October 2020 
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OCTOBER 2020 | WWW.THE-SCIENTIST.COM

CAN SCIENCE PREDICT PEOPLE’S BEHAVIOR? THE FALL OF SURGISPHERE NEURAL LINKS BETWEEN HUNGER AND CURIOSITY

PLUS

A HISTORY OF SELF-EXPERIMENTATION

BRAIN-BODY CROSSTALK CONVERSATIONS BETWEEN NEURONS AND THE IMMUNE SYSTEM SUPPORT LEARNING, MEMORY, AND MORE

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OCTOBER 2020

Contents

© MICHELLE KONDRICH; © CATHERINE DELPHIA; © ISTOCK.COM, ENOT-POLOSKUN

THE SCIENTIST

THE-SCIENTIST.COM

VOLUME 34 NUMBER 10

Features

ON THE COVER: © STOCKSY.COM, ADDICTIVE CREATIVES

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Combining measures of attention and emotional state, we are getting closer to forecasting human behavior.

Crosstalk between the immune system and the nervous system is proving essential for the health of both body and mind.

Tiny, Illinois-based Surgisphere Corporation stunned scientists and the public earlier this year when its influential COVID-19 studies fell apart under scrutiny and the company disintegrated overnight. But the problem started long before 2020.

Predicting People

BY PAUL J. ZAK

Intimate Conversations

BY ASHLEY YEAGER

A Perfect Storm

BY CATHERINE OFFORD

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Department Contents 13

9

FROM THE EDITOR

Wielding Fear

The primordial emotion is apt to run amok. But harnessing it can lead to responsible behavior and sound thinking. BY BOB GRANT

11

CRITIC AT LARGE

The Disinformation Pandemic

For scientists to have a chance of defeating COVID-19, they must also work to quash the rising tide of bad information surrounding the disease. BY GENNA REED

13

NOTEBOOK

Microglia fight off viruses that invade the brain through the nose; similar brain regions linked to both hunger and curiosity

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44 THE LITERATURE Weight training in monkeys strengthens neural connections; non-concussive head injuries linked with white matter changes in athletes’ brains; neural activity called alpha waves have an unsuspected origin

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SCIENTIST TO WATCH

Michelle Gray: Huntington’s Disease Detective

E.A. MOSEMAN ET AL., SCI IMMUNOL, 5:EABB1817, 2020; © KELLY FINAN; STEVE GONG

BY AMANDA HEIDT

48 BIOBIZ Reading Minds

A nascent but growing consumer market is driving the development of sleek new tools for decoding brain activity. BY JEF AKST

48

53

READING FRAMES

Lessons About Fear from Our Deep Past

By studying the diversity of antipredator traits in nonhumans, we can learn to better manage the tradeoffs between caution and reward. BY DANIEL T. BLUMSTEIN

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FOUNDATIONS

Scientist as Subject BY AMANDA HEIDT IN EVERY ISSUE

8 10 54

CONTRIBUTORS SPEAKING OF SCIENCE THE GUIDE

CORRECTION:

In the September 2020 story “The Peopling of South America,” the language was updated to reflect the fact that Cuncaicha is the oldest known site in the high Andes, not the Andean region, and that Monte Verde is in southern Chile, but not near the country’s southern tip. The map graphic was also updated to correctly show Monte Verde’s location. The Scientist regrets the errors.

ANSWER

PUZZLE ON PAGE 10

H CO L VO C WE N Z E

S A S R T E X T A O E L T NUM I C RN I C K E O L RO MO L C P A CQU I R E D A L E O A LWA Y S G F R S S

J C R E P A N N T B N E S S E R A T S E E CU L E H O A RMS I E E N E R A S E

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Online Contents

THIS MONTH AT THE-SCIENTIST.COM: VIDEO

VIDEO

VIDEO

The Chemistry of Morality

The Sound and the Fear

The Interfacing Brain

Feature author Paul J. Zak, a neuroeconomist at Claremont Graduate University, discusses the role of oxytocin in mammalian social behavior in a 2011 TED Talk.

See University of California, Los Angeles, animal behavior researcher Dan Blumstein explain common characteristics of vocalizations that express fearful emotions.

Watch entrepreneur Connor Russomanno talk about his work on brain-computer interfaces.

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• Scientists have begun to uncover the mechanisms that may explain why some vaccines appear to protect people against more than just the target pathogen. • Should peer reviewers be paid for their work? AND MUCH MORE

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Contributors Daniel Blumstein grew up in the suburbs of Philadelphia, escaping to the nearby wilderness to backpack,

canoe, and mountaineer surrounded by plants and animals. Shortly after beginning college at the University of Colorado Boulder, in 1982, he realized that it was possible to make a career out of studying animal behavior. Thereafter, it was an easy decision for him to double major in environmental conservation and environmental, population, and organismic biology. After graduating, while cycling around the world, Blumstein happened upon a group of golden marmots (Marmota caudata)—cat-sized, semi-social rodents that live in burrows—in Khunjerab National Park in Pakistan, kicking off a decades-long interest in marmots that persists to this day. He completed a PhD in animal behavior at the University of California, Davis in 1994, and eventually landed a faculty position at the University of California, Los Angeles. As an ethologist, he studies social and antipredator behaviors in many animals, including all 15 species of marmots. When asked why he chose these charismatic rodents, Blumstein has a quick answer: “They’re diurnal and they have an address,” making them easy to mark and trap for study over long periods of time. Marmots also use an intricate series of verbal calls to signal danger, making them an ideal species in which to study the evolution of fear. In “Lessons About Fear from Our Deep Past” on page 53, Blumstein shares insights he’s gleaned into the human emotion from more than 35 years of watching animals behave. For Genna Reed, it was the lack of her own backyard growing up in New Jersey that first made her interested in the environment. As an undergraduate in biology at Lehigh University in Pennsylvania, and later as a master’s student majoring in environmental policy design at the same institution, Reed spent summers analyzing water samples from the nearby Hackensack Meadowlands, a series of sprawling wetlands subjected to decades of environmental abuse by industrial development. The recognition that corporations could shirk responsibility for actions that polluted the environment—and the toll those decisions exacted on local ecosystems and human communities—made her realize that “as much as I loved doing the work in the lab, I wanted to help bridge the work to the policy and help protect people’s health,” Reed says. After stints at the Environmental Protection Agency and the public interest organization Food & Water Watch, Reed joined the Union of Concerned Scientists in 2015, where she is now the lead science and policy analyst for the organization’s Center for Science and Democracy. Reed works to combat scientific misinformation, an endeavor made even more essential during the COVID-19 pandemic. The coronavirus, she explains, has created an accompanying “infodemic”—an overabundance of information, some of it false, that sows confusion and distrust. “During a pandemic, that is incredibly dangerous,” Reed says. “There are lives at stake.” On page 11, she shares how scientists can leverage their knowledge to help the public make informed choices and how the onus falls on each person to advocate for sound science in federal decision-making.

