program at the oci revitalized an area of research, earning for the Physics Division an enlarged international reputation. Often, secondary cancer prevention programs were enhanced because such programs are based on early detection. Improved methods of imaging made it possible to find very small early tumours, helping prevention programs based on early diagnosis. Research in imaging improved service to patients not only at the oci/pmh but across the city. With the addition of research in imaging, the Physics Division provided the clinical radiation therapy service with all the tools it needed for excellent clinical care. The limitation remained that radiation is only curative when cancer is localized and has not spread. Here, collaboration with Medicine and Biology was required to provide the therapeutic combinations that were beginning to show promise in preventing or treating metastatic cancer. The mainstream of the Physics Division continued to be the research and development arm of the radiation oncology. The senior staff usually had additional, even dominant, personal research interests. These programs gave Physics the breadth it needed to be an attractive place to work and learn. The programs provided important mechanisms for collaboration with others in the institute. These individual and collaborative projects were as important to the oci as the support the Physics Division provided for radiation therapy.*

robert bruce Robert Bruce made contributions to the Physics Division’s major programs; early in his career he made observations on the effects of radiation on blood vessels. Although he often collaborated in the physics ** The Physics Division had a subculture of its own. Competitive sports were an important part. More visible to the rest of the oci was the annual Physics contribution to the Christmas party. “Physics Sings” was always loud, tuneful, and greatly appreciated.

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programs that supported radiotherapy, his major contributions came from his independent initiatives. His style was evident in his use of his colony assay for leukemic cells. He saw the method as an opening to a novel view of how drugs kill cancer cells while sparing normal tissue. He would identify an area that he considered worthy of development. He was an elegant experimentalist, with the capacity to devise simple but conclusive designs. Bruce was always successful; he either was a source of change or was able to disprove a hypothesis, even when he himself was its source. Bruce pioneered the use of computers very long before they came to be common. Computer terminals joined other apparatus in the halls of the sixth and seventh floors of the oci. Although the early terminals were clumsy, they served to initiate the oci staff into a computerized world. Johns himself used computers in a physics/statistics course he was developing by trying it out on the oci scientific staff. Bob recognized the value of computers in calculating radiation doses, and improving planning for radiation therapy. His medical background allowed him to begin to computerize both hospital records and the analysis of clinical results. Spermatogenesis also caught Bruce’s attention. He saw it as another differentiating system, open to the same methodology that had proved so useful in hematopoiesis. For several years his students, and particularly a visiting scientist, Marvin Meistrich, dissected the differentiation steps that lead from spermatagonia to mature spermatozoa. His methods included physical separation to purify cells at different stages of development and radiation experiments to pinpoint where proliferation was essential. His next enthusiasm was cancer of the colon, a problem that would occupy him for the rest of his career. His objective was, and remains, to find ways of preventing the disease. This seemed possible if, as he proposed, dietary carcinogens were important in causation. He set about searching for the damaging compounds. He set up an assay for mutation developed by Bruce Ames. The Ames test used bacteria as indicators. A strain of E-coli was available, with a mutation that prevented its growth on certain media. When the bacteria were exposed to mutagens, the mutation in the gene was reversed, allowing growth. Large numbers of bacteria could be exposed and the small percentage with the reversed mutation could be selected by their ability to form bacterial colonies. Bruce was attracted to the method because it was both quick and quantitative. Its major drawback was that not all mutagens are carcinogens; as a consequence the Ames assay often detected species that, though mutagenic, were irrelevant to the colon cancer problem. Bruce

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turned to more chemical approaches to look in the stool for compounds with chemical structures known to be associated with carcinogenesis. He used two quite different experimental systems. One employed either rats or mice; he could modify diets or administer putative carcinogens. He invented a way to look at whole colon mounts at low magnification. He was able to recognized crypts with early cellular changes that would be expected to progress to cancer. One of the indicators he used was apoptosis or programmed cell death. He was certainly early in the study of apoptosis; the process is now known to play an important role in growth, differentiation and cancer. His second model consisted of experiments on human volunteers. They agreed to eat specially-prepared limited diets and to collect stools over periods of weeks and sometimes months. In this way Bruce was able to monitor the effects of diet on the stool content of suspected carcinogens. This part of the work was essential to his goal of prevention, since diet modification is feasible; changes in lifestyle might be accepted if known to reduce tumour incidence. Unfortunately, he was not able to identify an appropriate diet that was certain to prevent the disease. While the main line of his research was clearly close to his heart, Bob Bruce did not abandon his previous interests. Often his smaller research projects reflected his desire for simplicity. For example, Bruce saw that counting colonies in culture dishes was a time-consuming job, with serious risk of error. Routinely, single cells in suspension are counted, using a device by which cells, one at a time, pass through a small hole and are counted electronically. Bruce had the idea that small colonies might be counted in a similar fashion, using a larger hole. The test of the idea needed a way to grow very small colonies in a liquid medium. Bruce succeeded in finding the necessary culture conditions and was able to count small colonies electronically. The developmental work was important, for Bruce found that culture medium containing methylcellulose was suitable for growing his minicolonies, and that they grew only when the methylcellulose was present at one critical concentration. These observations were the basis for the use of methylcellulose to grow hematopoietic colonies. The concentration of methylcellulose required for colony formation was that determined by Bruce and his students as they developed the minicolony technique. The experience is a further example of how research, undertaken for a certain purpose, may miss its original objective but provide the key to another, perhaps more important, application. Bruce continued his interest in hematology. He saw the need for a large supply of purified erythropoietin (epo) for studies of early cells committed to red cell production. He devised a remarkable way to

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make the hormone. It was well known that epo was increased markedly in anemia. Bob decided that a large anemic animal was required as a source of serum from which the hormone could be extracted. He bought a sheep and smuggled it at night into the basement of the oci. There he irradiated the animal so that red cell production stopped and it became anemic. The experiment succeeded; Bob collaborated with Dr Robert Painter, a biochemist, who purified epo from the sheep’s serum. The value of this approach was short-lived. When the gene responsible for epo was cloned, the hormone could be produced in large quantities by recombinant technology. Nonetheless, the story of the irradiated sheep, and its lasting odour, became an oci legend. Bob Bruce was widely recognized as an innovative and successful cancer scientist. A successful business man, Mr Ludwig, was establishing and funding small specialized cancer research units in close association with important centres. In 1981 Bruce was appointed director of the newly-founded Toronto Ludwig Institute. Fortunately, on the oci property, there was, a large house, which had once been the residence of a Catholic bishop. This building, always called the Bishop’s Palace, had been used as an isolation animal colony, with special laboratories for viral research. The Ludwig philanthropy completely renovated and equipped the Bishop’s Palace to meet Bruce’s specifications. His program was an expanded search for ways to prevent colon cancer. As director of the Ludwig Institute Bruce was technically no longer on the staff of the Physics Division, but oci flexibility allowed a synergistic relationship with the Ludwig Institute. Unfortunately in 1988, after an external review, the Toronto Ludwig Institute was discontinued. Perhaps Mr Ludwig expected practical results rather than basic science. In any case, the oci was glad to reappoint Bruce to the Physics Division.

gordon whitmore Gordon Whitmore’s collaboration with Jim Till in radiobiology was an important component of the Physics Division’s support for radiation therapy. Whitmore was also a major contributor to Siminovitch’s program in somatic cell genetics. He had good help from post-docs, notably Bud Baker and Larry Thompson. Based on excellent tissue culture facilities, Whitmore and his collaborators isolated Chinese hamster cell (cho) mutants that were temperature sensitive or drug resistant. Studies of these mutants led Whitmore into examining the mechanism of action of chemotherapeutic drugs, including the vinca alkaloids and cytosine arabinoside. Whitmore was also an excellent graduate supervisor. His many students now hold important posts in other Canadian universities; Frank Graham at McMaster and Mike McBurney at Ottawa are typical examples.

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Whitmore was one of the most outward-looking of the oci scientists. In addition to his ten-year tenure as chairman of Medical Biophysics, for three years he served the Faculty of Medicine as associate dean for Basic Science and Research. This was the first time that an oci scientist held important decanal office; it allowed the institute to develop the policy of permitting staff to spend as much as 50 percent of their time in a university post. Usually the university repaid the institute; but the salary and benefits were maintained at the oci. This enlightened policy allowed the oci to participate in the governance of the university without weakening its own scientific staff. Whitmore also served on many national and international bodies. He was chairman of nci(c)’s Research Advisory Committee. He held office in international organizations and scientific societies, including a term as president of the Radiation Research Society. All of these activities helped to maintain and increase the oci presence in the world of science.

peter ottensmeyer Peter Ottensmeyer returned to the oci in 1967, to bring to the Physics Division a new program. As a doctoral student, Peter had worked successfully in the uv photochemistry program. He did his post-doctoral work in France, where he was introduced to electron microscopy. In Toronto, Howatson continued his conventional program of using the electron microscope (e/m) to examine very thin sections of appropriately stained biological material. This technique allowed Howatson to visualize in detail cellular structures, such as membranes, mitochondria, and ribosomes; virus structure was readily examined by his methods, and proved very useful in studies of viral carcinogenesis. Ottensmeyer was determined to look at much smaller structures, even individual molecules. He had a background not only in physics, but also in engineering. With these, he was able to modify conventional electron microscopes so that they could make images that were analogous to those obtained with the high resolution “dark-field” technique of light microscopy. In another modification the electron beam impinged on an object at an angle, giving an image with a shadow. Substitutions of metals in organic molecules allowed the identification of the positions of specific important atoms, such as carbon. Ottensmeyer’s work with high resolution e/m images was highly complementary to the other imaging work that was in progress in the Physics Division. Computerized image analysis was essential both for the macroscopic images obtained by ultra-sound or cat scans and for the molecular images Ottensmeyer made with his modified electron microscope. Peter, like his Physics Division colleagues, was loyal to the oci as a whole. His subject matter, organic molecules, was a bridge of interest

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Peter Ottensmeyer with his electron microscope, taken shortly after joining the staff of the Physics Division when he returned from his post-doctoral fellowship in Europe.

to the biologists. He fostered the connection by decorating the corridor walls near his laboratory with his latest pictures, together with good explanatory diagrams. These changing exhibits, “The Ottensmeyer Gallery,” were a visible attraction to staff, students, and visitors alike. Peter’s manner was always very direct. His opinions were strongly held and voiced effectively. He was to continue to play a significant role in the institute when later he became chairman of Medical Biophysics.

ray bush Ray Bush was, without doubt, one of the most significant contributors to the success of the oci. His affiliation was with Radiation Oncology, but he was an active laboratory research scientist, conducting his work in association with the Physics Division. Bush was born in Toronto but did his B.Sc in Physics at the University of London, in England. He returned to Canada and worked as a physicist first at Northern Electric and then at the Atomic Energy Corporation. He spent a year as a physicist at the Colombo Plan Cancer

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Clinic in Rangoon, Burma. Perhaps it was his exposure to patients that persuaded him to return to Toronto and enter medical school. He graduated in 1961, and after the mandatory rotating internship, came, for the first time, to the oci as a resident. At that early stage in his career he showed his interest in research, conducting a dosimetry study with Harold Johns. This was not trivial work; it led to a publication in the prestigious American Journal of Roentgenology.* Bush then became a graduate student in the Physics Division. His supervisor was Bob Bruce. Together they exploited the spleen colony assays for leukemic stem cells in studies of their radiation sensitivity. Again Ray Bush demonstrated his commitment to improving his chosen specialty. Ray completed his general clinical training with a residency at the Victoria General hospital in Halifax. For his specialty work, he went to the Christie Hospital in Manchester, the best known of the European radiation oncology centres. He came back to the oci in 1965 to join the Department of Radiation Oncology with his training in radiation completed. As a practising radiation oncologist, he continued a busy research program, addressing issues directly related to clinical problems. The laboratory work was conducted in the Physics Division, where he found a valuable collaborator in Dick Hill. Together Bush and Hill studied factors that affect the response of cells to radiation. Using the clonogenic assay, they were able to show that tumours in animals with reduced blood hemoglobin levels were less sensitive to radiation than similar cancers in normal mice. This observation was translated directly into clinical practice. Regularly, patients with even slight anemia were transfused with blood prior to radiation therapy to insure that their tumours were adequately oxygenated. The observation of the effect of anemia on radiation sensitivity is one of the few examples of hypoxia that has been successfully exploited in clinical practice. Bush earned a reputation for excellence; he was acknowledged and highly regarded by clinical and research colleagues alike. His standing with both communities was an excellent basis for his career as director, beginning in 1976.

** R.S. Bush and H.E. Johns, “Measurement of build-up on curved surfaces exposed to Co60 and Cs137 beams,” American Journal of Roentgenology, 87 (1962).

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The Middle Years, 1971–1981

By 1971, thirteen years after its formal opening, the oci/pmh was recognized nationally and international as an excellent centre for cancer care and research. For the clinical role, the pattern of patient referral was well established. About 50 percent of patients came from Toronto and its immediate suburbs. The rest were referred from northern and central Ontario. These regions required additional service; small teams of radiotherapists and medical oncologists paid periodic visits. These peripheral clinics spared patients the need to come to Toronto and helped in the follow-up of those who had been treated and returned to their homes. The research role was well served by the two divisions. Education in research was prospering in the Department of Medical Biophysics. A special course was mounted to train radiation therapy technicians. The exposure of undergraduate and postgraduate medical students to cancer patients was still fragmentary, but the curriculum time was supplemented by electives at the hospital. But the number of patients referred for treatment was increasing steadily. While this was a welcome sign of success and patient satisfaction, the lack of space and people to provide treatment was to be a dominant concern until 1986 when the decision was taken to build a new hospital.

role study By 1971, two years after the 1969 expansion, patients referred for consultation or treatment had reached almost four thousand. The problem

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of the increasing incidence of cancer associated with a growing and aging population was a major and increasing concern. Improvements in management of the disease also contributed to a workload that stretched facilities and imposed pressure on the professional, technical, and support staff. An internal committee considered the issue. Its members had no difficulty in projecting the increasing patient load or in calculating the facilities that would be needed. Their recommendations were so extensive and expensive that the Ontario Ministry of Health decided that a role study would be undertaken. Further, the study would encompass not only the oci but also the octrf and its regional cancer centres. The expectation was that the role study would lead to a provincial plan for cancer care. In 1972 the boards of the octrf and the oci jointly commissioned the consulting firm of Kates-Peat-Marwick to conduct the role study. Their study group, headed by Alan Backley, collected data and interviewed widely. They had no difficulty in confirming the findings of the internal oci committee: fundamental research was a world-class provincial asset. Clinical services were under siege because of the steady and predictable increase in the number of cancer patients coming for treatment. In considering remedies, the study group faced a question: what was the right size for the oci/pmh? The group concluded that, to meet the problem completely on site, the oci would have to almost double in size, even though a major expansion of the existing building would be so disruptive of ongoing work as to make it difficult, perhaps impossible, to continue to serve patients and do research. The alternative, finally adopted by the study group, was to limit new patients to fifty-five hundred per year; this could be accomplished only if alternatives were available for those not accepted at the oci/pmh. The solution was to provide Toronto with at least one more cancer treatment centre. It was agreed that octrf should establish a new facility at Sunnybrook Hospital, organized and administered in the same fashion as the other octrf regional centres. The new North Toronto Cancer Clinic was constructed as an expansion to the west of the main Sunnybrook Hospital building. Limiting patients coming to the oci also required a change in referral patterns. The study group recommended that this be accomplished by eliminating some of the peripheral clinics and redirecting patients to octrf centres, particularly the Hamilton clinic. This strategy was only partially successful; while some relief of the pressure to provide service was experienced, limiting patient numbers was not easy. Some expansion was needed even to provide radiotherapy to fiftyfive hundred new patients. The study recommended the construction of 90,000 square feet of additional space, most of it for outpatient clinics

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and hospital beds. A small expansion of research space was planned, principally to meet the needs of laboratory-based clinical research. As a critical part of implementing the expansion of the oci facilities, the board contracted the consulting firm Agnew Peckam to prepare a master program. The resulting plan showed the space allocated to every activity or department in 1972 and the space to be provided following an expansion. When the provincial government considered the role study and the oci master program, their own fiscal problems led them to decide against the expansion on Sherbourne Street. In a few years the results of this negative decision were to be very hurtful for cancer patients and the professionals that cared for them.

biological research At the time of the role study, the Biological Research had the greatest opportunity for development. Till, appointed head in 1969, had empty space and unfilled positions because Siminovitch had taken several biology staff members with him to the university. He joined Harold Johns in advising the role study consultants that new space for research was not required. Johns and Till held this view because they feared that larger research groups could not achieve the coherence that fostered the supportive, often collaborative, style that had brought success to both divisions. Till’s first new appointment proved a great success; he recruited Victor Ling to the division. Ling graduated with Ph.D in biochemistry from the University of British Columbia and then went to Cambridge for post-doctoral studies at the mrc Laboratory of Molecular Biology. His B.Sc was earned at the university of Toronto, and during his undergraduate years he spent a summer at the oci. Till had been impressed by Ling’s research as a summer student and had followed his subsequent progress. The two met again when the Vic was visiting Canada from Cambridge. Till’s authority allowed him to offer Ling an appointment without condition. Vic joined the oci staff in 1971, when his post-doctoral fellowship came to an end.

multi-drug resistance Ling was the first oci scientist with dedicated training in molecular biology. His natural association was with Siminovitch’s program in somatic cell genetics. He began to select drug-resistant Chinese hamster ovary cells (cho). The first drug he used was colchicine, an agent that inhibits the cell’s capacity to separate the chromosomes that duplicated during dna synthesis. He hoped to identify mutants with specific defects affecting the proteins required for chromosome separation

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(microtubules). Colchicine was also of interest because it was the prototypic member of a family of vinca-alkaloid drugs with similar action. Their potential as anti-cancer agents had first been recognized by Robert Noble, a Canadian cancer scientist, who isolated from primrose an agent that caused a drop in the white count of experimental animals. This drug, vincristine, and a similar agent, vinblastine, were found to be very effective in the treatment of lymphoma and other neoplasms of the lymphatic system. Ling’s experimental procedure was to measure colchicine dose response curves for cho cells, using a colony assay. He then expanded colonies surviving after exposure to high drug concentrations, and retested these. He found a modest increase in resistance to colchicine in the survivors. Encouraged by this, he repeated the procedure several times, with incremental decreases in colchicine sensitivity after each drug exposure. Finally, highly resistant clones were obtained. This result was as expected in the selection of somatic cell mutants. It was also expected that the mutation would be specific; that is, the mutant cho cells would be resistant to colchicine and perhaps similar drugs, but would remain sensitive to different cytotoxic agents. Ling determined drug dose response curves for normal and resistant cho cells using a number of chemotherapeutic agents. Unexpectedly, the colchicine-resistant cells also survived exposure to many dissimilar cytotoxic drugs. Ling had discovered a new cellular phenotype, multidrug resistance.* He saw at once that his finding might be important to understanding and perhaps overcoming a major clinical problem, the resistance of cancer cells to chemotherapy. It was also evident that he might not have selected cells with a single mutant gene. He had to consider that his resistant cells might be cho variants with many genetic or non-genetic differences from the parental line. Mutation of more than one gene would provide an easy explanation of resistance to many drugs. Ling understood that he needed to know much more about multidrug resistance, both to understand its mechanism and to devise ways to help patients. He did not detect a change in the cell’s mitotic apparatus. He postulated, that, rather than altering mitosis, the change in the cho cells was affecting transport or handling of drugs within cells. This view was supported by experiments in which Ling and his students measured the movement of drugs into or out of cells. A comparison of controls and variants showed the intracellular drug concentration was usually reduced in the variants and drug export from the cells was

** J.H. Gerlach, N. Kartner, D.R. Bell, and V. Ling, “Multidrug resistance,” Cancer Surveys 5 (1986), 25–46.

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increased. Ling suspected that a cell membrane protein was responsible for his observations and that increased amounts of such a protein might be the explanation for the multi-drug resistance phenotype.