but it would be a mistake to paint him as just an economist. While Zak does hold bachelor’s degrees in mathematics and economics from San Diego State University and a PhD in economics from the University of Pennsylvania, he is also a certified phlebotomist and a self-taught neuroscientist. Zak views economics as a lens through which to study the mechanisms behind human choices, he says. “Economics ultimately is about decisions, and so decisions are a wonderful fulcrum to understand the variations [in behavior] across individuals.” One of Zak’s main research focuses has been oxytocin, a hormone and neuropeptide. Little research existed in the early 2000s on the role of this “love hormone” in humans. Zak suspected oxytocin might be involved in trust, generosity, and charitable giving, aspects of our social selves that are “important for humans economically and socially.” He first showed that changes in oxytocin could be measured in blood rather than spinal taps. By combining multiple streams of physiological data—cardiac rhythms, nervous system activity, and skin conductance, in addition to levels of oxytocin and other signaling molecules—Zak developed a new measure called “immersion,” which can predict a person’s likelihood of donating to a charitable cause with 82 percent accuracy. On page 18, he shares more about the experiments that led him to launch the company Immersion Neuroscience to help clients better predict people’s behavior. 8

T H E SC I EN TIST | the-scientist.com

DAVI; JA-REI WANG; PAUL J. ZAK

Paul J. Zak may be the director of the Center for Neuroeconomics at Claremont Graduate University in California,

FROM THE EDITOR

Wielding Fear The primordial emotion is apt to run amok. But harnessing it can lead to responsible behavior and sound thinking. BY BOB GRANT

ANDRZEJ KRAUZE

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ear is in the air. People everywhere have been navigating a potentially deadly new reality, living for months under the weight of a seemingly relentless pandemic. Economies, hobbled by the severe disruption to business as usual, struggle to regain a foothold, and many livelihoods hang in the balance. In addition, a US presidential election, arguably the most contentious in modern history, looms on the horizon, and some politicians are capitalizing on the fear-filled climate to achieve their personal, policy, and electoral goals. This month’s Reading Frames essay, from University of California, Los Angeles, animal behavior researcher Daniel Blumstein, discusses the ecological power and evolutionary history of fear. The emotion has for millennia helped species avoid being eaten, and a balanced approach to risk-benefit analysis has helped some individuals prosper and multiply while others succumbed to starvation or predation due to an over- or under-abundance of caution, respectively. “Fear,” Blumstein writes, “is an essential ingredient in healthy ecosystems and helps maintain biodiversity.” But the emotion can sometimes overtake sound thinking, and that potential imbalance has utility in the political realm, Blumstein notes. “[Fear] makes us vulnerable to politicians with malevolent intentions who make compelling advertisements that efficiently tap into our well-honed neurophysiological fear systems.” While editing Blumstein’s piece for this issue, I started to think of the overabundance of fear that lingers in our collective consciousness and colors our day-to-day existence. Not even my seven-yearold daughter is immune. “Dad, can you turn the news off?” she recently said in the car after hearing a radio report about an eightyear-old child who was shot in Chicago. “It scares me.” With a pang in my heart, I muted the radio. In that moment, fear was something to avoid, to run from. But perhaps we need to rethink our relationship with the emotion. Blumstein writes that fear can be useful and constructive in many situations and across many species. The scared marmot that cowers in its burrow as a golden eagle soars above has its fear to thank for saving its skin. But if the marmot doesn’t balance that fear with the courage necessary to seek food and mates, it could starve or otherwise fail to pass on its genetic legacy. This is what we risk when fear runs amok. I think it’s what Franklin D. Roosevelt was getting at in the opening of his 1933 inaugural address: “. . . the only thing we have to fear is fear itself . . .” What followed this frequently cited phrase really drives home FDR’s point: “. . . nameless, unreasoning, unjustified terror which paralyzes needed efforts to convert retreat into advance.” Far be it from me to disagree with FDR’s famous sentiment, which I interpret as a call to trust in the country’s leaders in a time

of peril and upheaval as the US economy grappled with the Great Depression. But in our own challenging times, I would suggest that we embrace fear, rather than fearing or avoiding it. A healthy measure of fear can help us make smarter choices—wearing a mask at the grocery store, driving safely, investing wisely in the stock market, deferring to the advice of public health experts, etc. An overactive sense of fear can indeed be problematic, clouding our vision and leading us astray from our foundational ethics and morals. But on the other end of that spectrum, if we seek an existence free from fear, we are rejecting an elemental force that has shaped the course of our evolution and the functioning of our living planet. We must strike the same balance that successful marmots and our forebears achieved: have enough fear to modulate our behavior in constructive ways, but not so much that we abandon our values or squander opportunities. This is where the use of fearmongering by some in the political realm is particularly nefarious. To accomplish short-term political goals, such as getting votes or donations, some individuals are perfectly OK with sowing the seeds of terror. And in doing so, they often push logic, science, rationality, and kindness to the periphery. It is my sincere hope that as we progress through this challenging year, we realize that there are things that we should fear and that our trepidation, appropriately contextualized, will lead us in the right direction. But we must remain vigilant to avoid forsaking our humanity by engaging in an overactive, imagined, or exploited sense of dread. Let’s stop fearing fear so that we can understand it and use it to make ourselves, one another, and the world better. g

Editor-in-Chief [email protected] 10.2020 | T H E S C IE N T IST

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This is deadly stuff. You just breathe the air and that’s how it’s passed. And so that’s a very tricky one. That’s a very delicate one. It’s also more deadly than even your strenuous flu.

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BY EMILY COX AND HENRY RATHVON

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7. Cerebrum’s convoluted surface 8. Drill a hole in the skull of 9. Unit for measuring an electric eel’s shock 10. Hypoesthesia 11. German physician Carl, who researched encephalopathy 13. Maze runners in many labs 15. One of 100 in a googol 17. Tiny bit of a chemical compound 19. Nonheritable, as a trait 22. Brachia 23. When light speed is constant 24. Groups below families and above species

1. 2. 3. 4.

The present geologic epoch Drug for controlling cholesterol Neural impulse carrier Sample from bone marrow or fetal tissue (2 wds.) 5. Physician Edward, who pioneered vaccination 6. Felidae members 12. Firmly applied cloth dressing 14. Region at the end of a chromosome 16. Pertaining to eyes 18. Linear features of a food web 20. Young of a yak, camel, or whale 21. Stereotypical foes of 6-Down Answer key on page 5

10 T H E SC I EN TIST | the-scientist.com

—US President Donald Trump, explaining his understanding of the threat of SARS-CoV-2 in a February 7 phone call recorded by The Washington Post journalist Bob Woodward. These comments contrasted sharply with the muted position Trump voiced in public, for example, saying at a late-February press conference that the coronavirus was “a little bit like the flu.”

This may be the most shameful moment in the history of U.S. science policy. —H. Holden Thorp, Editor in Chief of Science, in a September 11 editorial reacting to the revelation that Trump understood the seriousness of SARS-CoV-2 even as he publicly downplayed the risk of the virus.

© JONNY HAWKINS

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CRITIC AT LARGE

The Disinformation Pandemic For scientists to have a chance of defeating COVID-19, they must also work to quash the rising tide of bad information surrounding the disease. BY GENNA REED

© ISTOCK.COM, FEODORA CHIOSEA

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s COVID-19 wreaks havoc across the world, scientists are making unparalleled, heroic strides to discover the virus’s biology and vulnerabilities. We have learned far more about SARS-CoV-2 than we knew about any pandemic-sparking pathogen in human history within a year of its emergence, and experts are working tirelessly to publicly share this information. These efforts should be bolstered and carefully considered by federal governments to save lives and stem the tide of contagion. In the US, however, the Trump administration has censored scientists, diminished the Centers for Disease Control and Prevention’s role in leading the pandemic response, politicized tracking and storage of health data, and attempted to undermine the credibility of its own researchers. A government actively silencing scientific voices has collided with a shrinking independent news environment and growing dependence upon social media for information. This has meant that there is a dearth of clear, science-based guid-

ance—and in that void, both intentionally false information (disinformation) and unintentionally misleading information (misinformation) proliferate. As COVID-19 continues to claim lives, some US political leaders and pundits are spreading disinformation to understate the pandemic’s severity, discredit public health experts’ advice on preventive social distancing measures, and sow distrust of government data. The World Health Organization has defined this landscape as an “infodemic:” “an over-abundance of information—some accurate and some not—that makes it hard for people to find trustworthy sources and reliable guidance when they need it.” Acceptance of disinformation can result in a cascade of dangerous events, such as consumers ingesting a form of chloroquine, government shelving important scientific work, scientists facing serious harassment, and the loss of public trust in the government as a source of science-backed advice, which is crucial to help keep us safe now and during future national crises. 1 0. 202 0 | T H E S C IE N T IST 1 1

CRITIC AT LARGE That’s why scientific voices are needed, now more than ever, to cut through the noise. Here are some ways that all scientists can help arm the public with the information they need to make evidence-based decisions about their lives as COVID-19 continues to spread. Promote science literacy. Research has shown there are partisan differences affecting trust in science and public health measures related to COVID-19, but people generally trust scientists as messengers. A 2019 Pew poll found that 86 percent of the more than 4,400 Americans surveyed had a great deal or fair amount of confidence in scientists. The coronavirus pandemic presents an opportunity for scientists to have conversations with friends, family, colleagues, and members of the public about scientific concepts. Wider understanding of the scientific process may lead to a fuller grasp of the time it takes to make discoveries and build knowledge about COVID-19. Likewise, it will help people understand that one study is not representative of the scientific consensus and less meaningful on its own—which is hard to hear when findings are desirable.

A government actively silencing scientific voices has collided with a shrinking independent news environment and growing dependence upon social media for information.

Address racism head-on. For too long, the scientific community has been perpetuating racist policies and practices that have excluded people of color—continuing to honor racist scientists, making work environments hostile, and participating in racist research that perpetuates falsehoods. While trust in scientists is generally high, trust in medical scientists is lower among Black adults than among other demographics. As a result, Black adults are more skeptical than Hispanic and white adults when it comes to experimental treatments for COVID-19. Communities of color are hit harder by the virus due to systemic racist policies that have led to health inequities, so scientists have a responsibility to rebuild trust and help ensure that accurate information is heard by those who need it most. A first step in rebuilding public trust among minority populations is for the scientific community to work toward being antiracist and advocate for radical change within research institutions. Scientists should foster inclusive, diverse, and equitable work environments to better recruit, retain, and lift up people of color in STEM fields. Make scientific information public. Scientists conducting and publishing research have more avenues than ever to make information about their studies and data accessible to the public. Researchers can post their work on preprint servers and publish in open access journals, pitch it to science and main12 T H E SC I EN TIST | the-scientist.com

stream journalists, summarize the findings in an article for diverse audiences, or share it far and wide on social media. Science agencies and research institutions have scientific integrity and media policies that protect scientists’ right to speak about their work. If this isn’t the case at your institution, advocate internally for its creation. If your scientific home does maintain these policies, hold it accountable and ensure they’re enforced. Inoculate the public against falsehoods with accurate information. There is so much power in accurate information communicated by experts. Quality information can help to shield the public against bad information. When confronted with false information on social media, scientists should call it out, debunk it, and cite sources so that people who engage with the post in the future will, if they look far enough, encounter the truth. Research has shown that warning people about the ways such information spreads and providing scientific facts can work to reduce the likelihood of dis- and misinformation taking hold. Scientists can also help guide others to credible sources for public health information and explain what makes a source reliable so that people seek out the right messengers as they make decisions to keep themselves and their families safe. Advocate for the role of independent science in decisionmaking. Science advocacy has grown in the wake of an unprecedented assault on federal science and scientists. Become a member of the Union of Concerned Scientists (UCS) Science Network or of another science advocacy organization, and join your peers showing up at virtual hearings, writing public comments, and asking local, state, and federal leaders questions about the information and experts they’re using to support their responses to COVID-19. Scientists can nominate themselves or peers to serve on federal advisory committees tackling some of the issues related to the virus to help the government make informed decisions. One of the lessons to take away from the myriad failures of this White House in responding to the spread of COVID-19 is that sidelining scientists’ voices during a public health crisis has grave consequences. It has resulted in the needless deaths of hundreds of thousands and in countless more lives turned upside down. It has also allowed the infodemic that accompanies and exacerbates COVID-19 to take hold. It will take more than scientists to get us out of this crisis, but scientists need to make their voices heard and tackle misinformation head on. A new generation of researchers is watching and learning, inspired by the heroes they see on the frontlines and those innovating to solve one of the world’s most devastating problems. Let’s give them the tools they need to help ensure that our country never makes the same mistakes again. g Genna Reed is a lead science and policy analyst in the Center for Science and Democracy at the Union of Concerned Scientists. Follow her on Twitter @gennareed and read her blog at https:// blog.ucsusa.org/author/genna-reed.

Notebook

E.A. MOSEMAN ET AL., SCI IMMUNOL, 5:EABB1817, 2020

Viral Invasion

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ailure to smell fresh cut grass or a poo-laden diaper is, at least these days, a potential sign of COVID-19 infection. “People say things smell funny or they can’t smell at all,” says Harvard University neurobiologist Sandeep Datta. Reading about people’s experiences of anosmia, Datta wondered how SARS-CoV-2, the virus that causes COVID-19, might be having this effect. One possibility was that the virus attacks cells that line and support olfactory neurons in the nose. Alternatively, SARS-CoV-2 could be directly targeting the neurons themselves. Datta’s and other researchers’ work— which so far includes genetic and cellu-

lar analyses in humans, rodents, and monkeys—suggests that mammalian olfactory neurons don’t have the right cell receptors for the virus to get inside them, meaning that the lack of smell most likely comes from the infection of olfactory support cells. But not everyone is convinced by the data; some researchers continue to argue that SARSCoV-2 can infect neurons in the nose and ultimately invade the brain this way. If the virus were able to enter olfactory neurons, it’s in theory a “very short route,” along a single neuron, from nose to brain, notes pathologist Debby van Riel of Erasmus Medical Center in the Netherlands. Van Riel, who began studying influenza’s ability to attack nerve fibers involved in olfaction decades ago, says she’s not convinced SARS-CoV-2

OCTOBER 2020

LINE OF DEFENSE: T cells (red) in the olfactory bulb of mice engage with antigens on vesicular stomatitis virus, leading to cell signaling (green) that ultimately prevents neuronal death.