p-glycoprotein Ling set about searching for the protein. In collaboration with Jack Riordan, a scientist at the Hospital for Sick Children, he used analytical techniques as his search tool. The methods involved the separation of membrane extracts on a gel using an electric field (electrophoresis). Different proteins in the extracts were separated because they moved at different speeds in the field. Protein bands could be identified in the gels by staining with specific reagents, such as silver. By refining this methodology, Ling and his group identified a large sugar-containing protein (glycoprotein) that was regularly increased in membrane extracts from resistant cells compared to similar extracts from controls. This work took several years; by the time the scientists began to consider that the protein they had found was responsible for multidrug resistance, many examples of drug-resistant cells had been isolated. Examination of these examples showed that the same protein could be found increased in most, providing correlative evidence for the protein’s role. Ling gave it a name, p-glycoprotein, where p refers to the pleiotrophic nature of the protein’s actions. Pleiotrophy is the term for many different effects that can be traced to a single source, usually a gene or a protein. The gel electrophoresis assay for p-glycoprotein was both clumsy and of limited use. A more sensitive and specific test was needed. Ling injected protein recovered from gels into rabbits, to make antibodies. These reagents were useful in detecting smaller amounts of protein; they also made it possible to detect p-glycoprotein specifically by staining separated proteins fixed on gels (western blots). Even better reagents were created by making monoclonal antibodies. This method is based on fusing antibody-producing lymphocytes to plasma cells growing continuously, and then selecting clones producing the desired antibody. Monoclonal antibodies can be produced indefinitely from such clones and have very high specificity. They are the reagents of choice where immunological means are used to detect an antigenic molecule, usually a protein.

finding the gene While Ling and his group were working on the identification of p-glycoprotein, they continued to think about the fundamental nature

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of the change that led to multi-drug resistance. The question remained: was one genetic event, such as a mutation or amplification of a single gene, the cause of multi-drug resistance? Alternatively, were multiple genetic changes required? Evidence was accumulating that favoured the single gene hypothesis. For example, the somatic cell genetics group showed that the multi-drug resistant phenotype could be selected regularly from cell populations, and, sometimes, with only a single selection step. It was unlikely that several similar changes would occur frequently and at about the same time. The association of a specific protein, p-glycoprotein, with multi-drug resistance, also strongly favoured a single gene. A definite answer to the question required a genetic test. Ling had available a collection of small pieces of mouse dna, each complementary to regions of the cells rna (cdna). In this collection, called a library, the fragments were produced by reverse transcription from rna extracted from cells. The cdna pieces were inserted into suitable bacterial viruses (phage). These viruses could multiply in the host bacteria; there a protein specified by the inserted cdna fragment was made, using the cell’s machinery. Ling searched through the library and identified a cdna clone that was making a protein recognized by his anti-pglycoprotein antibody. Labelled cdna, extracted from phage-infected bacteria, was a useful reagent, since it would bind to complementary rna or nuclear dna. For both molecular species a blot assay was used, in which the rna (northern blot) or dna (southern blot) migrated according to its size. p-glycoprotein-complementary bands could be recognized by such methods and their size determined. Northern blots revealed a rna of a size consistent with capacity to encode the number of amino acids in p-glycoprotein. However, more than one band was seen, indicating the presence of several rna species, each making a protein that was recognized by the antibody to p-glycoprotein. Southern analysis confirmed this result, showing that several p-glycoproteins are encoded by a closely-linked family of very similar genes (multigene family). An important finding from the southern analysis was that the amount of dna encoding p-glycoprotein was markedly increased in drug-resistant cells. This could best be explained if many copies of the gene were present; this is called gene amplification. The result showed that the increased amount of p-glycoprotein found in drug-resistant cells was the result, not of mutation, but of gene amplification. These results made it almost certain that gene amplification and increased p-glycoprotein were responsible for multi-drug resistance. It remained possible that the findings in rna and dna were correlations, rather than direct causes. Proof required a demonstration that increased

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dna encoding p-glycoprotein led to increased protein at the cell surface and multi-drug resistance. This proof could be found because techniques were available for introducing dna into cells (transfection), confirming that the new dna was integrated and functional, and then determining the phenotype of the recipient cells. Ling and his group succeeded in transfecting dna for p-glycoprotein into cells that had a very small amount of their own p-glycoprotein. Since the p-glycoprotein in control cells was low, it was possible to demonstrate, without doubt, that transfection of the p-glycoprotein gene had increased protein concentration. Ling was able to show that the cells transfected with the p-glycoprotein gene were multi-drug resistant. These experiments were solid proof that the proteins of the p-glycoprotein superfamily were responsible for multi-drug resistance. Ling’s systematic exploration of the multi-drug resistance used all the available methods of molecular biology. With his accomplishment it seemed possible that the oci’s inability to maintain biochemical projects was at last overcome. Multi-drug resistance was of obvious interest to medical oncologists all over the world, since they used chemotherapeutic drugs. Cancer specialists saw that, once again, original and important work was coming from the oci.

growth of biological research Vic Ling was Jim Till’s first appointment. In the next three years Till worked hard to rebuild the Division of Biological Research. Three principles guided him in the task. First, he looked for quality; the Ling appointment is a fine example of his ability to move quickly when he recognized ability. Second, he sought to reinforce existing strengths; in this way he intended to give the division focus and avoid dispersion of effort. Third, he recognized Harold Johns’s wisdom in seeing the Physics Division role, in part, as a research and development arm for Radiation Oncology. Till saw biology in a comparable relationship to Medical Oncology. This policy was evident in his support for the medicine-based research in human leukemia and bone marrow transplantation. Till offered potential recruits an initial three-year appointment. The idea was to insure that permanent senior scientists were of proven quality without relying too heavily on filling positions with former graduate students or post-docs. In practice, there was no difference between those appointed for three years and the senior scientific staff, The policy of making short-term appointments was not long maintained. Bud Baker, who, as a post-doc had proven his ability in the somatic cell genetics program, was appointed to the staff in Biological Research in 1971, the same year as Vic Ling. He continued to make an impor-

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tant contribution to somatic cell genetics during his stay in Toronto. However, in 1974 he returned to the United States, where he had a distinguished career in cell biology. Richard Stanley was working with Donald Metcalf at the Walter and Eliza Hall Institute in Australia when Jim Till met him at a meeting in Holland. Stanley’s interest was biochemistry, and his subject was the purification of factors stimulating hematopoietic colony formation in culture. Till was impressed with Stanley and saw that stimulating factors and their biology would be essential to the Toronto experimental hematology program. He was successful in persuading Stanley to come to the oci in 1972. Stanley’s research was directed toward the purification of a factor that stimulated the formation of colonies of macrophages (csf-1); he had a surprising but very convenient source, human urine. The clonogenic assay was also easily available and highly quantitative. With these techniques, Stanley made excellent progress. He did not then have the molecular methods that subsequently allowed the production of recombinant factors, using genes inserted into protein-production systems, such as bacteria or cell lines. Stanley’s program, by itself, was too limited to make a significant contribution to the overall hemopoiesis program. After four years, he left the oci to take up a research post at Mount Sinai Hospital in New York. David Houseman joined Biological Research in 1973. Till identified him as a young scientist, trained in molecular biology, and with great promise. Although his stay was short, lasting only two years, his energetic and outgoing personality made a major impression on his colleagues. The much more rapidly growing molecular field in the United States prompted him to return to Boston. Both Stanley and Houseman may have left the oci because the institute did not provide enough colleagues with similar interests to make a critical mass. Nonetheless, they, together with Bud Baker, who departed at about the same time, left as friends. They remained staunch allies. As such, and because of their location at major us research centres, they provided ongoing help and advice to oci scientists. Till made other appointments; his policy was to build on the existing strength in immunology. He saw the immune system as of vital importance in itself but also as model for both cellular regulation and molecular biology. In 1974 he added Reg Gorcynski to the staff. Reg was a former Ph.D student of Bob Phillips. During his doctoral program he had made a great impression for extremely hard work and wideranging interests in the immunological studies then conducted jointly by Miller and Phillips. He continued in the same energetic fashion as a senior scientist. His impact was reduced because his work tended to be diffuse. He resigned in 1983 to become a medical student. After

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obtaining his MD, he returned to immunological research, but not at the oci. Till strengthened immunology with two further appointments. In 1975 Michelle Letatarte-Muirhead joined the staff, followed two years later by Alistair Cunningham. Cunningham, from New Zealand, was a thoughtful student of b cell biology, who had written a useful text on immunology. Miller and Phillips knew him from their travels to meetings and suggested him to Till. The need for greater strength in molecular biology was appreciated widely. In 1973 Alan Bernstein, Till’s former Ph.D student, was recruited to the division. His Ph.D research was a study of bacterial membranes, using a combination of genetic and biochemical methods. These prepared him well for a post-doctoral in London, where he completed his training in molecular biology. His work when he returned to the oci centred on tumour viruses, particularly the Friend Leukemia virus complex. He recognized that infected mice suffered a two-stage disease. In the first stage, non-malignant erythropoietic proliferation led to greatly enlarged spleen and increase in the number of clonogenic erythropoietic cells. In the second stage, malignant erythroleukemia emerged. In culture, the leukemic stem cells formed huge colonies, red in colour because of their content of hemoglobin-producing cells. These remarkable colonies earned the local title of “cannonball.” Along with the description of the cellular events in the Friend leukemogenesis, Bernstein made good use of his expert knowledge of molecular biology to characterize the viral components in the Friend Leukemia complex. At least two viruses were described; one carried the transforming oncogene but was unable to replicate itself. Its continuing existence required cooperation with a second virus, able to grow, but not by itself malignant. His success in research and his powerful personality gave Bernstein much influence at the oci. Till made two additional staff appointments in 1974. Gerry Price and Tak Mak both made their first contributions to oci research and culture in the context of a program in human leukemia. The appointment of Tak Mak was of great significance for the oci since, as a senior scientist he was the next to make a unique discovery that earned him world-wide fame.

quality of life and behavioural research As Jim Till grappled with the challenge of building biological research, his own research interests changed. He continued to collaborate in

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experimental hematopoiesis but was seldom actively engaged in experiments. Rather, he initiated a new line, very different from either cellular or molecular biology. Till had a long-standing interest in statistics. His early training in physics left him with an understanding of the value of quantitative models. Now he turned both to a study of how hospitals were managed and how patients perceived their disease. Today this research would be called health systems research or perhaps health economics. Granting bodies and governments, now faced with problems in the public health care, would welcome it and fund it generously. When Jim began, some even questioned whether it was research at all. Till’s health care research had two principal thrusts. First, he concerned himself with how patients made decisions about their treatment. This involved measuring risk and perception of risk as seen by patients as alternative therapies were suggested to them. Often, the studies were conducted in the context of clinical trials. Patients recruited into trials receive a good explanation both of standard treatment and the new therapy to be tested. Patients were not entered into a trial unless they gave informed consent. The design of clinical trials provided a second thrust to Till’s work. He was not satisfied with the usual end points, such as changes in survival or extent of tumour response. He was among the first to see quality of life as important, or perhaps sometimes more important, than extended life or clinical remission. Both decision-making and life quality measurements required special instruments. Often patients were presented with short descriptive accounts, called scenarios, and asked to choose between one or more. Detailed questionnaires were developed to measure changes in feelings or functions, important aspects of life quality. Both of these methods required careful quantitation and detailed statistical evaluation. Till attracted collaborators to his new research field. Ian Tannock, who joined Bergsagel’s Department of Medicine in 1978, was an energetic supporter of the measurement of lifestyle. A clinical investigator, Tannock maintained basic work on the effects of intracellular ph on the sensitivity of cells to chemotherapy. His studies with patients were often designed with lifestyle measurements as endpoints, and he emphasized this approach strongly with clinical trainees. Alistair Cunningham, recruited as an immunologist, may have been influenced by Till’s thinking. He had begun to explore the idea that mental processes might affect the growth of human tumours. Till supported Cunningham with sabbatical leave so that he could do doctoral studies in psychology at York University. With his second Ph.D completed, Cunningham closed his immunology laboratory and concentrated on testing psychological strategies in the treatment of cancer.

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John Darte, first a radiation oncologist and later the second director of the oci/pmh.

new directors John Darte left the oci in 1962 to become chair of Pediatrics at Memorial University in Newfoundland. When Cliff Ash retired in 1975, Darte was persuaded to come back as the second director of the oci. He was appointed after a search conducted by a committee chaired by Robert Stevens, the chairman of the board. The use of a formal search was an indication that the oci was maturing as a public institution, with proper accountability. It was notable also, that, though John Darte had much oci experience, he was a Newfoundland professor; he might have been considered as an outside appointment. John Darte’s broad professional training included medicine, pediatrics, and radiation oncology. His early work in conducting the first hematopoietic transplants as treatment for leukemia gave him an understanding not only of the importance of oci research but also of its philosophy. His breadth may have been the reason he planned to bring the somewhat idiosyncratic institution he inherited into a more mainstream relationship with the Ontario hospital system. The role study of 1972 had recommended that oci/pmh seek accreditation by the Ontario Hospital Association. Darte saw this as a means of insuring

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that high standards of clinical care were maintained. Also important, preparation for the visit of the accreditation committee required an open examination of oci/pmh policies and procedures. The process insured that all of oci staff had a better understanding of the institution they served. Unfortunately, Darte died of an acute heart attack less than a year after becoming director. Robert Stevens chaired a new search committee that chose Ray Bush as the new director. The committee was convinced of his expert knowledge of radiation oncology and impressed with his wide experience. Bush proved to be a very active director. Not only did he continue John Darte’s plan for accreditation, but also became actively engaged in planning the delivery of cancer care throughout the province. As well as director of the institute, Bush was the chairman of the Medical Advisory Committee and the active medical staff. Until he resigned as director in 1988, he had a personal role in everything that happened in the oci, including research. His method was to ask questions, consider the answers, and then to be as helpful as possible. His directorship set a new style for the oci that would continue for the rest of the Sherbourne Street days.

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Interface Research

The proper size of oci research was a matter of debate. Till and Johns, the heads of the research divisions, told the 1972 role study consultants that critical mass had been achieved and further growth would be detrimental. McCulloch, with his responsibility for research in the Medical Department, was convinced that more resources of people and space were required. To make his case, he used the term “interface research” to describe laboratory work that had a direct application to clinical problems. This terminology, stressing the close relationship between laboratory and clinical research, seemed fresher than the usual “benchto-bedside” language that was commonly used to describe applied work. Now “translational research” is the approved language. The evolution of the terminology has not changed the nature of the enterprise. The case for interface research was supported strongly by Bergsagel and accepted by Ash, the director, and John Law, the administrator. It was included in the master program describing all oci-approved space and functions. New space was proposed for interface research. The Leukemia Program was already in place. McCulloch managed the laboratory component and Don Cowan was head of the clinical service. John Curtis, a graduate of Dalhousie, was recruited from Houston, where he was finishing his training as a medical oncologist. His special expertise in white cell and platelet transfusion strengthened the clinical component. As a subsequent evolution, a separate medical program in human marrow transplantation was initiated. Since stem cells are important to both leukemia and transplantation, the two programs were closely connected.

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the first phase of the human leukemia program The first phase of the human leukemia program was a direct evolution from the experimental work on normal hematopoiesis and used the same cell culture methods. The theoretical basis of the program was greatly influenced by the work of Phil Fialkow, a physician and geneticist who was at the University of Washington in Seattle. Fialkow’s work showed clearly that the leukemic population in each patient was derived from a single cell. Leukemia was a clonal disease; the thinking about clones that flowed from the work on spleen colonies was a firm basis for planning research into human leukemia. Two recent experimental findings were influential. The first came from studies of chronic myeloblastic leukemia (cml) by the nih leukemia group. The Philadelphia chromosome is a consistent marker of the dominant malignant clone in cml. In relapse of the disease, mature or maturing granulocytes are the dominant cell types in blood and marrow. Treatment with chemotherapy reduces granulopoiesis and permits the expansion of the red cell and platelet populations. This hematologic picture would usually be called remission. Surprisingly, when dividing cells in such patients were examined, the Philadelphia chromosome was found in all of them. The improvement after treatment, therefore, was achieved by changing the balance between hematopoietic lineages within the malignant clone rather than eliminating the leukemia. The second influential findings came from the experimental hematology group working at the Walter and Eliza Hall Institute in Australia under the general direction of Donald Metcalf. Malcolm Moore, a member of Metcalf’s group, found that marrow from patients with acute myeloblastic leukemia (aml) would grow in culture under the same conditions that were needed for normal hematopoietic progenitors. Feeder cells or conditioned media would support colony formation by aml marrow cells in either soft agar or methylcellulose. Moore and his collaborators tested marrow from a large number of patients with aml. They reported a variety of growth patterns, ranging from no growth to extensive myelopoietic colony formation, with varying degrees of differentiation within the colonies. Moore found correlations between such patterns and patient responses to treatment. While this association was not always confirmed in other centres, everyone, including the group in Toronto, observed that marrow cells from patients with leukemia were sensitive to the same biological agents that supported growth of normal hematopoietic colonies. Differentiation of cells in the leukemic cml clone was reason to think that aml clones might respond to normal regulatory mechanisms.

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The response of aml bone marrow to myelopoietic growth factors made it possible that these agents might be clinically useful inducers of differentiation. Taken together, these results supported a hypothesis that aml might be treated successfully by administering normal growth factors to patients. The hypothesis was the unifying idea that would motivate a collaborative program in human leukemia. Both scientific and clinical colleagues were persuaded. The leukemia program was always an active collaboration between clinicians and laboratory scientists. Don Cowan and John Curtis ran a clinical service, where patients were treated with the best available protocols. Blood and marrow from patients was sent to the laboratories for cell culture or other tests. When enough cells were available, some were stored in liquid nitrogen at very low temperature, to preserve the capacity of the cells to grow. The progress of the patients was documented carefully so that, when appropriate, a search could be made for associations between clinical outcome and laboratory functions. Later, the clinical service undertook a series of sequential clinical trials. When an idea was developed that might give improved results, a protocol was written, reviewed, and then used to treat a cohort of patients. The outcome for these patients was then compared with the results that had been obtained in the previous trial. As this process was developed over many years, ideas coming from laboratory findings could be tested for clinical value. John Senn, who had first developed the culture method for human granulopoietic colony formation, continued to be an active collaborator. He often brought specimens from his own patients at Sunnybrook Hospital. He participated vigorously in discussions and decisions. His seniority and experience were particularly valuable when Don Cowan resigned from the oci staff to become physician-in-chief at Sunnybrook. The idea that leukemia might be treated by inducing differentiation was not unique to the oci. Paul Carbone, of the American nih, was able to mount a direct test. An American pharmaceutical manufacturer, Abbott Laboratories, had developed technology for growing large numbers of mammalian cells in cultures that consisted of cells growing on a series of glass plates inside a large vessel. The cells could be nourished continuously by medium that flowed past the plates in and out of the container. Biologicals secreted by the cells could then be collected from the medium. Carbone saw that this system could be used to produce enough colony-stimulating factor for a small clinical trial. A small international group worked on the project. They visited Abbott Laboratories in Chicago to see the culture system. They tested samples of culture supernatants for their capacity to stimulate colony formation. Finally, they wrote the clinical protocol and monitored the trial.