Microglia were gobbling up bits of the virus from infected neurons in the olfactory bulb.

can infect olfactory neurons. But the discussion has reminded scientists how little they know about viral invasion through the nose. That’s why, she says, she was fascinated to read about recent experiments by Duke University immu1 0. 202 0 | T H E S C IE N T IST 1 3

NOTEBOOK

NEURONAL ROUTE: Six days after infection,

nologist Ashley Moseman and colleagues that tracked immune responses in mice that had had vesicular stomatitis virus (VSV) squirted up their noses. VSV is known to infect olfactory neurons in mice. The team was interested in what Moseman calls a “sneaky front door” for this virus to travel via nerve fibers that project from the nasal cavity and connect with neurons deeper in the brain. Mice that get the virus don’t die from the infection, even if it enters the brain, and they don’t suffer significant brain damage, either. Interested in how the mice avoided this damage, Moseman and his colleagues decided to tag VSV particles with fluorescent markers, then inject them into the mice’s noses to see if the team could uncover how the immune system responded to the infection. The fluorescent imaging showed that VSV was infecting neuronal fibers in the nose and also neurons farther up in the olfactory bulb leading to the brain. “VSV gets into neurons in the nose and actually kills those neurons,” says study coauthor Dorian McGavern, a viral immunologist at the National Institute of Neurological Disorders and Stroke. “But those neurons can grow back. They can replenish the system and restore sense of smell.” Neurons farther up in the brain can’t be regenerated, yet, oddly, they didn’t appear to die after infection. Probing further, Moseman, McGavern, and their colleagues revealed how those neurons that sat deeper in the brain were spared. Microglia, the primary immune cells of the brain, were gobbling up bits of the virus from infected neurons in the olfactory bulb. Although not getting infected themselves, the microglia were projecting those viral bits, like flags, on their cell surfaces, attracting killer T cells in the blood to come to the brain and mount an immune defense against the microglia, 14 T H E SC I EN TIST | the-scientist.com

rather than against the infected neurons, which also display viral bits on their surfaces. The interaction between the microglia and the killer T cells led the T cells to release cytokines that triggered the elimination of the virus from infected neurons without killing those neurons in the process, the team found (Sci Immunol, 5:eabb1817, 2020). “Microglia are playing an absolutely critical role here in protecting neurons within the brain,” McGavern says. What’s not yet clear is if the killer T cells do, in fact, kill the virus-flaunting microglia or whether the two types of immune cells interact in some other way to spur T cells to release the viruseradicating cytokines. “It’s possible that microglia sort of take that hit on behalf of everybody,” Moseman says, “and in doing so T cells avoid going to try to engage with neurons, which

don’t replenish themselves very well.” Microglia are replaceable, he speculates, so losing them might be less consequential than the irreversible damage of neuronal death. The work offers a glimpse at how the body and brain respond to invasion of viruses such as VSV through the nose, van Riel says. “If you know the way the body can handle an infection without causing severe [brain] damage, it could lead to new insights, which could lead to therapeutic strategies.” However, scientists still don’t yet have a good grasp of which viruses can enter the central nervous system this way. That may change as more researchers investigate whether or not SARS-CoV-2 can. The work might even suggest that each and every virus elicits a unique immune response in the brain, van Riel notes. “I think we’re only seeing the tip of the iceberg.” —Ashley Yeager

SCI IMMUNOL, 5:EABB1817, 2020

virus (green) appears in nerve fibers that project into the olfactory bulb (OB) of mice, meaning the virus has spread from the nose into the brain.

THE FUTURE OF NEURODEGENERATION RESEARCH

1

Fast conformational dynamics Proteins involved in the onset and progression of neurodegenerative diseases (ND) exist in different conformational states - as monomers or oligomers. Their characterization is very challenging because they can transition from one state to the other very fast.

CHALLENGE Many biophysical methods take a long time to set up and run - by the time the measurement is done, your protein may have changed its conformation.

SOLUTION With NanoTemper tools, setup and run times take only a few minutes so you can work with proteins with fast conformational dynamics with confidence.

2

Monomeric vs. oligomeric Studying small molecule or protein interactions in ND requires working under conditions that either favor the monomeric or oligomeric state of these molecules.

CHALLENGE Researchers need biophysical methods that allow them to work at low sample concentrations to study the monomeric state, and also at high concentrations to investigate the oligomeric state.

SOLUTION NanoTemper offers tools that perform measurements with sample concentrations from mM all the way down to pM. So you can evaluate the monomeric and oligomeric states.

THE FUTURE OF NEURODEGENERATION RESEARCH Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and others, cause neuronal degradation and death, resulting in progressive brain function deterioration. Although our understanding of neurodegenerative disease mechanisms is still in its relative infancy, scientists are shaping a clearer picture of neurodegenerative disease pathogenesis and development by the day. The characterization of several prominent molecular and cellular mechanisms common to multiple neurodegenerative disorders is paving the way for identifying new potential therapeutic targets and treatment approaches.

Understanding and Targeting Pro

Different neurodegenerative disorders often share simila histopathological presentations, such as the abnormal re aggregation of certain proteins (beta-amyloid (Aβ), tau, α TAR DNA-binding protein (TDP)-43, or polyglutamines).1

Spatial awareness Recent studies have identified physical, genomic, and proteomic spatial patterns of disease progression.2 Imaging techniques such as mass spectrometry-based molecular imaging help to determine in situ protein, lipid, metabolite, and peptide profiles.3 These patterns can also be discovered through –omics-based screening of tissue or fluid samples.2 Knowing that different elements are active in different brain regions at different times should go a long way towards shaping novel diagnostic approaches for early detection, allowing us to diagnose neurodegenerative disorders before they become symptomatic.



Prot

Heat s regula aggre HSP/H to yea

References 1. L. Gan et al., “Converging pathways in neurodegeneration, from genetics to mechanisms,” Nat Neurosci, 21(10):1300-9, 2018. 2. J. Xu et al., “Regional protein expression in human Alzheimer’s brain correlates with disease severity,” Commun Biol, 2:43, 2019. 3. W. Michno et al., “Molecular imaging mass spectrometry for probing protein dynamics in neurodegenerative disease pathology,” J Neurochem, 151(4):488-506, 2019. 4. N. Fujikake et al., “HSF1 activation by small chemical compounds for the treatment of neurodegenerative diseases,” In: Nakai A. (eds) Heat Shock Factor. Springer, Tokyo, 277-92, 2016. 5. I. Lindberg, et al., “Chaperones in neurodegeneration,” J Neurosci, 35:13853-59, 2015. 6. J. Shorter, “Engineering therapeutic protein disaggregases,” Mol Biol Cell, 27:1556–60, 2016. 7. F.M. Menzies et al., “Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities,” Neuron, 93(5):1015-34, 2017. 8. V.A. Polito et al., “Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB,” EMBO Mol Med, 6:1142-60, 2014. 9. T. Jiang et al., “Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance,” Neuropharmacology, 85:121-30, 2014. 10. I. Lonskaya et al., “Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer’s disease models,” Neuroscience, 304:316-27, 2015. 11. B. Wolozin, P. Ivanov, “Stress granules and neurodegeneration,” Nat Rev Neurosci, 20:649-66, 2019. 12. A. Currais et al., “Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain,” FASEB J, 31(1):5-10, 2017. 13. S.E. Hickman et al., “Microglia in neurodegeneration,” Nat Neurosci, 21(10):1359-69, 2018. 14. S.E. Hickman et al., “Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice,” J Neurosci, 28:8354-60, 2008.

Lysos for ne dysfu mTOR in vitr contin

15. H. Keren-Shaul et al., “A unique microglia type associated with restricting development of Alzheim 16. H. Asai et al., “Depletion of microglia and inhibition of exosome synthesis halt tau propagation,” Na 17. D.C. Lee et al., “LPS-induced inflammation exacerbates phospho-tau pathology in rTg4510 mice,” J 18. K. Takahashi et al., “Clearance of apoptotic neurons without inflammation by microglial triggering 19. V. Zujovic et al., “In vivo neutralization of endogenous brain fractalkine increases hippocampal TNF J Neuroimmunol, 115:135-43, 2001. 20. S.S. Minami et al., “Progranulin protects against amyloid beta deposition and toxicity in Alzheimer’ 21. J.M. Van Kampen et al., “Progranulin gene delivery protects dopaminergic neurons in a mouse mod 22. D.C. Lee et al., “LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice,” J 23. D.J. Finneran, K.R. Nash, “Neuroinflammation and fractalkine signaling in Alzheimer’s disease,” J Ne 24.H. Zheng et al., “TREM2 in Alzheimer's disease: microglial survival and energy metabolism,” Front A 25. F.M. LaFerla, K.N. Green, “Animal models of Alzheimer disease,” Cold Spring Harb Perspect Med, 2:a 26. H. Sasaguri et al., “APP mouse models for Alzheimer’s disease preclinical studies,” EMBO J, 36:2473 27. M. Goedert et al., “Propagation of tau aggregates and neurodegeneration,” Annu Rev Neurosci, 40:

otein Accumulation

ar egional α-synuclein, The underlying

mechanisms behind these phenomena also tend to overlap to some degree. Researchers are looking into the molecular interactions that take place in these common traits to find new ways to diagnose and treat disease.

Stress and inflammatory responses Stress stimuli and translational inhibition cause ribonucleoprotein stress granules to form. These are usually transient, protecting mRNA from degradation until translation can resume.7 However, agingrelated chronic stress signaling results in persistent stress granule presence, providing a launching point for pathological protein accumulation.7,11 Protein aggregation also stimulates inflammation, which in turn drives progressive neurodegeneration.12 Inflammation may therefore serve not only as a marker for early-onset disease, but also a therapeutic target to slow or arrest disease progression.



   

 



tein quality control

shock proteins (HSPs) and heat-shock transcription factors (HSFs) ate protein folding, with impairments leading to misfolding and egation. Scientists are therefore looking at increasing or prolonging HSF activity, or even introducing disaggregase HSPs endogenous ast as new ways to impede protein aggregation.4-6

somal autophagy also removes protein aggregates and is necessary ervous system function.7 Boosting autophagy or rectifying pathway unction through gene therapy approaches8 or by inhibiting R-dependent9 or AMPK-dependent pathways10 has protected ro and animal models from neurodegeneration and warrants nued investigation.7

mer’s disease,” Cell, 169:1276-90.e17, 2017. at Neurosci, 18:1584-93, 2015. J Neuroinflammation, 7:56, 2010. receptor expressed on myeloid cells-2,” J Exp Med, 201:647-57, 2005. Falpha and 8-isoprostane production induced by intracerebroventricular injection of LPS,”

’s disease mouse models,” Nat Med, 20:1157-64, 2014. del of Parkinson’s disease,” PLoS One, 9:e97032, 2014. J Neuroinflammation, 7(56):56, 2010. euroinflammation, 16:30, 2019. Aging Neurosci, 10:395, 2018. a006320, 2012. 3-87, 2017. :189-210, 2017.

28.J. Blesa, S. Przedborski, “Parkinson’s disease: animal models and dopaminergic cell vulnerability,” Front Neuroanat, 8:155, 2014. 29. F. Jacob, M.L. Bennett, “Modeling neurological disease using human stem cell-derived microglia-like cells transplanted into rodent brains,” Lab Anim, 49:49-51, 2020. 30. T. Saito et al., “Single App knock-in mouse models of Alzheimer’s disease,” Nat Neurosci, 17:661-63, 2014. 31. T.M. Dawson et al., “Animal models of neurodegenerative diseases,” Nat Neurosci, 21:1370-79, 2018. 32. K.S. Sheinerman, S.R. Umansky, “Early detection of neurodegenerative diseases: Circulating brain-enriched microRNA,” Cell Cycle, 12(1): 1-2, 2013. 33.M. Agrawal, A. Biswas, “Molecular diagnostics of neurodegenerative disorders,” Front Mol Biosci, 2:54, 2015. 34. J. Simrén et al., “An update on fluid biomarkers for neurodegenerative diseases: Recent success and challenges ahead,” Curr Opin Neurobiol, 61:29-39, 2020. 35. M.A. Metrick et al., “Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons,” Proc Natl Acad Sci USA, 116(46):23029-39, 2019. 36. F. Durães et al., “Old drugs as new treatments for neurodegenerative diseases,” Pharmaceuticals (Basel), 11(2):44, 2018. 37. C.W. Gantner et al., “Viral delivery of GDNF promotes functional integration of human stem cell grafts in Parkinson's disease,” Cell Stem Cell, 26(4):511-26.e5, 2020. 38. T. Martínez et al., “Silencing human genetic diseases with oligonucleotide-based therapies,” Hum Genet, 132:481-93, 2013. 39. S.S. Titze-de-Almeida et al., “The promise and challenges of developing miRNA-based therapeutics for Parkinson's disease,” Cells, 9(4):841, 2020.

Mighty Microglia

As the main immune cells in the brain (comprising 5-12% of all CN cells), microglia, largely directed by external stimuli, serve a diver range of neuroimmunity roles.13 Since abnormal microglial functi hallmark of many neurodegenerative diseases, scientists are expl the potential therapeutic benefits of modulating microglial functi

Microglia and neurodegeneration Microglial dysfunction exacerbates neurogenerative disease mechanisms. For example, decreased microglial clearance of Aβ increases aggregation. This promotes inflammation and creates deleterious disease-associated microglia (DAM) cells that present dysregulated expression of sensing, housekeeping, and host defense genes.14,15 Likewise, while microglia normally remove excess tau, proinflammatory microglial phenotypes promote tau aggregation and phosphorylation.16,17



Engaging f

Microglia exist i necessary: a sen environment fo removal, synap and a host defe proteins, cance preventing initi behavior agains potential.