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McCulloch was a member of Carbone’s working party. As such he was able to insure that at least one oci/pmh patient was included in the trial. Three patients were treated, each at a different institution. The results were the same in each case. The injection of the semipurified material caused a marked and dangerous fever in the recipients. No evidence of differentiation was observed in the leukemia cells, nor was there clinical evidence of improvement in the underlying disease. The project promptly and properly came to an end. The role of hematopoietic growth factors in the treatment of leukemia remains controversial. Carbone’s early trial is an example of a clinical experiment undertaken before the science was in place. Molecular identification and cloning of growth factors now permit purified proteins to be used, without the unpleasant side effects seen in the three early trial patients. Even with these preparations, differentiation of leukemic cells is not seen. If growth factors now have a place in the treatment of leukemia, it is to speed up the recovery of normal cells, shortening the dangerous time in aplasia. The early trial increased the Toronto group’s contacts with the international community of leukemia investigators. More important, the failure of the trial required the re-examination of the thesis upon which the leukemia program was started. Perhaps induction of differentiation was not the answer. Culture assays of leukemic marrow for the early progenitors of granulopoiesis (cfu-c) and erythropoiesis (bfu-e and cfu-e) showed a wide patient-to-patient variation in progenitor values. Marrow from many patients failed to grow myelopoietic colonies at all, while, in a few instances, growth was greater than normal. These findings might be seen to support a block in differentiation as the basic lesion in aml. A different possibility was considered, based on Fialkow’s finding that aml populations were clones. In the work with spleen colonies, wide clone-to-clone variation was seen when the nodules were examined for new cfu-s or plated to measure colony formation in culture. This heterogeneity was the experimental basis for the stochastic model of clonal expansion. In the model, variation was considered to be the outcome of random events, governed only by definite probabilities. The question was asked: could the patient-to-patient variation arise from random choices occurring during the expansion of leukemic clones? Sam Lan, a post-doctoral fellow working with Jim Till, measured cfu-c, bfu-e and cfu-e in marrow for more than forty aml patients in relapse. In agreement with previous results, the colony numbers were usually low. Occasional high or intermediate values were found; when the distribution of colony numbers was plotted, it was found to be skewed, the same distribution that was seen when new cfu in spleen colonies were measured. While this result was compatible with

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a stochastic process as the basis for heterogeneity, it remained possible that some intrinsic property in each clone was expressed in its differentiation pattern. If this were the correct explanation, then the pattern should be repeated in each clonal expansion. It was feasible for Lan to test whether a stochastic or intrinsic mechanism determined colony number. The patients were treated with chemotherapy which reduced the size of each clone. The clones re-expanded as they recovered from the drug. Lan could measure cfu-c, bfu-e, and cfu-e again and ask whether the second values were positively correlated with the first. If such correlation were found, it would be strong evidence that each clone “bred-true” in response to an intrinsic program. In the experiment, the opposite result was obtained; there was no correlation between the first and second measurements. The stochastic hypothesis was upheld. It followed that measurements of myelopoietic colony formation in marrow from aml patients would not be informative since the values obtained would reflect only randomness.

t h e b i o l o g y o f aml b l a s t c e l l s : the second programmatic phase The next phase of the leukemia program was designed with the understanding that growing apparently normal progenitors from patients’ marrow would be unlikely to give useful results; rather, the emphasis was on aml blast cells. aml blasts are morphologically undifferentiated cells. They are the characteristic leukemic population in the disease and are the basis for diagnosis. Blast cells can be obtained readily and safely from the peripheral blood or marrow of aml patients. Even before Sam Lan’s study, preliminary attempts had been made to culture blasts from peripheral blood. Their proliferation in culture was studied using incorporation of tritiated thymidine into dna as a measure of growth. Although clumsy and time-consuming, the work provided evidence that blast growth was stimulated, and was dependent upon, interaction with an accompanying lymphocyte population. When such lymphocytes were cultured in the presence of a mitogen, the plant lectin phytohemaglutinin (pha), the medium also stimulated blast cell proliferation. It seemed possible that the highly malignant blast cells of aml might, like normal myelopoietic progenitors, respond to stimulators produced by accompanying cells. Might it not be possible, therefore, to devise a colony assay for blast cells by adapting the methods used for normals? Early experiments were encouraging; when blasts were immobilized in methylcellulose in the presence of lymphocyte conditioned medium, small colonies of about twenty cells were often seen after five to seven days incubation. It seemed that the clumsy

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suspension assay might be replaced by a colony method if the procedure could be made both reproducible and quantitative. It was at this stage in 1976 that Ronnie Buick joined McCulloch’s lab as a post-doctoral fellow. Born in Scotland, with his graduate education at the McArdle Laboratories in Wisconsin, he was well trained as a biochemist. His remarkable ability to accept a novel challenge was immediately demonstrated, for he undertook the development of the clonogenic assay for leukemic blast cells, a problem not related to anything in his previous experience. He quickly established the assay as a quantitative measurement of a minority of the cells in the blast population. Then he asked if these clonogenic blast cells were stem cells, as defined in the earlier work on normal hematopoiesis. He collected the cells from single blast colonies, and plated them under conditions that favoured blast colony formation. Some of his experiments were positive, showing that new blast clonogenic cells were generated during growth of blast colonies. These experiments proved that clonogenic blast progenitor cells had a self-renewal capacity, the property that was essential if clonogenic cells were to considered stem cells. It followed that the minority population of clonogenic blast cells maintained a much larger population of morphologically recognizable blast cells. The blasts were a lineage that resembled the normal in that both had a stem cell population giving rise to descendants with little or no ability to grow. The difference from the normal was that the non-dividing blast cells retained their primitive appearance. A model could then be proposed. The leukemic clone was considered to be derived by malignant transformation of a multi-potent primitive cell. The transformed cell retained the ability to produce normal lineages, but, in addition, could give rise to blast stem cells. By reason of their capacity for self-renewal, these could maintain the blast population independently of the normal lineages. The oci model of an aml clone was very different from the views held by most hematologists. These considered that the blasts appeared immature because their capacity for differentiation was blocked. The same or similar block was thought to maintain the blast population in a non-proliferative state, from which the cells could emerge and restart growth. Research by Mark Minden, an Institute of Medical Science Ph.D student, provided concrete evidence that refuted the conventional model. He asked whether clonogenic blast cells were in a state of rest or rapid proliferation. He used the tritiated thymidine “suicide” method that Becker had developed to study spleen colonies; with this technique he showed that the clonogenic blast cells were always in a state of rapid proliferation. This result was as predicted in the oci lineage model of blast cells.

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A resting state for blast cells, consistent with the blocked differentiation model, had been supported by experiments using labelling with tritiated thymidine. Alvin Mauer had used this method to show that very little isotope incorporation could be demonstrated by radioautographs prepared from blast cells exposed to 3htdr. There was no discrepancy between this result and Minden’s findings. The colony assay used in the “suicide” experiment detected only the proliferative activity in a very small subpopulation of blasts. In contrast, Mauer’s experiment depended on morphological recognition of all the blast cell population. The problem was one of interpretation. Mauer and other hematologists considered the lack of thymidine incorporation to be a sign of a resting state. In contrast, in the Toronto model, absence of dna synthesis was the expected behaviour for the end cells of a lineage. How blast cells were viewed was important to chemotherapists. The goal of treatment was to reduce to zero the number of tumour cells, so that regrowth was impossible. Even at maximum-tolerated drug dose, success could not be explained if it were necessary to eliminate all the cells counted as blasts. In contrast, if only a minority population had to be sterilized, remission-induction could well be achieved at clinical drug doses. The oci view was that the blast stem cell population was the target for treatment; if it were eliminated, the end-stage blasts would disappear. Hematopoiesis might recover from surviving normal stem cells. As the clonogenic blast assay was used to examine blood cells from more aml patients, it became evident that there was a large patientto-patient variation. Could it be that blast stem cell numbers, like myelopoietic progenitors, were generated by a stochastic mechanism, and hence were uninformative? Repeated tests on patients, separated by time intervals, showed that blast cell growth patterns “bred true”; it seemed useful then to take advantage of the wide variation in blast stem cell numbers to look for associations between their characteristics and clinical responses. Two blast properties were obvious candidates for clinical significance: high self-renewal might be a sign of an aggressive population and a poor prognosis, and sensitivity of blasts cells to chemotherapeutic drugs might predict response. Buick measured self-renewal by determining the number of new blast progenitors in colonies. Consistently, in Buick’s hands, and later confirmed in other laboratories, self-renewal was found to have bad prognostic significance. The clonogenic blast assay could be used to construct dose response curves for the drugs used in treatment. Buick cultured blast cells in the presence of increasing drug concentration. He found that colony formation decreased exponentially, yielding plots that were similar in

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form to radiation survival curves. There was relationship between clinical outcome and drug sensitivity, but the correlation was not as strong as that for blast stem cell self-renewal. Neither was sufficiently powerful to be used in practice, either as a prognostic indicator or a way to choose treatment. The benefit of the work came from increased understanding of the disease rather than direct practical application. The leukemia program at the oci attracted talented people. Ronnie Buick became a scientific and administrative leader. Mark Minden joined that staff as a clinical scientist, combining laboratory work with practice. Tak Mak came to the oci in 1972 with a Ph.D in biochemistry from the University of Alberta and brought molecular biology to the leukemia program. When he came, the dogma was that information was encoded in dna, transcribed in rna, and then translated into protein. This widely-held concept of unidirectional information transfer had a major influence on ideas about how tumour viruses conferred malignant properties on their host cells. dna-containing viruses, such as polyoma and the adenoviruses, were considered to integrate into cellular dna, much as dna of lysogenic phage enters the genome of its bacterial host. The viral dna then provided the genetic information for the malignant phenotype. This model would not work for rnacontaining tumour viruses, such as the leukemia viruses. For these, the unidirectional information transfer model required that the viruses persist in the cytoplasm of the malignant cells and there supply the information needed for malignant growth. While, indeed, rna virus particles could sometimes be isolated from malignant cells known to be of viral origin, often the search for virus was not successful. These failures were excused by blaming inadequate methods that were not sensitive enough to isolate virus, which, in theory, should be present. Dogma often generates disbelief. Howard Temin, a professor at Wisconsin, was the most prominent opponent of the view that rna viruses had to survive in the cytoplasm. He and David Baltimore demonstrated, in preparations of purified virus particles, an enzyme that was capable of transcribing rna into dna. The discovery of this enzyme, appropriately called reverse transcriptase, made the unidirectional model untenable. Today, reverse transcription is part of the dogma; the enzyme is essential for many of the basic procedures in molecular biology and genetic engineering. Mak took advantage of the discovery of reverse transcriptase. His goal was to prove that human leukemias were caused by virus. Mak, rather than looking for particles, measured reverse transcriptase in human leukemic cells in culture. He obtained positive results, but infectious virus was never identified. In retrospect it may be that Mak was isolating telomerase; this rna-dependent enzyme is highly expressed in

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malignant cells. Regardless, the work cemented Mak’s membership in the leukemia program. He was excited as he explained the genetic structure of tumour viruses, and introduced concepts such as “long terminal repeats” and, of course, oncogenes. His abilities and intellect were obvious. Two years after he joined as a post-doc, Till appointed him as a senior scientist in the Division of Biological Research. For the oci in the mid-to-late 1970s the leukemia program was an example of a working collaboration, bringing together clinical and laboratory scientists.

the program in marrow transplantation The early work on hematopoiesis had depended on the transplantation of marrow cells into recipients whose marrow had been destroyed by radiation. Human marrow requires cell proliferation for its function. It can be damaged by radiation and certain chemicals, including a commonly-used antibiotic, chloramphenicol. Sometimes marrow fails for no obvious reason. The two commonest cancer treatments, radiation and chemotherapy, both damage marrow. Blood diseases, such as leukemia, are often fatal because marrow function failed. It was obvious that human marrow transplantation would be useful in many clinical settings. The animal work had defined the two major problems that needed to be solved for transplantation to work in man. First, a recipient recognizes cells from an unrelated donor as foreign and rejects them by an immunological reaction. Much information about the mechanism of graft rejection has come from studies using in-bred mice. Transplants between mice of the same strain are successful, since geneticallyidentical cells are not seen as foreign. The results of transplants between mice of different strains led to the identification of genes that were responsible for the rejection of foreign cells; these were called histocompatability genes. Since the products of histocompatability genes were proteins, they were antigens that could be recognized by antibody preparations of suitable specificity. In humans there is a single genetic histocompatability locus, mapped to chromosome 6. Since the locus is quite stable, it is found once in each chromosome 6; often a different form of the locus (allele) is present. Since each individual has two histocompatability alleles, members of a family may share four, two from each parent. Antisera recognizing most human histocompatability antigens are available, usually from blood transfusion recipients. These can be used to compare the histocompatability loci in different individuals

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when seeking a suitable donor. A brother or sister is usually chosen since a good match will be found in about 25 percent of the children in a family. Even when there is a good match, subtle differences will remain. Only when donor and recipient are identical twins will graft acceptance by complete, as it is in inbred mice. It remains necessary, therefore, to prepare human recipients for transplantation by whole body radiation, often combined with chemotherapeutic agents. With such selection and preparation, successful engraftment is usually achieved. The second major problem in marrow transplantation is not found when other organs, such as kidney, are engrafted. A marrow graft contains not only the stem cells of the myeloid lineages but also lymphoid cells and their precursors. As these cells begin to function in their new host, they recognize the environment as foreign and react against it. The result is a serious clinical condition known as graft-vshost disease or gvhd. Its manifestations include skin rashes, kidney and liver damage. In its severe forms gvhd is fatal. Like successful engraftment, gvhd is a function of the histocompatability differences between host and donor. The use of brothers or sisters as donors reduces the incidence and severity of gvhd. Miller and Phillips, still working closely with the hematopoiesis program, were then concentrating their efforts on the cellular biology of the cells responsible for immune responses. These had been identified in cell culture and characterized by cell separation procedures. The staput apparatus, described earlier, was very useful in the work. What the separation experiments showed was that the cells responsible for the immune response had a slightly different size from the stem cells needed for engraftment. The practical use of this information was seen at once. It should be possible to harvest marrow cells from a donor, and, prior to the intravenous injection into the prepared host, use a staput to remove the lymphoid precursor cells. Then the recipient would not receive cells that would react immunologically against their host. gvhd would be avoided and marrow transplantation would be much safer. This simple idea required much further thought and development before a clinical experiment could be undertaken. A large staput had to be constructed and adequate marrow samples were needed to test the apparatus. Culture assays were required to insure that the expected separation was achieved. On the clinical side, physicians had to undertake to select suitable patients for transplantation and to develop proper protocols for their preparation. Resources of people and space were needed for the extensive special care that would be required during the time before transplanted marrow could recover sufficiently to protect the new host from infection and bleeding.

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The excitement of the idea carried the group past every difficulty. Indeed, uncharacteristically, the plan was described publically. Presentations were made, usually as part of the National Cancer Institute’s annual fund raising.* In a few months everything was in place to treat patients with leukemia with matched marrow transplants from brother or sister donors. Three such experimental transplants were undertaken in patients with leukemia. None were successful; although grafts were obtained, the patients had serious gvhd and did not have transplantinduced remissions. Later, many other groups attempted to remove cells responsible for gvhd from marrow prior to engraftment. With sensitive antibody-based methods, some success was achieved in reducing gvhd. Unfortunately, for patients with leukemia, the improved survival obtained was balanced by increased relapse of disease. This experience was a major reason for postulating that allogeneic marrow grafts have immunologically-based anti-leukemic effects, referred to as graft-versus-leukemia or gvl. When the clinical marrow transplant experiments were the excitement of 1972, Hans Messner was a Ph.D student in McCulloch’s lab. Messner was a German medical doctor, who had met McCulloch at a small hematopoiesis meeting in Freiburg and soon after joined the group in Toronto. His thesis work was a useful part of the ongoing studies of granulopoietic cells in culture that was then McCulloch’s major research emphasis. It was the transplant problem that caught Messner’s interest. When he finished his Ph.D in 1974, he determined to make marrow transplantation his major work. The oci encouraged him in this direction and in 1976, after completing his clinical training, he was appointed to the medical staff. His task was to start a clinical marrow transplant program and conduct the relevant research. It was expected that his laboratory would both support transplantation and bring new insights into the mechanisms determining the success or failure of transplants. The early attempts to attack the marrow transplant problem by Darte and McCulloch were based on the mouse experience in the hematopoiesis program. When they were not immediately successful, there was no determination to continue. The subsequent initiative, headed by Miller and Phillips, was based on the hypothesis that gvhd could be prevented by removing lymphoid cells from marrow. When the first attempts failed, the hypothesis was rejected and the program abandoned. These sharply focused attacks, dropped if not successful,

** One presentation was made at the Avon Theatre in Stratford, Ontario. The participants would later boast that “they had trod the boards at Stratford.”

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were characteristic of the early oci research style. Perhaps because the institute was small it was not thought appropriate to spend resources on projects that were not promising from the beginning. Messner was able to mount a systematic and dedicated program. Over time, he was able to improve greatly on the clonogenic assays for human stem cells. He discovered culture conditions that allowed the growth of clones that contained all of the three cell types characteristic of myelopoiesis. While the cell of origin of Messner’s multilineage colonies may not have been as primitive as the mouse cell giving rise to spleen colonies, it was a useful surrogate for assessing the capacity of marrow to be grafted into a new host. The value of marrow transplantation became generally understood, particularly among doctors specializing in blood disorders (hematologists). They understood that the hospital requirements for transplant programs were large, because of the need to support patients for the interval between the infusion of marrow and production of functional cells from the graft. Many considered that only a small number of transplant centres would be required to meet Canadian needs. The Canadian Hematological Society undertook to study the issue. Because of Messner’s program and its strength in experimental hematology, the oci played a prominent role in the study. McCulloch chaired the study committee; Messner was a member. A prominent advisory group of established transplantation experts was selected to provide advice. The committee prepared a detailed inventory of the people and facilities required for a transplant program. On this basis, health centres across the country were invited to submit proposals. When these were received, site visits were conducted by members of the advisory body. Following a general discussion meeting in Ottawa, a report was prepared, recommending the establishment of three regional transplant centres. One of these was to be at the oci. Not surprisingly, the committee’s recommendation for a small number of centres was not accepted. The high profile and prestige associated with marrow transplantation dictated that many hospitals and health science centres would establish marrow transplant units. Nonetheless, the leadership from the oci was evident and its standing in the national community increased. The oci transplant unit continued to be one of the best in the world as judged by comparison of results in an international transplant registry. Institutional support no doubt helped, but the principal engine for progress was the energy and dedication of Hans Messner. He obtained funding for marrow transplantation from the Ontario Ministry of Health independent of the bloc grant to the Princess Margaret Hospital. This protected the transplant service from the budget stresses that were then, and are now, felt in health care delivery.

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impact The prominent interdisciplinary programs provided tangible evidence of the commitment of the oci to the application of research to patient care. The two programs evolved differently with time. The leukemia program was always a clinical research enterprise. Its goal was to understand disease mechanisms, and, when feasible, test models in treatment protocols. The transplant program was a clinical service, supported by laboratory research. The culture studies in Messner’s own laboratory not only supported transplantation but enhanced understanding of blood formation. A major research output of the program was its careful documentation of clinical results. This information provided a sound basis for improving methods and extending the indications for marrow transplantation.

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The Style of Ray Bush as Director

John Darte was director for only six months before his sudden death. It is remarkable that in that short time, his personality made a lasting mark, particularly because of his intent to move the institute further toward the centre of cancer care delivery. Ray Bush succeeded him in 1976 and was director of the oci for twelve, often turbulent years.

leaders change John Law had retired as administrator in 1974 and was succeeded by his assistant, Garth Hayley. John Law’s influence had established the office of administrator as a close collaborator, almost an equal, with the director. Bush did nothing to change this useful arrangement. Hayley had learned his job from a master, and continued to act as a wise facilitator. Bush could concern himself with the major challenges facing the oci with the assurance that its day-to-day activities were in good order. When Hayley retired in 1980, Bush appointed Joanne Ratz, who had been Hayley’s assistant. She provided him with continuity, although her personality sometimes made her relationships with the other staff more tense than before, particularly in times when the whole institute was under pressure. Harold Johns retired as head of Physics in 1980. Gordon Whitmore was an obvious candidate to succeed him, and Bush made the appointment. At the time, Whitmore was head of the university Department of Medical Biophysics, but a year later, in 1981, his ten years as chairman came to an end. Whitmore was succeeded as University chair

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by Robert Phillips. These changes had major impacts on the oci and Ray Bush’s directorship. Gordon Whitmore, though trained by Johns, was very different from his predecessor. Where Johns was a catalyst for change, Whitmore was conservative. He approved of the way things were in the Physics Division and the oci. He was eager to continue the success of both, but preferred that the usual fashion persist. Joanne Ratz did not have the confidence of the medical or scientific staff to the same extent as John Law or Garth Hayley. Both the changes in the leadership of the Physics Division and the administrator made Ray Bush a much more visible and directly influential director than Cliff Ash. Bush inherited a committee system as a management tool. Most oci functions had advisory committees which met periodically, but only the medical advisory committee (mac) was very influential. Consisting of the clinical chiefs and other medical staff members, it had an elected chairman. Its job was to insure standards of medical care through regulating important facets such as record keeping and management protocols. There was no comparable body for research until, in the mid 1980s, the board established a research advisory committee (rac). Bush struck a new committee that he hoped would bring his senior staff into the decision-making process and insure their support for his main policy directions. He chaired the director’s executive committee (dec). Its members came from administration and the medical and scientific staff. Joanne Ratz and the chief financial officer, Eva Govoni, were the administrative members. The medical staff was represented by the two clinical chiefs and the chairman of mac. Both research heads were members. Finally, Pat Holder, the chief of nursing was at the table, bringing the perspective of her important contribution to patient care. Others came when their particular knowledge was needed. Regular meetings, often weekly, were formal and minuted. Votes were rarely taken, and final policy decisions were those of the director.

the research divisions Ray Bush maintained a direct interest in the work of the research divisions; he also encouraged the interface programs. For example, in support of the marrow transplant program, he, together with Bergsagel, started a new microbiology laboratory, headed by Peter Tuffnel. This improved service was needed because transplant patients often had lifethreatening infections, many of these caused by bacteria, fungi, or viruses that would not be dangerous to individuals with a functioning immunological system. Research gained new space on the west ends of fifth, sixth, and seventh floors. The fifth floor space in the Department

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Ray Bush, the third director of the oci.