IN PURSUIT OF A CURE Animal Models Transgenic animals replicate geneor protein-level etiologies,25-27 while signaling pathway-based disease causes can be mimicked in animals using pharmacological inhibition.28 Chimeric models featuring modulated human cells introduced into animals may better represent clinically relevant phenomena.29 Interestingly, creating phenotypic phenomena such as protein deposition and aggregation do not always lead to the same behavioral changes in animals as observed in patients.25,30 Novel models should focus on reproducing specific aspects or features to isolate and characterize related mechanisms. Multi-omic approaches will aid researchers in determining how well a given model matches human pathogenesis and progression.31

detection of pro biomarker meas a more compreh modalities to pro

NS rse ion is a loring ion

or rectifying dysfunction. Our understanding of microglia remains incomplete because of an inability to study the cells in their native environment. Improving ex vivo recapitulation of local environments or developing transcriptomic and epigenetic profiling is crucial to properly harnessing microglia against neurodegenerative disease.13

Regulating microglia for therapeutics 

functional plasticity

in three main states, toggling between them as ntinel state where they constantly scan the external or changes, a housekeeping state that promotes debris ptic remodeling, and other routine upkeep processes, ense state that protects against pathogens, accumulated er cells, and other threats.13 This plasticity is integral to ial pathogenesis. The potential ability to direct microglia st disease mechanisms offers appealing therapeutic

Early Detection Early detection is vital to effective treatment since neurodegeneration often starts decades prior to any visible symptoms.32 Neuropathology generates numerous novel signatures, but detecting these biomarkers has proven difficult.33,34

Researchers have greatly improved assay sensitivity, with common circulatory markers such as Aβ and tau now detectable at femtomolar concentrations.34 Amplification techniques facilitate otein aggregates at very low levels in tissue samples.35 Fluid surements complement MRI and PET imaging to establish hensive diagnostic picture. Tracers now allow imaging ovide spatially relevant molecular-level information.34

Three major signaling pathways regulate microglia function: Trem2, Cx3cr1-fractalkine, and progranulin. Trem2 signaling is integral to microglial phagocytosis, proliferation, and survival, Cx3cr1-fractalkine interactions mediate sensing and housekeeping homeostasis, and progranulin pathway activation limits inflammation.13,18-21 Deficiencies in these three pathways—individually or in tandem—have been linked with neurotoxicity and increased disease risk.18,19,22 Naturally, augmenting microglial regulatory pathways is a therapeutic target, with progranulin overexpression and increased fractalkine signaling benefitting animal models of Alzheimer’s and Parkinson’s disease.20,21,23 Much work remains, given the complex nature of these pathways.24

New Therapeutic Avenues Neurodegenerative disease treatment currently focuses on mitigating symptoms and delaying progression.36 That is changing. Scientists are exploring new methods that attack pathogenic mechanisms, such as blocking the production of aggregating proteins using short hairpin RNAs, miRNAs, antisense oligonucleotides, and CRISPR, or recapitulating dead neurons with stem cell-derived de novo tissue, which can be further enhanced using neurotrophic factors.1,37-39 Scientists are also investigating broader systemic targets, such as boosting CNS cellular metabolism, decreasing local inflammation, or restoring ionic homeostasis.1 Finally, advances in in silico drug screening advances mean previously characterized compounds are being repurposed to combat neurodegenerative disease.36

3

Intrinsically disordered proteins Intrinsically disordered proteins (IDP) - those without rigid 3D structures - are associated with many ND. Their structure changes depending on the environment or ligands, which makes is very difficult to work with them.

CHALLENGE Characterizing IDP with biophysical methods that require immobilization to a solid support and put limitations to the buffer conditions can disturb IDP folding state.

SOLUTION

4

High molecular weight aggregates Misfolded proteins escape cellular quality controls and form aggregates that have the potential to compromise cell function. Because they can have high molecular weight, these aggregates are tricky to work with.

CHALLENGE In order to understand the modulation of these aggregates by measuring binding affinities, researchers must find technologies that allow them to study high molecular weight aggregates.

SOLUTION Evaluating high molecular weight aggregates with NanoTemper technologies is simple because measurements are independent of the size and mass of the binding partners.

Studying IDP with NanoTemper technologies is so easy. You skip immobilization and measure in solution and in close to native conditions.

nanotempertech.com/neurodegenerative-diseases

THE FUTURE OF NEURODEGENERATION RESEARCH About NanoTemper Technologies Our mission at NanoTemper Technologies is to enable everyone to do science that matters by always pushing the limits. We’re focused on making biophysical tools that address challenging characterizations in any industry. Working with customers striving to make a difference in the world gets us excited. If you’re looking to screen hits, measure binding affinity, characterize protein stability or protein quality for challenging targets like intrinsically disordered proteins, PROTACs, membrane proteins, or RNA-based therapeutics, let’s talk.

Hungry for Knowledge In Greek mythology, Orpheus descends to the underworld and persuades Hades to allow him to take his dead wife, Eurydice, back to the realm of the living. Hades agrees, but tells Orpheus that he must not look back until he has exited the underworld. Despite the warning, Orpheus glances behind him on his way out to check whether Eurydice is indeed following him—and loses her forever. The story hints at a dark side to curiosity, a drive to seek certain kinds of knowledge even when doing so is risky—and even if the information serves no practical purpose at the time. In fact, the way people pursue information they’re curious about can resemble the drive to attain more tangible rewards such as food—a parallel that hasn’t been lost on scientists. To inves-

tigate the apparent similarity between curiosity and hunger, researchers led by Kou Murayama of the University of Reading in the UK recently devised an experiment to compare how the brain processes desires for food and knowledge, and the risks people are willing to take to satisfy those desires.

Similar brain regions are involved in both hunger and curiosity.

Beginning in 2016, the team recruited 32 volunteers and instructed them not to eat for at least two hours before coming into the lab. After they arrived, the volunteers’ fingers were hooked up to electrodes that could deliver a weak current, and researchers calibrated the level of electricity to what each participant reported

was uncomfortable, but not painful. Then, still hooked up to the electrodes, the volunteers were asked to gamble: they viewed either a photo of a food item or a video of a magician performing a trick, followed by a visual depiction of their odds of “winning” that round (which ranged from 1:6 to 5:6). If they accepted the gamble and won, based on a random, computergenerated outcome, they’d receive tokens that gave them a better chance of getting the pictured food or the explanation for the magic trick at the end of the experiment. If they lost, they’d instead get tokens that increased their chances of getting an electric shock at the end of their session. On being presented with their odds of winning, participants reported how desirable they found either the food or the explanation of the magic trick, and whether they were willing to accept the gamble. Not surprisingly, the chances of winning and the desirability that participants assigned the food or magic reveal