of Medicine provided laboratories for clinical scientists. New isolation rooms were used to protect marrow transplant recipients in the dangerous period before the graft produced functional cells. A new and larger seminar room was included in the sixth floor space. The area to the south between the oci and the adjacent Wellesley Hospital was filled in, with a lunch room and medical staff offices on the fifth floor. Laboratories were added on the sixth and seventh floors for the research divisions. With these additions the heads of Biological Research and Physics expressed satisfaction with their facilities, in keeping with the dominant view that the research divisions were at nearly optimal size for effective interaction and collaboration. Harold Johns encouraged the growth of the physics program in medical imaging. His staff in this area sought active clinical associations, and considering their work to be an interface program. Jim Till continued to build Biological Research. Victor Ling’s steady progress in finding the genetic basis of drug resistance remained on ongoing and expanding part of the division. Till struggled to find enough space for Vic as his increasing reputation brought him students and postdoctoral fellows. Till’s appointments in 1974 were not only support for strength but also diversification. Tak Mak’s work on the molecular

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biology of rna tumour viruses added needed strength in molecular biology. In the same year, Till appointed Gerry Price, who, as a postdoctoral fellow, had been part of the leukemia program. His principal contribution was as a critic. He repeatedly challenged those developing the clonogenic assay for leukemic blasts to prove that the cells they were studying were not simply normal lymphocytes. As a senior scientist, he studied cell membranes, an area that Till considered to be both important and under-represented. Till knew that his division already had a considerable concentration in immunology, represented by Miller, Phillips, Gorcynski, and Michelle Letarte-Muirhead. Alastair Cunningham strengthened the program by giving added emphasis to antibody-producing b lymphocytes. Cunningham was personally affable, able to converse on many issues, and very concerned with interpersonal relations. In his previous experience in England, Australia, and New Zealand, he had enjoyed the custom of afternoon tea, as a pleasant occasion where often lively conversation led to novel experiments. He did his best to introduce the tea routine to the oci. Till supported his efforts; he even vacated the large office of the head of Biology, so that it could be used as a staff lounge and tea room. The tea ritual did not take root. The wide corridors with shared equipment, the frequent seminars, the student committee meetings, the atmosphere which encouraged challenges to ideas, provided the oci staff and students with quite sufficient means for stimulating intellectual interchange. Till moved back into his office. The immunology program was helped by the cell separation work begun earlier by Miller and Phillips. The technique of separating cells by flow cytometry was well established. The method could be used as an analytical tool to determine, for example, the distribution of certain proteins on the surfaces of lymphoid cells. These proteins were often markers of a stage in differentiation. Using the apparatus to isolate marked populations allowed a more complete biological characterization of differentiation. While progress was steady, it was also clear that an important technical and intellectual component was, at best, underrepresented. The immune system was the model of choice for studying the molecular basis of cell differentiation, and particularly the generation of diversity. This characteristic of immunologically-competent lymphocytes allows them to recognize many different antigens, including foreign cells and invading pathogens. To fix this gap in the program, Phillips recruited a well-trained molecular biologist, Nobuo Hozumi. In 1978 Till appointed him to the staff in Biological Research. Phillips encouraging Hozumi to collaborate not only with immunologists but with the other scientists. This enterprise, though useful, had

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Ronnie Buick, first a post-doc, then a senior scientist, and finally the first vice president for research.

only limited effects, hindered in part by Hozumi’s difficulty in communicating in English. In spite of his policy of building immunology, Till’s criterion for staff selection was predominantly excellence. He certainly recognized Ronnie Buick’s unique quality. After his time in the leukemia program, Buick went as a staff member to work with Sid Salmon at the University of Arizona. Salmon was making headlines because of his attempts to use clonogenic assays to individualize chemotherapy. Buick’s participation in the studies made him well known in major American clinical cancer research circles. Till and McCulloch, still working together, brought him back to the oci in 1978. He was appointed a senior scientist in Biological Research. For a time, Buick continued his work on human tumours, but he realized its limitations. Solid tumours, unlike leukemia, did not easily yield cell suspensions that could be manipulated and cultured. From his cancer cell culture experiments he selected his personal research theme, the molecular biology of breast cancer. This he tackled with energy and success. His science was only a part of Ronnie Buick’s great reputation at the oci. His humor, capacity for friendship, his good sense and even judgment made him a

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colleague to be admired and copied. It was to be important for the future that, among his contempories, Tak Mak was already a good friend.

controversy Ray Bush presided as director at a time when the oci flourished, grew, and achieved an international reputation as a major cancer centre. There were, however controversies that were sufficiently important to disturb the atmosphere, although none was serious enough to threaten the unity and productivity of the oci. Jim Till had achieved great success in building the Biology Division he had inherited from Siminovitch. By the late 1970s a new generation of stars was succeeding the scientists who had established the institutional identity in tumour virology, radiation biology, immunology, and stem cell studies. Four young men had the personal authority that clearly marked them for success. Victor Ling had already demonstrated both innovation and persistence in his work on multi-drug resistance. Alan Bernstein quickly showed his strength in his Friend virus-induced leukemia studies. Tak Mak added depth in the area of molecular biology. He was particularly able to transfer to his colleagues, not only new knowledge about genetic organization, but also real enthusiasm. Ronnie Buick was opening new avenues of cell biology that also made full use of molecular methods. Both Bernstein and Mak worked on leukemia viruses, so it was natural that some degree of collaboration would develop. Yet the often strong personalities of the collaborators may come into conflict. This happened with Bernstein and Mak. Issues such as credit for discovery and style in graduate supervision were certainly involved. Till did not succeed in resolving the dispute. It continued for years, long after the Sherbourne Street days were over. Both Bernstein and Mak had very successful personal careers;* it remains a question whether their long antagonism influenced their achievements. The Bernstein-Mak quarrel was a rough spot in the fabric of Biological Research. A second controversy was much more important to the institute as a whole. When Cliff Ash was director, he was also head of the Department of Radiation Oncology. This arrangement was fitting

** Mak’s success earned him many awards, including election to the Royal Society of London and a foreign associate of the National Academy of Science of the United States. His foundation and leadership of the amgen Institute will be described later. Bernstein succeeded Siminovitch as head of the Lunenfeld Institute at Mount Sinai Hospital. He later became the first chairman of the Canadian Institutes for Health Research, the expanded successor to the mrc.

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Bill Rider, an influential radiation oncologist, was effectively head of the department from the retirement of Cliff Ash until the arrival of Bill Duncan.

at the time, since, at its foundation, treatment of cancer with radiation was the oci’s dominant focus. Ray Bush had a broader concept of the oci. He saw the institute he directed as a comprehensive cancer centre, with responsibility for all aspects of cancer treatment, research, and education. His own role, therefore, was to give leadership to all these activities. Under Ash, certain individuals had been recognized as clinical departmental heads; Bergsagel in Medicine was an example. Unlike the research division heads, clinical chiefs were not recognized as such in official documents, such as the annual report. Bush began to change this, and titles were included in the report for 1984. Before that, and officially then, the head of Radiation Oncology was not Ray Bush but William Rider. He was an energetic but idiosyncratic man, with his own view about his specialty. His leadership was both permissive and supportive. Rider retired early in 1985. Bush decided that he should be replaced as head of Radiation Oncology by a new senior appointment. An extensive search identified William Duncan as the best candidate. He was then head of Radiation Oncology in Edinburgh, Scotland, where he had established a reputation not only in clinical practice but also in radiobiological research. Duncan accepted the appointment and

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William Duncan, who became head of Radiation Oncology on the retirement of Bill Rider.

joined the oci in 1985. He fitted well a Canadian image of an English consultant. Always well-dressed, he carried an air of authority. He quickly established his high position in radiation oncology, although he did not continue an active personal research program. Duncan let it be known that his major reason for coming to Toronto was his admiration for Ray Bush and the anticipation of a productive working relationship with him. Sadly, it proved that Duncan and Bush were incompatible. Their differences were at least two levels: first, and perhaps most important, they did not agree on the role of radiation oncology in cancer care. Bush was considered that each patient should have the advantage of careful planning that would lead to surgery, radiation, or chemotherapy, alone or in combination, as the experts in each field recommended. Duncan, in contrast, saw radiation oncology as a stand-alone discipline. Cooperation with others was not impossible, but, for patients whose treatment was to be radiation, the control was to be firmly in his hands or those his colleagues in the department. At a second, more day-to-day level, the two men differed markedly in leadership style. Bush had his attention fixed on his long-term vision for cancer treatment in Ontario, and the role of the oci in this larger task. He dealt with other issues, more specific to the management of

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the oci, as problems arose. He delegated responsibility to those he had appointed to leadership roles, and was content to comment on their reports and make suggestions as these seemed to him to be useful. Duncan’s approach was centred on the oci and particularly on radiation oncology. He wanted specific planning and performance objectives, with defined time horizons. He had little patience with Bush’s more free-wheeling style. The conflict was soon common knowledge. Unfortunately, some polarization occurred, particularly as Duncan had strong support from his colleagues in radiation oncology, while Bush had more diffuse help from staff in medicine and research. The struggle between the two made the day-to-day management of the institute more difficult. A greater negative impact was that the differences between the two men hindered planning for the future.

the last head of biological research Jim Till was appointed as head of Biological Research by Cliff Ash and enjoyed the respect and support of both subsequent directors. As his time in office lengthened, his level of comfort seemed to decrease, perhaps because his own research interests were not widely shared in the division. He was ready for a new challenge. This came as an offer from John Leyerle, the dean of the Graduate School (sgs) at the university. At the time, Till’s long-time collaborator, Ernest McCulloch, was the assistant dean at sgs. Leyerle sent McCulloch to offer Till the post of associate dean for the division in the school that administered the graduate programs in the life sciences. So it happened that the two old friends met in the office of the head of Biological Research to talk about Till’s future, and, as a corollary, the future of the division. Leyerle’s graduate school was an exciting place, driven by his own personality and his determination to raise standards. He had six professors in decanal positions, four as associate dean with sectoral responsibilities and two, the assistant dean and the vice dean, with central responsibilities. The seven deans met weekly; their discussions ranged beyond sgs concerns to university policies and the support for research. This is the milieu that gave rise to the Canadian Institute for Advanced Research, the pioneer of the concept of an institute without walls. The reputation of the sgs deans was such that members of the university outside the graduate school sought support for their own initiatives by making presentations at the weekly deans’ meetings. McCulloch presented this picture to Till, persuading him to discuss the appointment further with Leyerle. In a few days Till had accepted Leyerle’s offer and resigned as head of Biological Research. For a short

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time the two discoverers of spleen colonies served together as graduate deans. McCulloch’s three-year term came to an end soon after Till joined. He did not accept renewal, fearing that a prolonged diversion from his research would be disadvantageous to the work and his own professional career. In contrast to the director-decided way which had been used for the appointments of previous research division directors, Bush established a formal committee to search for Jim Till’s successor. The search committee was chaired by Mr Stevens, the chairman of the oci board, and had a membership widely representative of the oci. Throughout the spring and summer of 1982 the committee interviewed candidates. The process took some time, indicating that the decision was not automatic. Eventually, the post was offered to McCulloch. The offer itself was a break from oci tradition, but more in keeping with university practice. The appointment was for a term of five years, renewable after review. In practice, Bush never conducted a review. McCulloch remained in office until the division itself disappeared in a reorganization of oci research. When he accepted the job, McCulloch did not know that he was to be the last head of Biological Research. In the previous decade, McCulloch’s connection to Biological Research had been through the leukemia program. His major appointment continued in Medicine and he was shown on the biology mast head as a senior research associate. His administrative role at the university led him to believe that some university practices might beneficially be adopted by the oci. For example, he set up a small executive committee, with members chosen for their importance to the research objectives of the division. This committee allowed him to develop priorities that would be widely accepted and understood. His first objective was to strengthen molecular biology in the division, and particularly the regulation of gene expression. He also planned to increase the divisional presence in biostatistics. Till had appointed a statistician, Antonio Chiampi, in his program in assessing quality of life in clinical trials. McCulloch saw statistical research as a significant way in which the division could help clinical investigation and interface programs. It was possible to implement these priorities because there were a number of resignations. Cliff Stanners and Gerry Price both resigned in 1983, to accept positions at McGill. For Stanners, the opportunity to be a leading member of an excellent biochemistry department was not to be declined. He remained a steady oci friend. Price was recruited by McGill because he had mastered the technique of cell separation by flow cytometry. At the time, this method was just being generally accepted as important in all aspects of cell biology. Price went to Montreal to manage a flow cytometry laboratory.

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Two years later Lou Siminovitch accepted the task of building a research institute at Mount Sinai Hospital. No one was surprised when he looked to the oci for the scientists he needed. Alan Bernstein was his prime recruit. Alan saw in the new research institute an improved chance to advance his career. Indeed, when Siminovitch retired as head, Bernstein succeeded him. Lou’s second recruit was Nobuo Hozumi. Hozumi’s reason for moving was to enjoy a research environment which was not tightly focused on a single disease. He correctly saw that neurobiology was a promising field and one that was not likely to be fostered at an institute devoted to cancer. The Hospital for Sick Children was also successful in seeking recruits from the oci. Bob Phillips accepted a senior research position, where he was in an improved position to collaborate with Brenda Gallie on the problem of retinoblastoma. Phillips’s departure created a special problem, for, at the time, he was chairman of Medical Biophysics. He considered that he had the right to take the chair with him. In contrast, many at the oci considered that the department and its leadership must remain at the institute where it had started. This view prevailed; Philips resigned the chair and was replaced by Peter Ottensmeyer of the Physics Division. Later, Ciampi left to join the biostatistics department at McGill. The last departure was Reg Gorcynski, who left in 1989 to become a medical student. Ernest McCulloch’s university experience influenced his recruitment process. Rather than himself selecting those to be appointed, the positions were advertised. The executive committee also acted as a search committee. When a potential candidate was identified, the individual was invited to visit the oci and present a seminar. Care was exercised to insure that each candidate met as many staff as possible. McCulloch was determined that no one would be appointed if there was a substantial objection. He reasoned that success depended on collaboration and the goodwill of colleagues. The recruitment process meant that new appointments were made slowly. The delay was worthwhile, since careful consideration of each candidate lessened the chance of failure. Among the first recruits were three young molecular biologists. Sam Benchimol came warmly recommended by Andy Becker, his Ph.D supervisor. Sam had completed a post-doctoral in London, England where he had studied the oncogene p53. This was the first of a class of negative oncogenes who function by interrupting normal growth processes. Richard Gronostajski and Neil Miyamoto both had developed systems for studying gene expression. Together these new members of the division signalled the importance attached to molecular biology. Ray Bush added more research statisticians to the division, the new appointments being made jointly to Biological Research and the hospital Department of Biostatistics, with the salary split between the two.

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David Tritchler and Sal Minkin both joined under these rules. Minkin was interested in developing new ways to analyse survival curves and other measurements of importance to the leukemia program. His analysis was almost always required before data could be published. He also prepared useful computer programs that allowed investigators to calculate the parameters of survival curves and estimate the significance of comparisons between such curves. David Tritchler was useful in the decision-making studies that Till had initiated. These research programs was reinforced by the appointment of Hilary LlewellynThomas. Originally trained as a nurse, she had earned a Ph.D in the Institute of Medical Science with Jim Till as her supervisor. With this background she found a stimulating environment at the oci and made a worthwhile contribution to the work. McCulloch’s final appointments were more senior. Both came from the Basel Institute of Immunology, an important research centre, founded by Niels Jerne. Norman Iscove, once McCulloch’s Ph.D student, continued to work on hematopoiesis in Basel. Iscove had an interest in returning to Toronto and the formal recruiting process found him to be highly acceptable. After much delay, he finally accepted an appointment to the division and with the rank of full professor in Medical Biophysics. Iscove suggested strongly that one of his Basel colleagues should also come to Toronto. Chris Paige was an American, with his graduate degree from Sloan Kettering in New York. His interest was in lymphopoietic differentiation, with particular emphasis on measurements of the precursors of the b-lymphocyte, antibody-producing lineage. Chris joined soon after Norman. His university appointment was an associate professor in Medical Biophysics; he soon gained promotion to full professor. Chris continued his collaboration with Norman Iscove. Together they began to look for the mechanisms by which bipotential progenitors enter into one, but not the other lineage.

the t-cell receptor Early in 1983 an excited Tak Mak came into McCulloch’s office, announcing that he had found the holy grail of immunology. He had isolated a gene encoding the antigen receptor on t-lymphocytes. t cells are responsible for those immunological functions not mediated by antibodies, including reaction to viruses and cells considered to be foreign. The molecular basis for antibody production in b-lymphocytes was well known at the time. Genes encoding the heavy and light chains of immunoglobulin are encoded in dna; these chains have variable and constant regions. During transcription into rna the genes for immunoglobulin chains are spliced differently so that diversity is generated.

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135 The Style of Ray Bush as Director

The processed rna is a template from which immunoglobulin cell surface receptors are made. A potential antigen will bind to a surface receptor with a complementary structure. The lymphocyte with bound antigen proliferates, forming a clone whose cells make immunoglobulin with the proper structure to bind to the simulating antigen. Such immunoglobulins are then identified as antibodies. Similar information was not then available for t-lymphocytes. Extensive searches for an analogue to the immunoglobulin receptor were not successful. Lacking a t-cell receptor, it was not possible to understand t-cell regulation or recognize changes in t-cells in disease. Such information is important for t-cell malignancies or diseases where an individuals’s own tissues are recognized as foreign by the immune system. An immune reaction against “self,” called autoimmunity, has been implicated in many diseases, such as rheumatoid arthritis and other disorders of the body’s connective tissue. The search for a t-cell receptor was a high priority in immunological research, since closing the gap in understanding t-cell function might open to the door to prevention or treatment. This is why, when Tak Mak was successful, he called the t-cell receptor the holy grail of immunology. The discovery of the t-cell receptor did not happen without preparation. Mak decided to tackle the problem because new methods were being developed for detecting gene activity, distinguishing genes that were being transcribed from those that were inactive. It became possible to compare gene activity in two different cell populations. The method was called subtraction since dna complementary to rna from one cell population was mixed with rna from the other. Messages active in both cell types bound to each other. The bound complexes could then be separated from unbound messages. These were considered to be the products of genes active in one cell type but not the other. Mak reasoned that if he compared b-lymphocyte cell lines with t cells, he could identify messages from the t-cell receptor since the t-cell receptor genes would not be active in b cells. The subtraction method had many difficulties. Often messages would be detected but their origin not identified. When Mak proposed his experiment to a review team from the National Cancer Institute of Canada, he met the scepticism common to those considering applications that depended on subtraction. In fact, the proposed experiment was not approved. Fortunately, oci scientists did not think nci(c) reviewers to be infallible. Mak worked hard at making his experiment succeed. He was able to identify the t-cell receptor message because of its marked homology to immunoglobulin, solving the problem of identifying relevant genes. Failure to make an association was the reason that many applications of the subtraction technique were not fruitful.

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By coincidence, another nci(c) site visit took place shortly after Mak had announced his finding; urged on by McCulloch, Mak made a description of his finding the opening and key part of his presentation to the panel.* There was an immediate sensation, because the immunologists in the visiting group saw the importance of the discovery. It is probable that no other way of announcing the finding would have had such an immediate and widespread response. Important discoveries are often simultaneously made in two different laboratories. Using subtraction, Mark Davis of Stanford University also found the mouse t-cell receptor. Mak and Davis responded to their success in different ways. Davis held his clone closely in his own laboratory, so that he might have the advantage of exploiting it before it was available to others. Tak, in contrast, made his clone widely available. Soon it was clear that Mak’s strategy was effective and his fame spread rapidly. While most were careful to give Davis equal priority, Mak saw his career skyrocket almost as soon as his discovery was reported. The t-cell receptor discovery showed how the oci had matured. For the first time, a press conference was held to announce the finding. Responses were received from across the globe. Tak and his senior colleagues had to man telephones to reply to both press and to other scientists. The oci had long been well recognized by scientists for its excellence in research. The t-cell receptor discovery made its reputation public. Success in research almost always is disturbing to administrators. Tak was no exception. He asked for more resource of space and money. Bush met with dec, reinforced by Charles Hollenberg,† to discuss a response. Urged by McCulloch and Hollenberg, it was decided that everything possible should be mobilized to meet Mak’s legitimate claims. The major problem was space, for biological research was already cramped. Others, especially Vic Ling, had proper demands for expansion. An attractive proposal came from Yale University but after consideration, Tak Mak decided to stay at the oci. He was to be a powerhouse for progress in the future.

** Y. Yanagi, Y. Yoshikai, K. Leggat, S. Clark, I. Aleksander, and T. Mak, “A human t cell-specific cdna clone encodes a protein with extensive homogy to immunoglobulin chains,” Nature 308 (1984), pp. 145–9. *† Charles Hollenberg had made a formidable reputation for himself during his ten years as chairman of the university Department of Medicine. At the time of Mak’s discovery he was vice-provost for Health Sciences. Later he was to become chairman and ceo of the Ontario Cancer Treatment and Research Foundation.

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137 The Style of Ray Bush as Director

psycho-social support Ray Bush provided a solution to a problem McCulloch faced early in his term as head of Biological Research. Jim Till had hired Alastair Cunningham to add strength in b-lymphocyte biology to the immunology programs. His work on b cells at the oci was not remarkable; it seemed he had lost interest. In fact, he was attracted to the concept of mind-body relations. He soon found that there was a literature suggesting that mental activity might affect the progress of cancer. With Till’s agreement, Cunningham closed his laboratory and took a prolonged sabbatical to study for a Ph.D in psychology at York University. As the research component of his program, he developed an experimental design for comparing psychological interventions among groups of patients. His protocol was to assign patients either to a very structured psychological help program or a waiting list. While on the waiting list, patients received only group support of a general nature. Cunningham had constructed a psychological program that he hoped would be effective at least in improving quality of life and perhaps in prolonging survival. The patients were instructed by Cunningham in several different mental exercises, designed to improve self-image, strengthen their own control over their feelings and even to visualize the tumour with the hope of inhibiting its growth. Patients in the active group or the waiting list control were evaluated for quality of life, using standardized questionnaires. When McCulloch took office, Cunningham had successfully defended his thesis. He had completed an experiment where a waiting list control had been compared to a group receiving his intervention. In both groups the quality of life had improved, but the change was significantly greater in the active treatment group. In discussion with McCulloch, it was clear that each saw the priorities differently. McCulloch, with a background in clinical trials of leukemia, did not find the difference between the control and intervention groups sufficiently impressive to move on. Rather he thought the experiment should be repeated and efforts made to find out which components of the intervention protocol were contributing to any improvement observed. Cunningham considered that his intervention method had been proven to be effective. He resisted any suggestion that its components should be changed, since an alteration might reduce its power. For Cunningham, the priority was to apply his method to as large a cohort of cancer patients as possible, in order to test the hypothesis that the psychological manœuvre might improve survival. McCulloch insisted that Cunningham accept patients into his trial only if they were referred by their own physician on the oci clinical staff. In practice, only a small proportion

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of the possible subjects agreed to enter the program, which was demanding both of time and concentration. These attributes are not always in great supply in patients suffering from cancer. McCulloch’s opinion was that Cunningham’s protocol did not have enough research rigour. He dreaded the thought of having to defend the studies in front of a critical review team. McCulloch used the methods he had learned at university to register disapproval. He restricted Cunningham’s annual salary increase as much as possible, and the letter informing him of the salary decision included a statement for the reason behind it. The situation was changed by an unhappy event. Cunningham developed cancer. Surgical treatment, while giving hope of a cure, could provide no assurance and Alistair was unable to tolerate the prescribed adjuvant chemotherapy. He decided to attempt his own method. A course on mind-body relationship was then being offered on the west coast. Cunningham was granted a year’s leave to take this instruction. Fortunately his disease did not recur and he was able to continue his work, fortified in his conviction by his own experience. At this point, Ray Bush made his contribution. Recognizing McCulloch’s unease, he set Cunningham up with space in one the oci buildings and sufficient help to man his patient groups. Ray argued correctly that some patients would benefit from group therapy and that the oci should supply it. Cunningham’s work could be seen properly in that context while not eliminating the possibility that there might be benefit beyond the psychological support provided. The program persisted even after the oci moved to University Avenue. There it still provides assistance to those patients who feel that the group sessions will be useful to them. There was more conventional psychological support at the oci. Michel Silberfeld, a psychiatrist and a member of the consultant staff, was active both clinically and in biological research. Thereafter, the oci was never without qualified psychiatric help to manage the severe mental problems of patients, either arising from their responses to cancer or when illnesses developed unrelated to their malignant disease.

moving with the times Rapid change was the rule when Ray Bush was director, change affecting not only how radiation was delivered and the number of chemotherapeutic drugs available, but also in other areas outside medicine. Advances in research were happening with dramatic speed, especially in molecular biology. Imaging, a special research priority for physics, was adding new modalities, such as ultrasound and nuclear magnetic

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imaging. Advances not directly related to the institute’s mission were also rapid and important. Prominent among these was an increase in the use of computers. Bob Bruce had pioneered computers for medical record-keeping. The Physics Division responded by setting up a central computer, connected by cable to terminals in scientists’ offices. The staff in Biology also needed computers, especially for word processing. Terminals began to take the place of typewriters on the desks of secretaries. The whole method of writing papers, grant applications, and letters evolved, as it was quickly seen that word processing allowed ongoing evolution of manuscripts. When e-mail became available, it provided a new and powerful instrument for communication. The research biostatisticians often found the central system too slow for many of their calculations, nor could it be adapted easily to sophisticated statistics software packages. As their research proposals became accepted by nci site visit teams, they were able to use grant funds to obtain powerful stand-alone machines, such as Sun workstations. Thus, in the research divisions, several computer modes were in use, although the central facility with peripherals remained dominant. The clinical departments developed computer capabilities in parallel with those of research. There was a central hospital computer department. Most of the clinicians used stand-alone machines rather than peripherals. The clinical and research computer systems remain separate, a policy that was required to protect the confidentiality of the patient information on the hospital computers. Change was not restricted to technology. Social views were also on the move. Academic research in universities and practical research in for-profit companies were coming together. In the United States, university faculty often started biotechnology companies to commercialize their findings and to insure that useful knowledge was exploited in a way that helped patients. Tak Mak was well aware of this development and wanted to obtain patent-protection for his t-cell receptor clone. A foundation had been established by the University of Toronto for this purpose, with the mandate to help faculty obtain patents and to find business partners to bring the resulting product to market. The oci leadership considered this route, but found it cumbersome. A small oci patent committee was established with McCulloch in the chair, working closely with a patent lawyer, James Lake. Mak’s clone received protection and Vic Ling soon followed with patents for antibodies to p-glycoprotein, the cell membrane pump that protected cells against toxins, including chemotherapeutic drugs. These patents became profitable by reaching licence agreements with appropriate companies. In the case of the t-cell receptor, a special company was formed. Monies from licences were used in several ways, part went

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directly to the inventor, while both the institute and the research division also had a share. These funds were, of course, useful; perhaps more important, oci scientists saw that they had acceptable routes to seek financial rewards for their efforts. Taken together, Ray Bush could be confident that, under his direction, the oci could recognize change and adapt to it without comprising its role as a cancer centre.

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Response to the Crisis of Space and Equipment

In 1983 the Ontario Cancer Institute celebrated its twenty-fifth birthday. The public was invited to an open house, where both clinical and research accomplishments were displayed. A club was formed for the members of the staff who had been active for the first quarter century. The leaders, especially the director, were well aware that in spite of the euphoria there was a very real problem. When the institute was first planned, it was expected that about three thousand new cancer patients would be seen each year. This number was soon exceeded, by 1983 the number was 6,555. The problem was not only numbers. The indications for radiation therapy had been extended to more kinds of cancer. The methods of administering radiation were becoming more complex as linear accelerators began to be used much more extensively. Bergsagel and his medical colleagues were seeing patients that needed chemotherapy, and the concept of combining chemotherapy with radiation was increasingly accepted. Breast cancer provides an example of the changes in practice that were having a major impact on oci facilities and staff. Rather than a major reliance on radical surgery for treating breast cancer, much less destructive operations were becoming common which were effective when combined with local radiation. Clinical trials showed that the addition of chemotherapy was beneficial. The result was a treatment that was more easily tolerated, did less damage to normal tissues and, if the disease was not too advanced, gave patients at least a 50 percent chance of long-term survival. But the reduced emphasis on surgery and the greater requirement for radiation and chemotherapy helped to increase the load on the oci.

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Since the incidence of cancer is a function of population size and age structure, both demographic factors contribute powerfully to the growing number of patients. Other factors are also influential, including improved diagnosis and better medical services for people whose expectations from the health care system are also more pressing. Only a single known factor acts in the opposite direction, towards decreasing the burden of cancer. The important role of smoking as a causative factor not only for lung cancer but malignant growth in many other sites provides the basis for a preventative strategy. As with other obvious ideas, it has proved much easier to recommend stopping smoking than to achieve it. Some progress has been made; fewer males smoke, a change that has decreased lung cancer incidence in men. Sadly, women, and particularly young women, continue to smoke; for them lung cancer is increasing. The demands for service were placing a major load on equipment, especially with the move to replace Cobalt 60 machines with more powerful linear accelerators. The clinical and support staff were stressed by patient load, greatly exceeding that for which the facilities were designed. The research divisions were not as stressed as the clinical services, since the scientists had some opportunity to match their efforts to their resources. Success in research, nonetheless, brought demands for more space. Bit by bit the need for laboratories encroached on every corner. Even some washroom areas were converted to dark rooms. All the professional disciplines, clinical and research, faced the common problem of recruiting excellent staff into inadequate facilities. Bush and his staff spent much time and showed ingenuity in finding space, not only for more patients but also for more intensive treatment. Fortunately, John Law had the foresight and resources to acquire most of the land and surrounding buildings. It was possible to move many important administrative functions out of the hospital into adjoining buildings. Patient comfort was facilitated greatly by the Princess Margaret Lodge. This building, a small hotel-like facility, provided comfortable quarters for out-of-town patients receiving therapy but not needing admission to hospital beds. The lodge was created and operated successfully in no small part because of the enthusiasm of Mrs Egmont Frankel, the leader of the volunteers. These women relieved the staff of some of their support functions. Buildings on the oci property were not entirely used for work. The ground floor of an old and elegant mansion on Wellesley Place was the site of parties and receptions, celebrating times like Christmas, or the achievements of staff members as these were recognized by national or international awards.

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a second role study The overcrowding was becoming intolerable. The response was a second role study, commissioned in 1984. In many ways, this undertaking was more ambitious than its 1972 predecessor. Two consultant firms, rmc (Resources Management Consultants) and Currie, Coopers and Lybrand, were engaged by the boards of the oci and the octrf. More than two hundred interviews were conducted and several seminars and interim reporting meetings were held. Two committees helped direct the work: a management committee with representatives of both boards and their staff; and a steering group responsible for day-to-day arrangements. An international advisory panel was established, with experts in oncology from the United States and Europe. The scope was wide-ranging, including not only the major medical disciplines but also nursing and dentistry. The oci staff were deeply involved with the consultants in the conduct of the work. Precise predictions could be made about the incidence of cancer and the facilities required for radiation therapy. Even beyond these secure numbers, ideas about how treatment would change and research would succeed gave the final report a sense of the vision of comprehensive and coordinated attacks on the cancer problem. The exercise, while often exhausting, brought the staff together and increased the feeling of common purpose. The final report was comprehensive; its recommendations many and detailed. There were two main thrusts: first, an excellent provincial cancer care program was in danger because of inadequate funding, and second, that the Ontario Cancer Treatment and Research Foundation and the Ontario Cancer Institute, both established by acts of the provincial legislature, should be merged to form an Ontario Cancer Agency (oca). The report noted that a major recommendation on the 1972 report had not been accepted. In 1982 the provincial government had stopped the planning for expansion of the oci. As a consequence the shortages of space and equipment had continued and become worse. A telling statistic was a comparison of the growth in Ontario population and the increase in cancer: 16 percent for the first, 37 percent for the second. The recommendation was for a five-to-seven year capital expansion program with a budget of $100 million together with a $50 million budget for new equipment, particularly modern radiation therapy machines and imaging devices. The report considered the space needs of the oci. Several possible solutions were suggested. In the short term, a new building was proposed to the north; in the long term, construction of an addition to the

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west that would double the size of the existing building. This expansion might occur in one or two stages. The more radical solution – a new building to meet all the requirements – was considered but not recommended. Yet the report stressed the deficiencies of the oci building, describing at as long and narrow, with many departments fragmented. The recommendation of a merger between the oci and the octrf was a reflection of Ray Bush’s firm opinion. The need for close consultation between surgical, medical, and radiation oncologists was described with examples of how patients would benefit. The report detailed how the proposed oca would be organized, and plans for research collaboration were provided. A detailed program of cancer prevention was included in the report, as an example of how the new structure would provide a more comprehensive cancer program for the province. During the role study there was some signs that the merger concept was not always welcomed. It is not surprising that management and staff of the octrf would be concerned by the difference between their dispersed model, with regional centres attached to host hospitals, and the vision of the oci as a research powerhouse and tertiary referral centre. Research was a sore point, since the octrf clinics saw the wellsupported and protected research divisions of the oci as privileged in comparison to their own units. These were often manned by investigators with time-limited octrf research appointments. In 1984, before the study, the octrf Sudbury clinic was founded. When it became operative, the oci ceased to man peripheral clinics. Patients previously served by these clinics then received their care from the Sudbury Centre and its outreach clinic. When the role study was begun, therefore, the practical links between the two institutions were not great, making a bridge more difficult to construct. The consultants’ enthusiasm for the benefits of merger prevailed, and it be came a major recommendation. The report included a detailed implementation plan. Its major feature was that the funding shortfall was the first priority. The planning for an oci/octrf merger should not start until the deficiencies at the oci and the foundation centres had been repaired. The report predicted that negotiations for a merger, if simultaneous with the rebuilding of the clinical and research facilities, would interfere with the latter and might well distract the provincial government.

a n e w oci/ pmh i s t o b e b u i l t The Ontario government accepted the recommendations of the role study, with an important change. In the 1972 report the consultants

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145 Response to the Crisis of Space and Equipment

had advised against major renovations at the oci site because these would disrupt delivery of care for more than ten years. To avoid the same result if the specific recommendations of the 1985 report were adopted, the decision was made to build a new oci and to provide additional funds for the octrf clinics. Two hundred million dollars was allocated to improve cancer care. Of this $133 million was for the rebuilding of the oci. The province expected that their $200 million would not be enough and mandated that an additional $50 million would be raised from the public. The announcement of government support for the rebuilding of the oci was greeted both with enthusiasm and relief, for it was obvious that without such a program the institution could not survive. With the decision to build a new oci, the major thrust of the director and his staff was towards the planning of the new building. It remained necessary to deal with inadequate buildings until the new facilities were available. Yet the promise of the future provided a needed enthusiasm. The last phase of the oci on Sherbourne Street had begun. Robert Stevens now saw his own contribution to the oci coming to a successful end. In 1985 he resigned as chairman of the board and was succeeded by Kenneth Clarke. A young successful business executive, Clarke brought to the task an enthusiasm and an understanding of the environment of the times; he would need both. That same year William Duncan came as head of Radiation Oncology. His views and personality were to have a profound effect on the planning of the new oci/pmh.

choosing a site Since the institute was to be rebuilt, the first question was where should it be located? Four potential sites were considered. There was a large parking lot across Sherbourne Street from the existing hospital. Space was available on the north side of the Sunnybrook campus, adjacent to Bayview Avenue. A lot on the west side of University Avenue immediately to the north of Mount Sinai Hospital could be redeveloped. Finally, the Toronto Hospital could make space on Elizabeth Street. The choice was both difficult and important. The oci board asked the consulting firm Woods Gordon for another study. Alan Backley, Woods Gordon partner was appointed as a “fact-finder.” The task was not to make a recommendation but only to determine the advantages and disadvantages of each of the proposed sites. Backley had been a major author of the 1972 study. In the interval he had served a term as Ontario deputy minister of health. He was clearly

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well qualified for his task and might be expected to provide the basis for a choice that would be acceptable to the government. Backley reported in February 1987. Faithful to his mandate, he listed the pros and cons of each site. Many factors were considered, including the academic and clinical environment, the size and suitability of the available land, transportation, parking, zoning and finance. Of these, strong clinical support from an adjacent hospital was a paramount need. The Elizabeth Street, site was easily eliminated as not being big enough. Sherbourne Street was the next to go. This decision was not easy. The site was large enough, and many of the staff, particularly those with long service, saw that the traditions of the oci could best be maintained by staying on Sherbourne Street. The distance from the major teaching hospitals of the university was seen as a benefit, one that had contributed significantly to the success of the oci. The deciding negative factor was the assessment of the clinical facilities at the Wellesley Hospital, togther with the problem of accessing emergency help from across Sherbourne Street. Bill Duncan was firmly of the opinion that the the Wellesley Hospital was inadequate to support oci’s cancer treatment programs. Many found this opinion surprising, since, from its beginning, the oci had depended on the Wellesley for clinical consultation and special services such as the intensive care unit. Pathology was a shared service between the two institutions, with Tom Brown as chief on both staff rosters. Duncan’s view was supported by his colleagues in Radiation Oncology. The convincing argument was that clinical resource that was adequate when the oci started might not be appropriate for the greater expectations for the new building. Two sites remaining under consideration. Sunnybrook Heath Science Centre was to the north. Originally built as a veterans’ hospital, it was acquired by the University of Toronto from the federal government and refurbished as a civilian teaching hospital. Its clinical facilities were extensive, its reputation excellent. Sunnybrook’s proposal was ambitious; they planned to merge with the Wellesley Hospital, thus preserving its oncology program. The downtown site would be kept as a satellite to serve the city core. Ray Bush supported the Sunnybrook option. He saw that the large available space for building was not only more than enough for the immediate future but provided for the possibility of further growth. The presence of the established Bayview Cancer Centre of the octrf was seen as an advantage. If the merger of the two institution was achieved, the two cancer treatment centres could work together in excellent synergism. The university Faculty of Medicine supported the Sunnybrook option. The dean saw that the addition of the oci to his northern campus would add to its strength, giving it an influence almost equal to that of the established teaching

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hospitals close to the St George campus. There were also disadvantages: the proposed site was not close to the main hospital; it might be difficult to access emergency services or intensive care. The research division heads were ambiguous; while they liked their separation from the St George campus, they also knew that major facilities, the advice of colleagues and interesting seminars were only a short walk away. They made the point that a move north would require a frequent free bus shuttle between Sunnybrook and the main campus. The remaining option was space on University Avenue next to Mount Sinai Hospital just south of College Street. This environment was the richest in Canada for clinical services and medical science. The Toronto Hospital and the Hospital for Sick Children were just across University Avenue. The St George campus was to the north, making it easy to use both the scientific and cultural resources of the university. Danny Bergsagel, the chief of Medicine, was the major proponent of the University Avenue site. Perhaps he was influenced by his early experience at the M.D. Anderson Cancer Center, which was in the heart of the immense Houston Medical Center. Other saw serious disadvantages to downtown. The site itself was small and would restrict the design of a new building. Buildings with an heritage designation were already there. Permission would be required to change them and it would almost certainly be necessary to retain their 1920 design frontage on University Avenue. Although the subway would be close, parking would be both limited and expensive. This was a major concern for many cancer patients were not well enough to use public transport. Perhaps the major worry was that the autonomy of the oci might be lost in the presence of such powerful neighbours. Jim Till put this fear most forcefully; he said “the oci would be swallowed up in a ’black hole’ if it moved close to the old, large and well-established hospitals that formed the core of the Medical School.” It was clear that the decision would be for the director to make. Since Bush had been seen to be an advocate of the Sunnybrook site, most thought the institute would be moving north. In fact, quite suddenly, Bush changed his mind and made the decision to move to the University Avenue site. Characteristically, he never provided a detailed reason for his decision.

the joint conference committee and the board Ken Clarke was quick to discover the underlying tensions and unease at the senior levels of the oci staff. Disagreements between Bush and Duncan were evident to him. The method of setting salaries was a

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Ken Clarke, the dynamic chairman of the board during turbulent times.

potent cause of tension between the departments of Radiation and Medical Oncology. Duncan had moved to establish his colleagues as a clinical association separate from the physicians and was able to negotiate directly with the administration for salary levels. This was but one of many areas of disagreement between the two major clinical departments. Clarke determined to be a proactive chairman with the immediate objective of improving communication and confidence. To this end he formed a new committee, called the Joint Conference Committee. The membership was drawn from the board, the administration, and the professional staff. In addition to himself as chairman, he brought Mr Livingston and John Dirks, the dean of Medicine, from the board. Ray Bush (the director), Joanne Ratz (the administrator) and Miss Holder (the director of nursing) were the administrative members. Bill Duncan and Ralph Blend, the chairman of the Medical Advisory Committee (mac) represented the clinicians. McCulloch, Gordon Whitmore and Peter Ottensmeyer brought research perspective to the deliberations. For the first meeting, Clarke gave a dinner at the King Edward Hotel. All the members were encouraged to make brief presentations of their own memories of the institutional past and hopes for the future.