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NOTEBOOK

16 T H E SC I EN TIST | the-scientist.com

regions involved in the two motivations were indeed the same. When participants viewed either the food or the curiosityinducing stimulus—which, in this functional MRI (fMRI) experiment, could be either a magic trick or a trivia question—a region deep in the brain called the nucleus accumbens became more active, particularly if they rated the food or solution as highly desirable. If the subjects then decided to accept the gamble, three areas known to be involved in reward processing—the nucleus accumbens, the bilateral caudate nucleus, and the ventral tegmental area—lit up more than they did if participants decided not to take the chance. The experiment showed that curiosity, like the desire for tangible reward, induces people to take risks, “and it seems to have [a] very similar underlying mechanism in the brain,” Lau says. “This study is particularly interesting because it investigates how curiosity can act as a motivational drive,” says Andrew Lutas, a neuroscientist at Beth

People are not just willing to pay, say, a few cents for it, but are also willing to take the risk of an electric shock. —Ming Hsu University of California, Berkeley

Israel Deaconess Medical Center who studies neural circuitry in rodents and was not involved in the work. The fact that similar brain regions are involved in both hunger and curiosity means that discoveries made in animals about foodrelated reward circuits in the brain are also likely to be relevant to curiosity and other drives that are difficult to study in model organisms, he adds. Researchers have typically measured human curiosity by asking subjects how much money they’d pay for a piece of information, or having them tell researchers how desirable the information was to them, notes Ming Hsu,

ANDRZEJ KRAUZE

each correlated with their likelihood of accepting the gamble. But the category of the reward—food or satiated curiosity—was not a statistically significant predictor of participants’ decisions. Behaviorally, at least, the drives were similar in how they affected the participants’ risk-taking. The research team suspected that the neural processes underlying the risk-taking would also be similar for the two types of motivation. “There is a body of literature suggesting that, as far as the neurobiological mechanisms [go], they seem to be similar to a certain extent,” says cognitive neuroscientist Johnny King Lau, a postdoc at the University of Reading and the study’s first author. To test this hypothesis for their risk-taking scenario, the researchers ran an experiment similar to the first, this time with a different set of subjects making their decisions inside an MRI machine as their brains were scanned. The patterns of blood flow revealed by the scan indicated that the brain

IRRESISTIBLE URGE: Edward Poynter’s Orpheus

WIKIMEDIA

and Eurydice depicts the mythical Greek hero just before his curiosity gets the better of him.

a neuroeconomist at the University of California, Berkeley, who also was not involved in the study. “To show this with electric shock I thought was very cre-

ative, very novel,” he says. “And it really, I think, underscores the point of just how valuable curiosity is that people are not just willing to pay, say, a few cents for it,

but [are] also willing to take the risk” of an electric shock. While the research team’s fMRI scans implicate the same brain regions in processing hunger and curiosity, the images don’t have the resolution to identify the specific circuitry involved, Hsu notes, so a question for future studies will be “whether the same neurons are firing the same way with respect to curiosity and food.” Another unanswered question, he says, is what makes some facts uninteresting to people, while other tidbits—say, celebrity gossip—are irresistible to many. “We can measure the amount of curiosity that people express,” he says. “But what we don’t know is, why are people curious about some information but not others?” —Shawna Williams

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18 T H E SC I EN TIST | the-scientist.com

BY PAUL J. ZAK

CREDIT © ISTOCK.COM, LINE MAKSIM TKACHENKO

People

Combining measures of attention and emotional state, we are getting closer to forecasting human behavior.

CREDIT LINE

1 0. 2020 | T H E S C IE N T IST 1 9

W

hen he asks if I need help, I am mortified. At 38,000 feet, the stranger next to me believes I’m having a crisis. Maybe I am. I’m crying uncontrollably as I watch the scene unfolding before me on the seven-inch screen. Damn that Clint Eastwood. Movies, songs, and photographs can bring us to tears of joy or sadness. Why did Million Dollar Baby reduce me to a quivering mess while other people enjoy it without the emotional overflow? My lab has spent much of the last 20 years measuring brain activity to predict when an experience will induce emotional reactions. Our research established the neurochemical oxytocin as a key signal that the brain values an experience and thereby affects people’s decisions, and a vast literature now describes oxytocin’s role in motivating prosocial behaviors such as trustworthiness, generosity, and charitable giving. Recently, we found that combining measures of oxytocin with other neurochemicals allows us to build models that accurately predict what individuals and populations of people will do—such as whether they will be invested enough in Hilary Swank’s character to cry when she dies. Neural measures are valuable because people have difficulty articulating the motivations for their actions. As a result, survey-based research can lead organizations that supply goods and services to waste time and money offering people the wrong things. To improve market assessments, my team and I have worked to identify what neurological correlates are able to forecast human behavior. We even launched a startup and developed a software platform so that companies can use neural responses to predict which TV shows and movies will be hits and which songs will reach Billboard’s number one, as well as to identify learners who have effectively understood education and training and to drive up productivity after virtual meetings. While scientists are just beginning to use neurological measurements to predict what

20 T H E SC I EN TIST | the-scientist.com

people will do, the technology holds great promise to improve people’s lives.

Trusting oxytocin Since its discovery by English pharmacologist and physiologist Henry Dale in 1906, oxytocin has revealed itself to be the quintessential mammalian peptide, being part of a cascade of factors involved in childbirth and parental care. Synthesized in the hypothalamus, it functions both as a hormone—binding to receptors on cells in organs in the body such as the uterus (to trigger contraction) and breasts (to initiate milk letdown)—and as a neuromodulator, binding to receptors on neurons in the brain. Animal research over the last 40 years has established that oxytocin mediates social behaviors.1 When group-living mammals encounter familiar conspecifics, oxytocin is released in the brain and motivates approach behaviors. The peptide also plays a critical role in maternal attachment, pair bonding, and even the maintenance of cross-species “friendships” that are valuable for protection, food sharing, and learning through play. Oxytocin is typically measured in cerebrospinal fluid in animals. When I hypothesized that oxytocin might explain human social behaviors, I did not want to subject people to spinal taps. An odd property of oxytocin is its simultaneous release in the brain from cells of the hypothalamus and in peripheral blood from the posterior pituitary. Taking advantage of this property, my lab developed a protocol to measure the change of oxytocin in blood that would reliably reflect the change in the brain. But oxytocin has a 3–5 minute halflife and relatively fragile chemical bonds, so we would have to draw blood rapidly, and keep it cold while it was processed. It was a tricky procedure to sort out, and for a month my arms were riddled with prick marks as I let my PhD student Bill Matzner, also a practicing physician, practice on me, the only test subject I knew would consent to multiple needle sticks. Once we learned how to handle the blood samples, we still needed a way to stimulate oxytocin release. Childbirth