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The Joint Conference Committee’s mandate required it to meet twice yearly. In fact, meetings were much more frequent, depending on the work at hand. The first task was a discussion of the values that were shared by the members and, by extrapolation, the groups they represented. This process was designed to build bridges of understanding. To give the discussions form, the committee determined to prepare a written statement of the vision of the oci/pmh; this was then expanded by a fuller description of the mission. Many drafts of both statements were written, discussed, and dissected. All pointed to the goal of reducing morbidity and morality from cancer; all emphasized the importance of patient care, research, and education. Finally, at a board retreat in 1994, the statements were adopted. The vision: to be one of the world’s leading cancer centres. The mission: to enhance cancer control through the integration of clinical care, research, and education. Clarke also saw that there was a gap of confidence between the board and the oci staff. Some thought that the composition of the board, based in large part on representation of the university, octrf, and other teaching hospitals, did not always give proper precedence to the concerns of the oci/pmh. To counter this unease, Clarke invited both research division heads as well as the heads of the major clinical departments to attend board meetings as observers. Though not members of the board, their views were sought and clearly were influential when decisions were made. Finally, Clarke made it clear that he was personally available to the staff. He passed out his office and home telephone numbers, sometimes written on the back of a package of matches. He attended meetings and celebrations where he could listen and respond to ideas from the staff.

meetings of the director’s executive committee After the site decision had been made, the director and his executive faced two different but interrelated problems. First, the work of the institute had to continue in an inadequate building with aging equipment and greatly hindered by a provincial decision to limit and reduce funding for health care. Second, there was an urgent need to plan for the new building, and to do so in such a way as to insure a happy partnership with other institutions, including the hospitals on University Avenue. Both tasks fell principally on the same group of people who formed the director’s executive committee or dec. With Bush as chair, the core of the committee included Joanne Ratz, the administrator, Bill Duncan and Danny Bergsagel, the heads of Radiation and Medical Oncology, and Gordon Whitmore and Ernest McCulloch, the

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heads of the research divisions. It is no exaggeration to say that the meetings of this group were tense, even unpleasant. The personality conflict between Ray Bush and Bill Duncan set the atmosphere; rather than consultation and problem-solving, argument and dissent were dominant. Nor was the dissension obscured by surface politeness; the problem became so well known that Clarke had to intervene personally. His opinion of the behaviour in the committee was given with characteristic wit; he called the dec members “lawyers in lab coats.” Eventually he asked one of his best board members, Bill Livingston, to attend regularly, knowing that his presence would insure that progress was made.

the functional program In parallel with the task of keeping the institute functioning, the same group of people had the major responsibility for planning for the new building Avenue. The first requirement was to produce a complete description of all of the activities envisaged for the new building, including their requirements for space, equipment and staff. It was an important part of the task to estimate as accurately as possible the funds required. This functional program was prepared with the help of the consulting firm, Agnew Peckham. Many meetings were held, as each department or function was discussed in detail. In many areas, the work was an update of the 1980 functional program, which followed the earlier role study. There were certain important differences. For example, it was assumed that six thousand new patients would be seen annually for radiation therapy. Sixteen megavoltage therapy machines were needed which could only operate if the staff of radiation oncologists and technicians increased The needs of research were different from those that had guided the previous study. McCulloch was convinced that Biological Research must be bigger. He was pressed by the proper needs of successful scientists, particularly Ling and Mak. His attempts at recruitment of new staff were sometimes frustrated because he could not offer adequate space. These specific pressures were, in his view, a manifestation of a general increase in the size of successful research programs. Further, the desire for more clinician participation in research could not be met unless proper facilities could be provided for them. Gordon Whitmore was in agreement; together they made careful estimates on the space needed in the new building, based upon agreed square foot requirements as a function of number of principal investigators, graduate students, post-doctoral students, and technicians in each program. An innovation

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in research planning was to identify investigators whose work was conducted with paper, pencil and computer; much work in biostatistics, epidemiology, and behavioural science used only these tools. Their work spaces were called “dry labs” in contrast with the “wet labs” needed by scientists who experimented with cells or chemicals. The functional program had to consider the institute’s powerful neighbours on University Avenue. A dominant theme, much championed by Joanne Ratz, was that many economies could be achieved by sharing services with adjoining hospitals, particularly Mount Sinai. So powerful was the idea that “sharing” became elevated from a policy to a virtue. Almost everything was a candidate. The library, the cafeteria, housekeeping, building services were all discussed. Major professional departments were not immune. Three forms of sharing were defined, depending of whether a service was provided by another hospital to the oci, or if two institutions contributed parts of a function, or if a single department was established, with one chairman. The discussions of all these projected common activities were vigorous and often heated, as oci staff wished to maintain autonomy, particularly in the key academic disciplines, such as imaging, laboratory medicine and pathology. In the end, the discussions came to nothing. The expected savings from sharing proved to be illusions, since the structural modifications needed by Mount Sinai to implement shared services were too costly to justify any operational economies. As this work was progressing, a new dimension was added to the task. The government and the oci board set a limited budget for the new building. The planners saw that the scale of many of their proposals exceeded the funds available. The need to scaling back increased the tension in the meetings and the heat of the discussions. In spite of these many difficulties the functional program was finally completed and was presented to the board in August of 1988.

choosing an architect The next major step was to choose an architect for the new building. The choice was made through an open competition. Three firms of architects prepared models for the inspection of senior hospital staff. The decision proved easy. The firm of Zeidler Roberts showed an imaginative concept. Eberhart Zeidler would himself be the lead architect. His past record was impressive, including the McMaster Health Science Centre. In designing the new building, he faced two major constraints: he was required to retain the historically significant facades of the buildings at 610 and 612 University Avenue; even using both buildings,

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The architect, Mr Zeidler (centre) explains his plans for the new building. To his left are Gordon Whitmore and Ralph Blend, a radiologist and chairman of mac. Facing him are Ken Clarke, board chairman, and Dr Thall, a member of the board.

the University Avenue site was small. He solved the first problem by placing the main entrance to the new hospital on Murray Street. A door would still open at 610 University Avenue, and this would remain, for reasons of prestige, the hospital’s address. Two strategies were used to make the best use of the space available for the building. First, Zeidler used atriums as a principal element in his design. He could then take the walls almost to the edge of the property but retain a sense of openness. Two atriums were to be constructed, stacked one on top of the other. The hospital services and out-patient facilities surrounded the first atrium, while the second, separated from the first by a translucent ceiling, was surrounded by three floors for laboratories and a fourth for the animal colony. The radiation facilities were below ground, where the necessary shielding was easier to provide. The inpatient facilities were to be built above the second atrium. This position, at the top of a tall building, allowed Zeidler to give patients windows that faced out onto a street or into the open space above the research atrium. Zeidler put two models of his proposed building in the main lobby at Sherbourne Street. Both staff and visitors were pleased with his vision of the future. The promise of better quarters

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made it easier to work temporarily in the difficult and cramped space of the original hospital.

the resignation of ray bush as director No one doubted that Ray Bush had high ideals for the oci. His ambition was to create a province-wide cancer care system, with oci/ pmh as a resource and referral centre. He saw that such a system would make multi-disciplinary care available throughout Ontario. Bush envisaged the oci as dominant in the merged organization. Bill Meakin, then head of octrf, saw his own institution as leader. Tensions existed between the two men, limiting the possibility of cooperation and creating uncertainty in both staffs. Ray Bush did not always succeed in gaining the support of his departmental or divisional heads. The deteriorating relations between Bush and Duncan was a major reason for low morale in the clinical staff. The problem was particularly evident at dec, where the clinical and research leaders seemed to be drawn into controversy. Whitmore, perhaps because of the traditional ties between the Physics Division and Radiation Oncology, often favoured Duncan. He asked Bergsagel and McCulloch to meet together with him and Duncan. These confidential gatherings took place in Whitmore’s office, usually in the late afternoon. Whitmore correctly informed Ken Clarke about the meetings, and of his expectation that a consensus might be reached on whether or not the four would recommend to Clarke that he ask Bush to resign. At their last meeting three were in favour of resignation, one was opposed. Whitmore at once phoned Ken Clarke; the board chairman asked if the four were unanimous. When he was told the split in view, Clarke stated that he would not ask for a resignation. After this decision there were no further meetings of the group of four. The dissension in dec mirrored that in the clinical staff. The Medical Advisory Committee had doubts about how the money they earned was being used. Duncan had the support of his staff, particularly the young radiation oncologists. The physicians, in contrast, were uneasy about the policies of their radiation oncology colleagues. Ken Clarke, always an active chairman, was worried about disagreement and drift. A day-long meeting was arranged away from the hospital, at McLean House, a retreat site on the Sunnybrook campus. All the senior staff attending as well as many board members. It was hoped that open discussion would end with resolution of the real or perceived problems. The talk was vigorous, but, by the day’s end, unity had not been achieved. Fortunately, while McCulloch and Whitmore were

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deeply involved through dec, the research scientists escaped much of the turmoil and their morale remained high. Finally, in 1988, Bush offered his resignation. He planned to return to the Department of Radiation Oncology and resume his career in therapy. Clarke accepted his decision and made a gracious announcement to the board. Sadly, Ray Bush died of cancer in the hospital to which he had given his career, less than two years after quitting his post as director.

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Preparing to Move

A search was initiated for a successor to Ray Bush. This time Clarke hired a professional search company, Caldwell and Partners, to find a new director. The search company narrowed the field to two candidates, both experienced in Hospital Administration. The choice was Don Carlow, who was then senior vice-president of the Winnipeg Health Science Centre. Although he had an md, Carlow’s work and interest were in the running of health facilities rather than in the direct delivery of care. Carlow was a man of slight stature; but there was nothing slight about his mind or his determination.* His first priority was to reorganize the administration of the oci/pmh to conform with modern hospitals. An early step was to change his own title. He ceased to be director and became president and ceo, since this was the title held by other hospital heads. Carlow introduced new tools, such as a program of continuous quality improvement. A feature of his method was to use effectively the talents of the staff at all levels and to give them a sense of involvement with the hospital programs. His plan was to level the administrative structure so that reporting relationships were clear and not always through his own office. He held effective retreats, sometimes only for his own senior staff, but also often with the board. These ** Carlow had a frank conversation with Ken Clarke when he accepted the appointment. Clarke told him that staff morale was low at the oci and that there were internal conflicts. He advised Carlow that it was his expectation that there would be important changes in the senior leadership within the next three years.

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Don Carlow, last director of the oci/pmh and first president and chief executive officer.

meetings served both to foster communication and to allow wide input into policy reforms. The effects of his changes were soon felt; much of the tension that was evident during the last days of Ray Bush was lessened or even dispelled.

relocation approval When Don Carlow took up his appointment in September of 1988, the decision had been made to relocate the hospital to University Avenue. The functional program was nearly complete, the architect had been chosen. Carlow’s challenge was to translate these decisions and plans into reality. The first task was to obtain approvals at the civic, provincial, and even federal levels. While meeting these requirements, decisions were needed that would comply with the strict budget limitations already accepted by the board. Toronto City Council and the Ontario Municipal Board (omb) had to approve. A public school was located on Orde Street, just behind the proposed new oci site. Parents of students at the school protested; they were fearful that radiation would escape the hospital and injure their children. Approval by the Atomic Energy Control Board (aecb)

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was required. The school delegation continued their opposition even at this level. Fortunately, scientific understanding of radiation therapy machines was sufficient to overcome unfounded worries; council, omb, and aecb gave approval. The country and the province were in economic difficulties in 1988, when final decisions needed to be made. Leaders in the private sector were concerned that they might not be able to meet the fundraising objectives set by the project. The provincial government, facing a large budget deficit, had a funding freeze in place. It may be that the high regard for the oci held by patients and their families helped overcome both obstacles. The then premier, Bob Rae, had first-hand experience, since his brother had been treated at the pmh. He persuaded his cabinet colleagues to lift the freeze. This public support may have stiffened the resolve of the business leaders who were responsible for fundraising. Regardless, the necessary approvals were in place. The approvals were contingent on the planned budget for construction. This constraint was much in mind when bids were requested from construction companies. The maximum available for the main building was $125 million, a sum that was less than most felt would be required. The tenders were opened in an atmosphere of anxiety. The relief was great when the lowest bid, from Ellis Don, a highly regarded construction company, was for exactly $125 million. The poor economic times may have been an advantage, as Ellis Don was prepared to accept a low profit margin in order to keep active and retain its skilled workers. Ken Clarke and his board appointed a building committee to oversee construction. The chairman was Jack Rabinovitch, the vice president of Trizec.* Mr Rabinovitch was well qualified for his task, which he undertook cheerfully and with great energy. The oci staff now faced the formidable task of translating the functional program into a functional plan, where the actual physical facilities would be specified. Fortunately, planning talent was to hand. Dick Hill played a particularly effective role, displaying his ability to manage the physical and the practical.

long waiting lists for radiation therapy The most pressing of the ongoing problems was the recruiting and retaining of nurses and qualified radiation therapy technicians. Both

** Jack Rabinovitch is much more than a business man; he created Canada’s richest prize for fiction, the Giller Prize, in memory of his wife, Doris Giller.

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were in short supply internationally and both were essential if cancer patients were to be treated. This was especially true for radiation therapy, where a shortage of machines and qualified operators led to long waiting lists. Every effort was made to find suitable people, even sending staff to Europe to recruit nurses. In spite of these efforts, the problem for radiation therapy was severe. Duncan consulted not only his own staff but also the Ontario College of Physicians and Surgeons. Then he took a strong position; he closed the waiting lists and refused to consider new patients until those already scheduled had been treated. The medical oncologists at the Department of Medicine disagreed. They thought they should do their best for all the patients they could see even if the resources available for each individual were less than optional. In their view, it was not ethical to refuse to do the best possible for all patients. The disagreement was taken to the board. There the discussion was vigorous, but, eventually, the policy of the radiation oncologists was affirmed. The treatment crisis affected the whole province. The octrf, in collaboration with the oci, set up communication mechanisms that allowed patients to be directed to the provincial cancer centre that was most able to provide treatment. Sometimes, patients were sent out of the province for radiation in centres in the United States. This was the first major manifestation of inadequate cancer treatment facilities that was to cause recurrent disruption even after the oci moved to the larger facilities on University Avenue. The early stages of construction allowed one important project that would provide some relief from the problem of providing radiation therapy. A sub-basement physiotherapy department in Mount Sinai Hospital was rebuilt and radiation therapy machines installed. These increased the physical facilities needed for treatment. Adjustments to the plan for the main building were required to insure a physical link between this satellite facility and the main therapy department. Even when the new machines in the satellite became available in 1989, the real bottle-neck – the shortage of skilled radiation oncologists, technicians, and nurses – remained.

research staff find new opportunities Following Harold Johns’s initiative, many of the staff in the Physics Division were engaged in research into new methods of making diagnostic images. They were developing and improving such methods as nuclear magnetic and ultrasound as well as the more classical radiationbased techniques. To improve diagnosis and staging of cancer, it was

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essential that the devices and ideas emerging from the research be tested in the clinical arena. Like many of the oci/pmh service departments, diagnostic imaging did not have a research history. Members of the imaging department were not eager to change their career direction to include a larger research commitment. As a result, the research staff found it difficult to establish the collaborations essential to their work. The discontent of the physics imaging scientists became an issue in the last months of Ray Bush’s directorship. Characteristically interventionist, he attempted, without success, to solve their problems. Several prominent members of the Physics Division left as a group and joined the research staff at Sunnybrook Medical Centre. There the imaging research was a major city-wide force in advancing diagnosis by proper use of new methods and devices. The exodus of the imagers had several effects on the oci. Clearly, an important research thrust had been lost. Don Carlow saw an opportunity to strengthen research through recruitment. Peter Ottensmeyer, as head of Medical Biophysics, saw the problem differently. His dilemma was the nature of the academic status of his colleagues who had moved to Sunnybrook. He and his executive committee took the important decision that the imagers would retain their university appointments in Medical Biophysics. It followed that, for the future, the department would have at least two physical locations. No longer would Medical Biophysics serve only the oci. Shortly after the move of the imaging group, Chris Paige was offered the leadership of research at the Wellesley Hospital. Arthritis was the major clinical strength of the Wellesley and Hugh Smythe, a leading authority on musculo-skeletal disease, provided leadership to the program. With the backing of the Canadian Arthritis Society and other resources available to him, Smythe had obtained funding for basic immunological research to support the clinical program. Paige’s own interest was immunology as he saw the chance to sharpen his research focus and to build a collaborative group. He accepted the Wellesley appointment; however, since the two hospitals were joined both physically and by shared services, Paige maintained a strong link to the oci.

reorganization of research Both the head of Biological Research and his predecessor agreed that the existing structure dividing research into two divisions did not provide an attractive prospect for professional advancement. At Sherbourne Street the research space was insufficient for programs of the size that people like Ling and Mak needed. The plans for the new institute went far in providing the needed physical resources. These, combined with

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organizational changes, might make the oci an attractive place for the best scientists. Both Till and McCulloch were certain that science relative to cancer had become broader; a division into biology and physics made little sense. The two collaborators took their thoughts to Carlow in an initial meeting. He saw their ideas of change for research as highly consistent with his own views about the organization of administration. As a first step, Till prepared a paper describing the concept of a unified research organization. There should be a single research head, but several divisions, each defined by discipline and each with its own director. After further thought, it was decided to use the existing Research Advisory Committee as a vehicle to discuss Till’s paper. McCulloch as chairman of the committee was well situated to give the discussion of the unity concept prominence. The committee itself consisted of the research division heads and the clinical chiefs. Carlow was an ex-officio member and attended important discussions. Several committee members did not take easily to the major change proposed in Till’s paper. Gordon Whitmore, the head of the Physics Division, argued that the existing organization had proved highly successful. Duncan saw the unity concept as a strengthening of research at the cost of the clinical departments. He held strongly that he had responsibility for clinical research in his department. He would not accept a role for any research director. The committee worked hard to accommodate him. One proposal was that clinical research might have two forms, one including those investigations that needed research laboratories, and the other, patient-based work that needed, at most, statistical support. Many clinical trials would fall into this latter category. The idea was advanced that the first class of clinical research, which would include interface programs, properly belonged in the research division, while the second would remain the responsibility of a clinical chief. Duncan appeared satisfied, but as drafts of an committee document were prepared, he always found reason to complain. When drafts were revised in the hope of meeting his requirements, new objections were made, sometimes even to wording that Duncan had himself suggested. At last, with Carlow’s support, the committee submitted its detailed recommendation for a unified research division. Carlow insured that the planned reorganization was accepted. He decided that the title of its leader would be vice president, research. A search committee established to find the new leader chose Ronnie Buick, a very popular appointment throughout the institute. He moved quickly to the next step in research organization. Wisely, he maintained many of the old terms in the new organization, but gave the words new meaning. He established five divisions in place of the previous two. He avoided controversy or ill-feeling by maintaining both McCulloch

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and Whitmore as division heads, the former in the new Division of Cellular and Molecular Biology, the latter in Experimental Therapeutics. Whitmore continued to be responsible for clinical physics while a search was under way for a new head. Vic Ling’s ability and success were acknowledged by appointing him as the head of a Division of Structural Biology, his long-term interest. Norman Boyd, a clinician in the Department of Medicine, had expert knowledge in the epidemiology of breast cancer. Buick showed his sure touch by going outside the research staff to appoint Boyd as the head of a new Division of Epidemiology and Biostatistics. The new research divisions were tangible evidence of Buick’s commitment to a broadly based program that addressed the cancer problem in many different ways. He and his senior colleagues had the opportunity to recruit scientists to make the new divisions both credible and effective. Many of McCulloch’s staff in Biological Research found a natural home in his new division of Cellular and Molecular Biology. His tenure, however, had to be short, for he reached mandatory retirement age within a year. Tak Mak was an obvious choice to be his successor. Mak, using a formal search process, made two important appointments. Pamela Ohashi had earned her Ph.D under his direction and had proved herself an effective investigator during a European post-doctoral experience with Rolf Zinkernagel, who later earned a Nobel prize. She strengthened greatly the molecular approach to immunology that had been at the heart of Mak’s own work. His second appointment was more senior. Jim Woodgett was an established investigator in the important but difficult molecular biology of signal transduction. His energy and enthusiasm, as well as his expert knowledge, soon established him as a research leader. Gordon Whitmore also had long-serving colleagues from the former Physics Division to join him in Experimental Therapeutics. Dick Hill and Mike Rauth continued the core work on radiation biology that was directly relevant to radiation therapy. John Hunt’s work on ultrasound was the only imaging program that remained at the oci. Clinicians who needed laboratory space for applied and translation research found a natural home in Experimental Therapeutics. Ian Tannock and Charles Ehrlichman from Medicine, Fei Fei Liu and Shun Wong from Radiation Oncology, brought both strength and breadth to Whitmore’s division. David Hedley made a special contribution. His expertise in flow cytometry and his knowledge of the mechanisms by which reactive oxygen species caused damage within cells after injury were natural complements to work on radiation and cytotoxic chemicals. Vic Ling undertook the leadership of the new Division of Structural Biology. He was convinced that three-dimensional pictures at the

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atomic and molecular levels were necessary to understand the complex molecular interactions that occur in gene regulation. Several of his colleagues shared his view. Peter Ottensmeyer had from the time of his return to the oci been engaged in developing electron microscopic methods for visualizing molecules and atoms. Jean Gariepy, originally recruited to manage the peptide synthesis facility, was thinking of proteins in three dimensions. Rich Gronostajski’s work on the regulation of gene transcription forced him to consider interaction between nucleic acid and proteins. While these scientists were a basis for a Structural Biology Division, they were not enough. Ling, with Buick’s support, added three recruits, chosen for their interests and skills. Mitsuhiko Ikura was an expert in multi-dimensional nuclear magnetic spectroscopy. He used this technique to obtain three-dimensional images of the interaction of the calcium-binding protein calmodulin with its ion. Sheryl Arrowsmith used the same general methods, but applied them to gene regulation in bacteria. David Rose, the third recruit, was interested in the binding of ligands to cell surface receptors. For his studies he used x-ray crystallography to visualize antigen-antibody interactions as a model for the binding of receptor and ligand proteins. With these impressive additions, Vic Ling was in an excellent position to move from two dimensional thinking to three. The new division needed funding for both staff and equipment. With Don Carlow’s support the Princess Margaret Foundation made a grant of $2.9 million to the new division. Norman Boyd’s Division of Epidemiology and Biostatistics provided clear evidence that Buick understood the need for breadth in cancer research. Boyd staffed his division with oci scientists who had been engaged in relevant research under a number of auspices. Bob Bruce brought the problem of the causation of colon cancer from his discontinued Ludwig Institute. His hypothesis was that items in the diet were either directly carcinogenic or precursors that could be activated by intestinal organisms. He had the able help of Michael Archer, a skilled organic chemist, with the technology required to characterize putative carcinogens. Jim Till found the new division a suitable base for his ongoing work on medical decision-making. The two biostatisticians recruited earlier into Biological Research, David Tritchler and Sal Minken, continued their statistical developmental studies in the division. Alistair Cunningham joined the new division, where he found less scepticism of his studies of mind-body relationships as he continued his ongoing program of psychological interventions in groups of cancer patients. The divisional structure provided evidence of the flexibility of the mature oci. Norman Boyd was cross-appointed to the octrf to lead their program in cancer epidemiology.

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With his new divisions in place, Buick was ready to move to University Avenue at the head of a modern cancer research team with high morale. The research culture established on Sherbourne Street, together with the international accomplishments of oci scientists, provided assurance that the larger forces of the major teaching hospitals and the St George campus would not overwhelm oci research. Indeed, the few blocks distance from the university centre which had provided protection in the early days were no longer needed. Closer ties with other scientists was seen as a major advantage to the move.

clinical reorganization In parallel with this reorganization of the research divisions, Don Carlow planned a similar move on the clinical side by appointing a vice-president oncology with responsibility for all the clinical services. Once again Caldwell Partners were hired to conduct a formal search. They reduced the field to two serious Canadian candidates: one was external, Michael Baker, the head of Medical Oncology at the Toronto Hospital, the largest of the university teaching hospitals. The other was internal, Simon Sutcliffe, a young but well-respected oci/pmh radiation oncologist. Supported by the Toronto Hospital ceo, Vicory Stoughton, Baker expected to continue his post at the Toronto Hospital while also undertaking the task on Sherbourne Street. Most felt that the oci/pmh needed a full-time vice president, particularly as so many changes and adjustments were being made in preparation for the move, so Sutcliffe was selected. Carlow and his new vice president oncology had inherited a major problem. Bill Duncan continued to be an obstacle to the concept of multi-disciplinary health care. Carlow was quick to recognize that his personality and views had a negative influence on the institute. When the anniversary of Duncan’s appointment came, Carlow set up a formal external review committee. This body interviewed Duncan and sought written opinions from others, including Dan Bergsagel and the two research division heads. With the report of this committee to hand, Carlow, with the support of the board, refused to renew Duncan’s appointment. This move was not universally applauded. Many of the radiation oncologists remained loyal to their chief, even though the vice president was himself a radiation oncologist. Some of the scientists in the Physics Division had similar views. Nonetheless, Duncan returned to Edinburgh where he again became head of radiation oncology, the post he had left to come to the oci. He did not go quietly; he sued the oci for wrongful dismissal, and asked for costs and substantial damages. His court action was unsuccessful, an outcome that saved the oci

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not only money but also embarrassment. Duncan did not forfeit the regard of his Toronto colleagues. When he came to normal retirement age, many from the oci travelled to Edinburgh to attend his retirement ceremonies.

changing mechanisms for research funding The oci/pmh had enjoyed a stable financial state for most of its stay on Sherbourne Street. Often there was a budget surplus because the cost of buying new major radiation therapy machines had been included in the estimates but the equipment had not been delivered. Research senior staff salaries were covered by a block grant from the octrf. Continuing success in science insured that grant requests were almost always funded. Core support from nci(c) provided stability in the research division. This mechanism changed at the time the decisions were being reached about the new building. The nci(c)officers were examining their research support policies. The issue was the balance between support for individual investigators and groups. The oci research divisions argued that their share of the nci(c) research budget should be at least stable and perhaps increase. They claimed that money granted to groups gave a high return because effective collaborations were fostered by block grants. The opposing view was that individual investigators were growing in number because of successful training programs. Their value to cancer research was based not only on their success as investigators but also on the linkages they provided to other areas of science through their university department colleagues. Examples could easily be found of research in basic science leading to discoveries highly relevant to cancer. Because individual nci(c) grantees were distributed widely across the country, they represented the national base of donors from which the Canadian Cancer Society solicited money in its annual campaigns. nci(c)’s Research Advisory Group (rag) had become uneasy about the assessment process used to decide on the funding of block grants. The increasing complexity of research made it more difficult to find a team of site visitors with all the scientific background needed for a credible report on progress and recommendation for renewed support. These concerns were coming to a head just as the oci research was being reorganized. An agreement was negotiated. The nci(c) would extend for one year its existing grants to the divisions. For its part, the institute would agree to a change in the grant procedures. Two or more investigators could apply for money to fund research proposals with a common theme and clear synergism. These program-project

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grants would have three- or five-years terms. They would be assessed by a site visit by experts in the specific area of the proposal. Program-project grants did not have the division-unifying quality of the previous block grants. They did have a new advantage in that some support services, such as secretarial help, could be funded from them. The oci was quickly successful in two applications. McCulloch, while head of Cellular and Molecular Biology, was awarded a five-year grant in support of the leukemia program. Norman Iscove, building on his long association with Chris Paige, submitted a collaborative program project with Paige. The subject was in experimental hematology, focused on lineage determination, the process by which a stem cell enters one, but not another cellular lineage. With these two grants, as well as support for individual grants from nci(c) or the Medical Research Council, Buick knew that his research institute was adequately funded as it moved to its new and larger facilities on University Avenue.

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Last Days on Sherbourne Street

The reorganization of the research and clinical divisions placed the Ontario Cancer Institute on a firm footing for its move. There remained obstacles, especially problems about money. Even in the final days, successful research provided opportunities that would greatly strengthen the oci on its new site.

fund-raising Until the decision was taken to build a new hospital, fund-raising had been passive. Donations were cheerfully accepted and retained in a parallel organization called the oci/pmh Trust. The trust was considered as the funding source of last resort, to be used for important purposes where money could not be obtained elsewhere. For example, start-up funds for equipment for new research staff usually came from the trust, as did important hospital equipment. This changed when the government announced that it would provide $200 million to improve cancer services in the province. Of this such, $185 million would be used for oci/pmh construction while the remainder would help the octrf improve its regional clinics. The new hospital was estimated to cost $235 million. The difference was to be raised by a capital campaign, the Ontario Cancer Care Fund, shared by oci/pmh and octrf, with a goal of $50 million. When the goal was reached, $33 million would be for oci/pmh and $27 million for octrf. The campaign chairman was William Davis, a former premier of the province. The joint effort proved unstable. When about $20 million had been collected, the fund-raising was reorganized, with a campaign only for

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the oci/pmh, with Anthony Fell, the ceo of Dominion Securities as chairman. He was ably supported by a “campaign cabinet,” chaired by William Davis. Members included the mayor of Toronto (June Rolands), the chair of Metro Toronto (Alan Tonks) and many others, including the former board chairman, Robert Stevens, who headed the special gifts campaign. Happily, many major business, social, and political leaders gave not only money but time and prestige to the effort. There was an effective slogan, “Making the move of a lifetime.” The old complex logo was replaced with a simpler design that showed a rising sun. The techniques proven to be effective in large-scale fundraising were used successfully. Fund-raising was certainly to be an ongoing effort. The trust was transformed into the Princess Margaret Hospital Foundation, with its own board, although Ken Clarke served both as chairman of the oci/ pmh board and the board of the foundation. Fortunately, capital had been accumulated over the previous years. Thirteen million dollars from the money collected by the previous Cancer Care Ontario campaign was assigned to the oci fund-raising effort. Successive foundation chairmen worked hard to insure that oci/pmh had an independent endowment. Both patient care and research could then be governed by stable institutional goals, rather than the ever-changing climate of government and granting bodies.* Community leaders was also involved in the work of the hospital. The Princess Margaret Hospital Council was established, consisting of patrons, such as former premier Davis, and representatives of large corporations and the press. The weight of council helped to establish more firmly the stature of the hospital. Nevertheless, the large body of loyal patients remained the principal public support for oci/pmh.

the provincial program The 1986 role study had recommended, as a long-term goal, the uniting of cancer services in Ontario, and negotiations aimed at a merger of the octrf and the oci/pmh were proceeding. Bill Meakin, the ceo at octrf, was a former member of the Department of Medicine at the oci. He continued to attend a clinic weekly at the pmh where he saw patients with endocrine cancer. Even with this relationship, Meakin had the responsibility to advance and protect octrf. Of necessity, this ** Staff participated actively in fund-raising. Both Don Carlow and Ron Buick were excellent and enthusiastic golfers. They originated an annual fund-raising tournament at the Oakdale Golf Club; the event was dedicated to George Knudson, a successful Canadian golf professional, who died of cancer at the Princess Margaret Hospital. Over the years nearly a million dollars was collected for research.

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sometimes led to conflict. Meakin was replaced by Charles Hollenberg, a former chairman of Medicine at the university and physician-in-chief at the Toronto General Hospital. His intellect, energy, and powerful personality made Hollenberg a major force in the medical community. It was soon apparent that he and Don Carlow did not have a happy relationship. It was, of course, necessary that the two institutions continue to collaborate, not only because funds flowed from the octrf to the oci/pmh but also because they were, for a while, partners in the major drive to raise $50 million. The planned merger was not to happen. At its new University Avenue site the oci had two buildings, but did not require much space at 620 University Avenue. The octrf moved into offices in this building, providing a common focus for cancer care. Even with this close physical proximity, cancer care in Ontario remained fragmented. Elsewhere in the country, and particularly in the western provinces, unified cancer care was achieved. The Vancouver Cancer Centre is an example. Although it did not have a dedicated cancer hospital, by 1990 it provided treatment for almost as many cancer patients as the oci. In addition to diagnostic and therapeutic services, it fostered many community-based activities that ranged from prevention to palliative care.*

t h e amgen i n s t i t u t e Increasingly, academic centres in North America were forging powerful links with industry. In the United States, academic scientists often founded companies to exploit their discoveries by bringing new products to the market. These liaisons were seen by American university administrators as sources of strength and funds. The academic origin of many of the new biotechnology companies was often reflected in their policies. Secrecy was not in order; rather, by opening their doors to university scientists they insured the continuing flow of knowledge upon which their commercial success depended. The oci had benefitted greatly from this openness. For example, large quantities of pure bioactive proteins could be produced from clones of genes bearing the information for their synthesis. While, in theory, this process seems straightforward, a commercial scale of operations was required to make useful quantities of pure protein. The companies, of course, hoped that these molecules would prove useful in treatment and hence profitable. Long before proteins could be sold, they were available for research.

** Information on provincial cancer agencies was kindly provided by Don Carlow. He is now the ceo of the Canadian Association of Provincial Cancer Agencies.

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The factors that were required for the growth in culture of hematopoietic precursor cells had been cloned. The clones were used by companies for factor synthesis. The Genetics Institute in Boston freely made available such factors to oci scientists working in experimental hematology. This collaboration proved to senior oci investigators that working with industrial partners was not only compatible with their academic mission but also an immense help to their research. The oci had already benefitted from the commercialization of research findings. The patenting and licensing of Mak’s t-cell receptor clone and Vic Ling’s antibodies to p-glycoprotein brought in a small but useful stream of money. Buick hoped that more could be generated from ongoing work. To facilitate technology transfer, an r&d nonprofit corporation, the pmh Research Corporation, was licensed provincially, with its own board but chaired by Ken Clarke. Not surprisingly, Tak Mak was quick to see the commercial potential of his own work and was eager to see it realized. Molecular techniques were being developed for altering the genomes of inbred mice. The first of these methods involved transferring genetic information into either fertilized ova or stem cells with the differentiation potential of ova (embryonic stem cells). These could then be transferred into the prepared uteri of female mice; there a fetal mouse would sometimes mature and form a living animal. Usually such mice had the transferred element, the transgene, in only one of a pair of chromosomes. Subsequent mating of these heterozygous animals gave progeny with the transgene at the same site in both chromosomes of the pair (homozygous transgenic mice). Then, by examining the phenotype of the transgenic animals new insights could be obtained into the function of the transferred gene. Tak Mak was pioneering an opposite strategy for defining gene properties. Techniques were then developing for targeting specific genes within cells in culture. A Canadian, Michael Smith, later won a Nobel Prize for his work on this “site-specific mutagenesis.” Homologous recombination in mammalian cells was discovered by another Canadian, Oliver Smithies, working in collaboration with Mario Capacci. Mak used an adaption of both methods to inactivate specific genes in fertilized mouse ova or embryonic stem cells. These could then be used to develop animals in which a native gene had been rendered inactive. Termed knock-out mice, such animals were useful in defining functions that were under genetic control. Knock-out mice, like transgenic animals, might be useful in drug development and hence have commercial value. A large new biotech firm in California, amgen, had contacted Mak with a view to funding work in his laboratory. As these negociations continued, the interest between the two parties increased steadily.

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amgen had a major program in hematopoietic growth factors as well as immunology, both interests shared with oci. In 1992 the negotiations led to a decision by amgen to establish a research institute in close association with the oci. Tak Mak was appointed its director, and he retained his full appointment in Cellular and Molecular Biology, although resigning as head of the division. Under a formal agreement between oci and amgen, the company undertook to rent space for research in the oci building at 620 University Avenue, immediately adjacent to the new construction at 610, with physical links between the two. Tak undertook to make appointments to his new institute using the established search methods, including meaningful oci input. Normally, scientists appointed to the amgen Institute would also hold cross appointments to one of the oci research divisions. In addition, amgen agreed to support a research chair at the oci and to make certain other funds available for oci training programs. A notable feature of the agreement was that amgen received no rights to the discoveries of oci scientists, although they might enter negotiations for licence agreements. The major benefit to amgen was the close association it would enjoy with oci research. Free flow of ideas, collaborations and joint seminars would be certain to support research within the amgen Institute. Inventions coming from the work there would belong to the company. Tak as director would insure that academic standards were high and that oci’s interests were well protected. It proved possible to renovate space for laboratories at 620 University Avenue at least two years before the new oci/pmh building was ready. Thus, an active research program was already in place before the oci scientists left Sherbourne Street.

building staff strength before the move A ground-breaking ceremony was held for the new building in 1992. Back on Sherbourne Street the two tasks remained – preparing to move, and maintaining ongoing programs. Carlow moved to strengthen and renew leadership. His vice-presidents were in place and with their help he rebuilt the next level on the clinical side. Dan Bergsagel retired as head of Medicine in 1990. His successor was Ian Tannock, who had an active program in Whitmore’s research division. With Duncan gone, and Simon Sutcliffe vice-president for oncology, Bernard Cummings was appointed as head of Radiation Oncology. Cummings, originally from New Zealand, had conducted successful clinical research on combinations of radiation and chemotherapy in the treatment of rectal cancer. This approach often succeeded in preserving rectal function, avoiding permanent colostomy, without sacrificing survival. Cummings

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saw the achievement of a long-held goal – the establishment of a university Department of Radiation Oncology, with himself as first chairman. Until then diagnosis and therapy had been combined in a single radiation department, an arrangement that impeded the academic development of radiation therapy. Diponkar Banerjee was recruited from the Western Ontario to become the head of Pathology. Banerjee had a personal research reputation in the field of monoclonal antibodies. These were becoming increasingly important in tissue diagnosis because of their capacity to identify molecules of interest. Plans to add a surgical department to the oci went back to the last days of Ray Bush’s directorship. There was no intention to have operating rooms. The goal was to have a surgical presence in the clinical arena so that all of the treatment modalities would be available to patients both at diagnosis and in the follow-up of their disease. Carlow succeeded in establishing a surgical department. He had to face opposition, since many were concerned that resources would be taken from other areas to support the new department. Denny De Petrillo was appointed first head of Surgery. His personal interest was in gynecology. This was a good fit since radiation oncology was important in the treatment of cancer of the uterus or ovaries. Two other appointments signalled an organization on the move. David Tufnell, the head of oci Microbiology retired. He was replaced by D.E. Low, the head of Microbiology at Mount Sinai. Clearly a shared service was anticipated; an associate microbiologist from Mount Sinai, Allison McGreer, was given the task of developing such an arrangement. With these appointments made, Clarke and Carlow could properly feel some confidence that the major clinical and research programs of the oci/pmh had the strength to prosper in their new environment. Ken Clarke saw his own role coming to an end. He stepped down as chairman in 1993, to be replaced by Edmund King, a successful businessmen, who had already served the oci well as chairman of the foundation board. He had the additional advantage of strong connections to the board members of the hospitals on University Avenue.

ready to go As the new hospital began to rise on University Avenue, final preparations to move became more pressing. The project on University Avenue was always straining at the budget; many staff meetings were held to discuss whether this or some other part of the functional plan could be eliminated. Bridges to Mount Sinai were particularly likely to fall to the budget axe. Other economies were decided upon; for example, all existing furniture and equipment would be moved to

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spare the expense of new purchases. Many a staff member knew that his or her desk and chair would be the same on University Avenue as it was on Sherbourne Street. An equally pressing money issue was a major concern to the administration. A pre-construction operating budget had to be prepared. This document would determine the funds that would be available after the move. The provincial government was running major deficits in its own budget. It was made clear that the oci/pmh proposal would be looked at with great care and even scepticism. There were strong suggestions that the bottom line for the University Avenue operation should not be very different from the Sherbourne Street budget. There was little option but to attempt to comply. As the time to move approached, many were concerned that the money restraints would seriously diminish the chance of improving both care and research in the new setting. In 1993, about a year before the projected move, Don Carlow resigned as ceo to take up an important hospital administrative position in British Columbia. This was not the time for a leisurely search. The board soon decided that Simon Sutcliffe should be appointed at once. He was in office at the time of the move, with little opportunity to think through his policies and to communicate them to his staff. He had important advantages, particularly the respect he had earned and his own easy manner. Even with this help, he had a difficult task and little personal experience to help him with it. The building was completed in the summer of 1995, and the research divisions moved into their new quarters on floors seven, eight, and nine of the new building, taking with them everything that could be moved. The patients and the clinical services moved in the late fall, so that the change was complete by Christmas. The mood was one of cautious optimism. There was an understanding that all could look forward to the advantages of the new site. Clinicians would have better support from a wide range of expert colleagues in the adjoining hospitals. Their patients would benefit from a more comprehensive clinical care, given in the bright new quarters on University Avenue. The scientists had, after many years, enough space. They were certain that their unique philoshophy would hold them together, even in the presence of the rich scientific communities at the university and the adjacent hospital research institutes. The inadequate hospital budget was a worry but, almost by silent agreement, it was seldom mentioned. Sherbourne Street days were done. The achievements of the first location would be continued and bettered in the next incarnation of the Ontario Cancer Institute/Princess Margaret Hospital.

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Glossary

abbreviations aml: acute myeloblast leukemia, a form of leukemia in which the dominant malignant cell population consists of cells with little, if any, evidence of differentiation. Untreated, aml is usually fatal in six months. cho: Chinese hamster ovary cells are widely used in tissue culture experiments. They are easy to grow and have the advantage of a very simple karyotype. dna: deoxyribonucleic acid, the chemical form in which information is stored in the cell nucleus and passed on to daughter cells at division. epo: erythropoietin, a hormone that is a specific stimulator of red cell formation (erythropoiesis). Unlike other molecules that stimulate blood formation in culture, it is not obtained from cells in culture. At first it was purified from body fluids; now it is made using recombinant molecular technology. This methodology yields sufficient quantities of purified protein for clinical use in stimulating red cell formation. nci(c): National Cancer Institute of Canada, the research arm of the Canadian Cancer Society. oci: Ontario Cancer Institute. octrf: Ontario Cancer Treatment and Research Foundation.

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pha: phytohemagglutinin, a plant extract that is capable of stimulating certain cells, especially lymphocytes to enter cell division. Compounds with this activity are called mitogens. pmh: Princess Margaret Hospital. rna: ribonucleic acid, the biochemical form in which information is used to synthesize protein. rna is derived from dna by transcription; protein is made by translation from rna. tgh: Toronto General Hospital. cell biology Calmodulin: A calcium binding protein, first discovered and characterized by a Canadian, Harold Copp. Apoptosis. Cells have a genetically-determined program that leads to their death and the orderly destruction of their dna. This physiological process contrasts with cellular destruction that leads to a disorganized cell death and is called necrosis. Cell clone: A population of cells derived from a single cell, Clonogenic assay: An experimental technique by which cells capable of forming clones are demonstrated, counted, and characterized. Conditioned medium: Cell culture medium taken from cultures of cells that make the substances that stimulate growth and colony formation. Generically, these may be called “colony-stimulating activity.” More specifically, lcm is medium in which peripheral blood leukocytes were cultured. pha-lcm is the term for medium from cultures of leukocytes grown in the presence of the growth stimulating plant product, phytohemagglutinin. p-glycoprotein: A large cell membrane carbohydrate-containing protein that acts a pump, moving molecules in or out of cells. It is responsible for the multi-drug resistance phenotype. disease Hodgkin disease: A malignant tumour of the lymphoid system; it may either be limited to a few nodes or be widespread. Hodgkin disease responds well to treatment with radiation and drugs.

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Aplastic anemia: A disease characterized by very low numbers of mature blood cells; it is the result of loss or destruction of the bloodforming cells in the marrow. Untreated, aplastic anemia is fatal; it is now often cured by marrow transplantation. drugs Colchicine: A drug that inhibits the action of microtubules, structures that are required for separation of chromosomes at mitosis. Colchicine is also the traditional treatment for gout. Vinca alkaloids: A family of drugs with colchicine-like action. Members of the family are effective chemotherapeutic agents in the treatment of lymphoid cancers. genetics Aneuploid: Cells with very abnormal karyotypes, with changes in chromosome number and morphology. Chromosome: The physical form in which dna is packaged with associated protein when a cell divides. A chromosome before division has two strands, linked at a junction called a centromere. At division, the strands separate with one going to each daughter cell. Genotype: The genetic information encoded in the dna of a life form. Haploid: A cell in which each gene is present as only a single copy, This contrasts with the usual diploid state, where each gene is present twice, once on each member of the chromosome pair. Karyotype: A description or picture of chromosomes in a dividing cell. Karyotypes are used to determine the species from which a cell came and to detect any abnormal changes in the chromosomes that might reflect disease or damage. Marker chromosome: Injury, for example by radiation, may lead to a chromosome that is abnormal in appearance but does not impair a cell’s ability to grow. Such a chromosome will be present in every cell of a clone; it serves as a marker, that allows the identification of clonal members even if they are present in mixed populations. Phenotype: The characteristics of a life form as determined by observation.

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enzyme Reverse transcriptase: The enzyme that allows rna to be transcribed into dna. Telomerase: The two strands of normal chromosome meet at a single position, called the centromere. The centromere is often not placed centrally, so that strand lengths are not equal. A short pair of strands is called a telomere. With aging or prolonged growth in culture, telomeres shorten. Their length may be maintained by a hormone called telomerase. Frequently, telomerase is increased in malignant cells and may be part of the explanation of their immortality. imaging Nuclear magnetic resonance imaging: Electrons circulating atomic nuclei have a spin that can be altered by magnetic fields; when the field is off, the electrons revert to their former spins. These changes carry information that can be used to create images of clinical importance. Ultrasound imaging: Sound can be used to identify anatomic features, including tumours; thus, an image is produced that does not require x-rays and may contain additional information, including information about the movement of organs, such as the heart. immunology Antibody*: A y-shaped protein molecule, beginning as a receptor on the surface of lymphoid cells. The ligand for the receptor may be a large molecule. Binding of ligand to receptor induces proliferation and the formation of a clone of cells that release the receptor into the lymph and then the blood. In these body fluids the receptor is called antibody; it binds only to the initial ligand or molecules very similar to it. Antigen: A molecule that binds specifically to a lymphoid cell receptor, causing proliferation and the formation of a clone. When the receptor

** The reader may note the circularity in the definitions of antibody and antigen. Antibody is a protein that binds and antigen; antigen is a macromolecule that binds antibody. Harold Johns was very taken with these interactive definitions; he enjoyed challenging oci scientists and distinguished visitors to define both terms.

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is released from the cell surface and becomes antibody, its ligand binds to it and is called antigen. physics Cerenkov radiation: Visible radiation, most in the blue or near ultraviolet parts of the spectrum, emitted when a charged particle passes through a medium at a speed greater than the speed of light in that medium. Although the speed of light in a vacuum is the fastest speed possible for any particle or light wave, in a medium of any type, light travels more slowly because of its interaction with the electric fields of atoms in the medium; thus high-energy particles may travel faster than light travels in some material. d o: The radiation dose required to reduce survival to 37 percent of control, measured on the linear portion of a radiation survival curve. d o is a measure of the radiation sensitivity of the population under study. Extrapolation number (n): The value on the vertical scale of a radiation survival curve where the linear portion intersects when it is extended backwards; n is a measure of the shoulder of the radiation survival curve. Isodose curves: Curves obtained as lines connecting three dimensional spaces where the same amount of energy was deposited after a specified exposure to radiation. Isodose curves can be obtained for experimental objects (phantoms) or, by calculation, for humans. Isoeffect curves: Similar to isodose curves except that lines join areas where the deposited radiation has the same effect. Multidimensional nuclear magnetic spectroscopy: Electrons circulating atomic nuclei have a spin that can be altered by magnetic fields; when the field is off, the electrons revert to their former spins. These changes carry information that can be detected using spectroscopes. When more than a single detector is used, informative multi-dimensional images can be obtained that carry useful information about molecular structure. Radiation survival curve: A dose response curve using paper with an arithmetic horizontal scale and a logarthmic vertical scale (semilog paper); radiation doses are plotted on the arithmetic scale and the resulting survival plotted on the logarthmic vertical scale.

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x-ray crystallography: A method for using radiation to probe crystals and determine features of their structure. virus Bacteriophage: A virus that infects a bacterium. Often abbreviated as “phage.” Retrovirus: rna tumour viruses, usually leukemia viruses, that have reverse transcriptase activity, allowing their genetic information to be incorporated into dna.

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Index

Adams, Ged 88, 89 Allward and Gouinlock (architects) 9, 11 American Association of Cancer Research (aacr), 9, 11 American Societies for Experimental Biology 54 American Society of Hematology (ash) 39, 53, 59 Ames, Bruce 92 Amgen Institute 169– 70. See also Mak, Tak Archer, Michael 162 Arrowsmith, Sheryl 162 Ash, Clifford 8, 11, 32, 42–3, 66, 67, 110 Backley, Alan 145–6 Baker, Bud 94, 104–5 Baker, Michael 163 Baltimore, David 117 Banerjee, Diponkar 171

Becker, Andrew 39, 57, 115, 133 Benchimol, Sam 133 Benzer, Seymour, 39 Bergsagal, D.E. 52, 62, 64, 110, 124, 153; appointed head of Medicine 42; characteristics 42–4; and site choice 147 Bernstein, Alan 106, 128, 133 bfu-e 81 Biological Research Division 14, 24–9, 36, 100–6, 125–8, 131–4; changes in 65–6 blast cell biology 114–16 Blend, Ralph 148, 152 Boag, Jack 90 Boshkung Lake, scientific retreats at 37–8, 83 Boyd, Norman 161, 162

Brenner, Sidney 39 Brown, Tom 13, 146 Bruce, Robert 14; work on epo 53–4; and malignant stem cell research 58–60; pioneering style 91– 4; and Ludwig Institute 94 Buick, Ron 115–16, 117; characteristics 127–8; head of unified research division 160–3; reorganization of clinical services 163–4 Burnet, MacFarlane 72 Bush, Ray 96–7, 114, 150; joins Radiation Oncology 97; collaboration with Hill 97; appointed director 109; style of management 123–38; controversies 128–31; and modernization

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180 Index 138–40; resignation 153–4 Canadian Cancer Society 13, 14, 6l Canadian Hematological Society 121 Canadian Institute for Advanced Research 131 Cancer Commission (Saskatchewan) 4 Cancer Relief and Research Institute (Manitoba) 4 Carbone, Paul 112, 113 Carlow, Don 155–7, 159, 160, 163–4, 168, 170; appointed director 155 Carver, Jeremy 60 Cederlund, J. 14 cell contamination 16–7 cell separation 79–80 Cellular and Molecular Biology Division 161, 170 cfu (Colony Forming Unit) 48; cfu-s 88, 113; cfu-c 77, 113–14; cfu-g 77; cfu-gm 77; cfu-m 77; cfu-e 81, 113– 14. See also haematopoiesis Chiampi, Antonio 132, 133 Chute, Laurie 65–6 Clarke, Kenneth 153, 155, 167; appointed chairman 145; acting to restore confidence 147–50 clinical physics 21–2, 86–7

clone 174; as origin of cancer 3; in cell culture 15–16; in radiobiology 22–4, 87–9; in spleen colonies 47, 48–50; in chemotherapy 56–8. See also cfu Cody, H.J. 4 colon cancer 54–5 Congdon, Charles 54–5 Cowan, Don 110 Cronkite, Eugene 54 Cross Hospital (Edmonton) 7 Cummings, Bernard 170 Cunningham, Alistair 106, 107; and patient therapy 137– 8, 162. See also McCulloch, differences with Cunningham, Jack 14, 21–2 Curtis, John 110 Darte, John 7, 43, 120; second director 108–9 Davis, Mark 136 Davis, William 166, 167 Defence Research Board 34 De Petrilla, Denny 171 Director’s Executive Committee (dec) 124, 149–50, 153–4 Duncan, William 145, 153; differences with Bush 129–31; and new site 146, 149– 50; appointment not renewed 163–4. See also Radiation Oncology

Eddy, Bernice 27, 28 Elkind, Mortimar 23–4 Epidemiology and Biostatistics Division 162 erythropoiesis (epo) 53–4, 80–1, 93–4, 113 Experimental and Therapeutics Division 161. See also Whitmore, Gordon Federation of American Societies for Experimental Biology 39 Fialkow, Phil 111 Ford, Charles 48–9 Frankel, Mrs Egmont 142 Fraser, Murray 4 Freireich, Emil J. 43–4 Friend Leukemia Virus (flv) 28, 80, 106 Frost, Leslie 6, 9 Fuest, Clarence 15, 66, 69 fund-raising 120, 166–70 Gariepy, Jean genetics 25, 24–5, 52–3, 102–4 Goranson, Ed 15, 31, 41, 69 Gorcynski, Reg 105–6, 126, 133 Govoni, Eva 124 Graham, Frank 94 granulopoisis 76–7 Gronostajski, Richard 133, 162 Gross, Ludwig 26 haematopoiesis 49–53, 77–85; lineages 78;

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181 Index cell separation 79–80; bfu-e 81; erythropoiesis 80–1; human 82 Halifax Visiting Dispensary 4 Ham, Arthur 14–15, 25, 32–4; appointed chairman of Medical Biophysics 18; writing style 34; characteristics 35–6; retirement 36 Hasselback, Richard 13 Hayley, Garth 69, 123–4 Helleiner, Christopher 25, 41 Hill, Richard 97, 157 Holder, Pat 124, 148 Hollenberg, Charles 136, 168 Hospital for Sick Children 6, 133, 147 Houseman, David 105 Howatson, Allan 14, 25, 93 Howson, Peter 67 Hozumi, Nabuo 126– 7, 133 Human Leukemia program 111–18 Hunt, John 14, 89, 161 Ikura, Mitsuhito 162 imaging 90–1, 126–7, 134–6, 158–9 immunology 71, 73, 75–6, 105–6. See also T-cell receptor Institute of Immunology 70 Institute of Medical Science (ims) 63–4, 70 interface research 110– 12, 124; leukemia

program, first phase 11–14; blast cell biology 111–18; marrow transplantation 118–21 Iscove, Norman 134, 165 Jerne, Niels 75, 134 Johns, Harold 14, 32, 41, 67, 77, 125; inventor of “cobalt bomb” 13, 21; appointed chairman of Medical Biophysics 37; courses in radiation physics 36–7; characteristics 37–8, 85; retirement 67, 123; and ultra violet light 89–90; and imaging 90–1. See also Medical Biophysics, Physics Kennedy, James 74–6, 82 King, Edmund 171 Koprowski, Hillary 75 Laidlaw, J.C. 63–4; director of ims 63 Lan, Sam 113 Law, John 110, 123, 142; as administrator 11–12, 19–20, 67–8; characteristics 67–9 “L” cells 17, 40, 77, 88 Leyerle, John 131 Ling, Victor 100–4, 125, 139, 161–2; early training 100; and P-glycoprotein research 102–3. See also multi-drug resistance

Livingston, Bill 148, 150 Llewellyn-Thomas, Hilary 134 Ludwig Institute 59, 94 Mak, Tak 106, 125, 128; and leukemia program 117–18; and T-cell receptor 134–6; head of Cellular and Molecular Biology 161; and Amgen Institute 169–70 malignant stem cells 56–60; detection of dna analysis 56–8; thymidine “suicide” 58; chemotherapy model 58–60 marrow transplantation 118–21 Mauer, Alvin 116 McBurney, Mike 94 McCulloch, Ernest 15, 16, 25, 55, 64, 131, 148; work on mouse irradiation viral theory 25–7; collaboration with Till 29– 31, 46–8, 126; spleen colony research 48– 50; and ims 63, 64; move to Medicine 64; Gairdner Award 70; graduate supervision 74; meetings at cottage 83–4; and interface research 110–18; and marrow transplantation 121; replaces Till as head of Biological Research 132–4; differences with Cunningham 137–8; retirement 161

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182 Index McCutcheon, Wallace 9, 11, 19, 67 McGreer, Allison 171 McLeod, David 67, 80 M.D. Anderson Cancer Center 42, 147 Meakin, William 12, 13, 153 Medawar, Peter 73 Medical Biophysics, Dept. 36–7, 49, 62, 64, 69, 233; admissions to 17–19; cross-appointment with University of Toronto 67 Medical Cell Biology Division 36, 66 Medical Genetics Division 36 Medical Oncology Division (tgh) 149 Medical Research Council (mrc) 35, 41 Medicine, Dept. of 12–13, 42–4, 69; established 12; expansion 61–3; strengthened under Bergsagal 64–5 Meistrich, Marvin 92 Messner, Hans 120–2 Miller, Richard 69, 76, 79, 119, 126 Minden, Mark 115, 117 Minkin, Sal 134, 162 Minyamato, Neil 133 Moore, Malcolm 111 Mount Sinai Hospital 6, 145, 133, 151, 158, 171 multi-drug resistance 102–4 National Cancer Institute of Canada

(nci(c)) 14, 34, 39, 95, 120, 135; block grants 34–5; Research Advisory Group 164–5 National Institute of Health (nih) 27, 28, 35, 111, 164 National Research Council (nrc) 35, 42 Noble, Robert 101 normal haematopoietic stem cells 50, 60. See also spleen colonies North Toronto Cancer Clinic 99 Ohashi, Pamela 161 Ontario Cancer Agency (oca) 143–4 Ontario Cancer Care Fund 166, 167 Ontario Cancer Institute (oci). See under Sherbourne Street Building, and under various departments and divisions Ontario Cancer Treatment and Research Foundation (octrf) 56, 19, 34, 99, 143–4, 158, 167–8 Ontario Institute of Radiotherapy 5, 8 Ottensmeyer, Peter 133, 148, 162; working methods 96 Paige, Chris 134, 159, 165 Painter, Robert 94 Parker, Raymond 16, 26 Pathology, Dept. of 13, 146

patients 98–100, 107, 112; and Mak’s therapy 137–8; increase in numbers 142–2; and radiation therapy 157–8 p-glycoprotein 102–4, 139, 169. See also multi-drug resistance Peters, Vera 8 Phillips, Bob 69, 76, 79, 119, 126, 133 Physics Division 14, 21–4, 29, 58–60, 69, 85–97, 123–4, 139, 158–9 polyoma virus 35; Toronto strain 27–9, 44 Price, Gerry 106, 126, 13 Princess Margaret Foundation 162 Princess Margaret Hospital Council 167 Princess Margaret Hospital Foundation 166–7 Princess Margaret Lodge 142 psycho-social support 137–8. See also Cunningham, A. pulse radiolysis 89 quality of life research 107–8, 137–8 Rabinovitch, Jack 157 Radiation Oncology, Dept. of 12, 85, 96, 128, 129–30, 145, 146, 149, 170–1 radiobiology 22–4, 29–31, 87–9 Rae, Bob 157 Ratz, Joanne 123, 124, 148, 151

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183 Index Rauth, Michael 4, 85, 88 research funding 34–4, 164–5 Richards, Gordon 8 Rider, William 11, 129 Riordan, Jack, 102 Role Study (1972) 99– 100 Role Study (1984) 143–4 Rose, David 162 Russell, Elizabeth 52 Salmon, Sid 127 Senn, John 82, 112 Sheinen, Rose 41 Sherbourne Street Building: original building 9–12; expansion (1967) 61–2; new research space 124–5; proposed new building 145–7; and Zeidler Roberts 151–3; move from 166–72 Silberfeld, Michel 138 Siminovitch, Lou 14– 17, 38–42, 65–7, 69, 71; genetic hypothesis 15; research in viral theory 25–6; appointed head of Biological Research 36; and somatic cell genetics 40–1; sets up Medical Cell Biology 66–7; moves to Mount Sinai Hospital 133 Smith, Michael 169 Society for Experimental Hematology 55

somatic cell genetics 39–41 spermatogenesis 92 spleen colonies 46–8; origin 48–50; stochastic model 51–2, 55; W/Wv mice 52; Sl/Sld mice 52–3; international response 53–5; hematopoietic microenvironment 55–6 Stanley, Richard 105 Stanners, Cliff 28, 31, 42, 69, 132 Stephenson, John 80–1 Stevens, Robert 67–8, 108, 132, 145, 167 Structural Biology Division 161–2 Sunnybrook Health Science Centre 145– 6, 159 Sutcliffe, Simon 163 Tannock, Ian 170 T-cell receptor 134–6, 139. See also Mak,Tak Temin, Howard 117 Tepperman, Arnold 82 Thompson, Larry 94 Till, James E.(Jim) 14, 16, 22–4, 66, 125; collaboration with McCulloch 19–31, 46–8,126; spleen colony research 46–8; and stochastic processes 51–2; appointed head of Biological Research Division 69; Gairdner Award 70; quality of

life research 100–7; and staff appointments 125–7; move to University of Toronto 131–2; on unified research 160 Toronto General Hospital (tgh) 5, 6, 145, 163 Trenton, John 55–6 Tritchler, David 162 Tuffnel, Peter 125 ultra violet light 89–90 Urquart, Norman 9 viral theory of cancer 24, 26 volunteers 142 Warwick, Harold 12–13, 42–3 Wellesley Hospital 6, 10, 146, 159 Whitelaw, Mac 13, 42, 44 Whitmore, Gordon 14, 16, 38, 69, 148, 150, 161; radiation biology research 22–4; appointed head of Medical Biophysics 67; collaboration with Till 88, 94–5; as head of Physics 123–4 Wightman, K.J.R. 74 Woodgate, Jim 161 Wu, Alan 77, 83 Zeidler, Eberhart: as architect of new building 151–3