and breastfeeding would not do, but the animal literature had demonstrated that oxytocin release could be triggered by a social stimulus. So I turned to a senior colleague for advice. In the 1990s, members of Vernon Smith’s lab at the University of Arizona experimented with sequential moneysharing tasks to document cooperation between strangers even when there is an incentive to cheat. The task they developed separates participants and masks their identities, allowing them to act freely without fear of judgment as they interact with one another by computer. Each participant earns $10 for agreeing to join the experiment and is randomly paired off with another individual into dyads of decision maker 1 (DM1) and decision maker 2 (DM2). After comprehensive instructions, the computer prompts DM1 to send between $0 and $10 to DM2. Both DMs know that whatever DM1 chooses to send is removed from her or his account, and that three times the amount is added to DM2’s account. DM2 then gets a prompt showing the tripled amount received along with the new total in his or her account, and is prompted to transfer an amount between zero and the account total back to DM1. The chosen sum is removed from DM2’s account and that same value is deposited in DM1’s account. Participants never meet, and are paid their account balances in cash privately when the experiment concludes. Both participants can walk away with more than their $10 show-up earnings if DM1 believes that DM2 will cooperate and if DM2 chooses to do so. Across many studies using this task, from Smith’s lab and other groups, that’s often what happens: most DM1s send some money to DM2s, and most DM2s return enough to bring DM1’s account balance to more than the $10 she started with. The consensus view by experimental economists is that the DM1 to DM2 transfer is a signal of trust. The DM1 transfer seems to say, using the southern California vernacular where we ran our studies, “Hey dude, we can soak these scientists for a bunch of cash. I trust that you understand why

I’m sacrificing to grow the pie and will flip some dough back to me.” The back-transfer from DM2 to DM1 is then a measure of trustworthiness. Smith, who later won the Nobel Prize in Economic Sciences for introducing experimentation to the field, told me that he had no idea why people cooperated with strangers on this task considering that DM2s can keep all the money without suffering any repercussions. I suspected that our human social nature, perhaps due to oxytocin, was the explanation. I hypothesized that DM1’s transfer of money, denoting trust in DM2, would cause an increase in oxytocin in DM2 that would spur him to reciprocate. The key to testing this hypothesis was measuring the change in oxytocin over the course of the experiment. In studies published in 2004 and 2005, we reported that 90 percent of DM1s sent some of their money to DM2s, and that the more money DM2s received, the larger their spike in oxytocin. 2,3 The magnitude of the oxytocin rise was also highly correlated with the amount of money DM2 returned to DM1. It wasn’t the money itself that caused the oxytocin surge; a control condition, where the DM1-to-DM2 transfer was determined randomly, and the participants knew DM1 had no choice in the matter, produced no oxytocin response and few back-transfers to DM1s. Rather, the data indicated that it was the intention of trust from DM1—reflected in the choice of transferring money—that triggered the rise in oxytocin in DM2. We also measured nine other neurochemicals known to affect the release of oxytocin or the binding of oxytocin to its receptor; none of these correlated with oxytocin release or money transfers. It appeared that oxytocin alone was responsible for reciprocity.

Putting oxytocin to the test Scientists by personality and training are skeptics. Even before publishing our findings relating the endogenous release of oxytocin to trustworthiness, I was concerned about causation. To demonstrate

that oxytocin caused trust-related behaviors, I had to get oxytocin safely into human brains. Synthetic oxytocin (trade name Pitocin) has a very safe drug profile; intravenous Pitocin is regularly used to speed up labor. But the evidence indicated that little or no intravenous oxytocin enters the brain. An intranasal oxytocin infuser, used to initiate milk flow for breastfeeding, was available in Europe but had gone off the market in the US, despite also being very safe. I found a Swiss pharmacy that would mail oxytocin infusers to me with a prescription, but after a year of corresponding with the US Food and Drug Administration (FDA), I was told that I would not be allowed to import the drug. In 2003, Swiss graduate student Markus Heinrichs, now a professor at the University of Freiburg, sent me his doctoral dissertation that used intranasal oxytocin administration to study social stress in humans. Heinrichs had shown that oxytocin reduced stress responses when participants interacted with one another prior to a public speaking task. Desperate to show oxytocin was causally related to trust, I called Markus and suggested a collaboration: he had the intranasal oxytocin infusers and I had the trust task. We put a group together and ran the study in Switzerland. Think of synthetic oxytocin as inducing the same physiological effect one would experience when meeting a friend. While in our previous experiments, DM1s did not get a social signal prior to making a choice and thus did not show a change in oxytocin, we expected that an oxytocin boost in the form of intranasal infusion would influence DM1s’ behavior. Sure enough, our experiment showed that oxytocin more than doubled the number of DM1s who sent all their money. Overall, DM1s who received an infusion transferred an average of 17 percent more money to the DM2s in their dyads than those given a placebo. At the same time, the additional oxytocin had no effect on DM2 behavior. This was not entirely unexpected, because there is already a strong desire to reciprocate trust, as evidenced in our previous experiments; more oxytocin, it

While scientists are just beginning to use neurological measurements to predict what people will do, the opportunity to improve people’s lives holds great promise.

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seems, could not push return transfers even higher. Our team published these results in 2005 in Nature.4 Shortly thereafter, I obtained approval to use intranasal oxytocin in the US. Our studies of endogenous oxytocin and exogenous oxytocin infusion showed that the

molecule affects many prosocial behaviors such as generosity toward strangers5 and charitable donations.6 These findings were extended by other labs showing that oxytocin administration increased empathy, did not make people gullible, and had context-dependent effects.7 While

patients with social anxiety, depression, and autism have dysregulated oxytocin, administering oxytocin in these patients does not seem to help alleviate the symptoms, likely because it does not change the underlying neural circuitry.8 My team also showed that endogenous and exoge-

CAPTURING IMMERSION

Immersion is a neurological state of attention and emotional resonance that predicts what people will do after an experience, often with 80 percent or greater accuracy. We identified it by comparing neural activity in people who took an action after an experience versus those who did not.

 1 Participants viewed a video about “Big” Ben Bowen,

© MICHELLE KONDRICH

who suffered from an aggressive brain tumor at age two and was featured in a fundraising campaign from St. Jude Children’s Research Hospital.

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nous testosterone, known to inhibit oxytocin release, reduced trustworthiness and generosity in money-sharing tasks.9 Oxytocin appeared to be a critical part of the fabric of human sociality. But we wanted to see how far we could go. After my experience watching

Million Dollar Baby, I wondered if more than just personal interactions could trigger the release of oxytocin.

Immersion in an experience Entertainment only works if one cares about the characters in the narrative.

Movies put this effect into overdrive by combining visuals, music, and emotional displays. Neurologically, it is odd that people who are cognitively intact and sitting in a movie theater (or on an airplane) will cry or laugh at a flickering image. I wanted to know if the movies and videos

 2

As participants watched Bowen’s story, we measured attention and emotional responses using brain activity as measured by electroencephalography (EEG) as well as multiple signals from the peripheral nervous system.

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 3 We also drew blood from participants before and after they viewed the video to measure changes in oxytocin, cortisol, and adrenocorticotropic hormone (ACTH).

 4 One-half of the hundreds of people who

viewed the video donated money to St. Jude. Our analysis predicted who would donate with 82 percent accuracy. 1 0. 2020 | T H E S C IE N T IST 2 3

Think of synthetic oxytocin as inducing the same physiological effect one would experience when meeting a friend.

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that elicited such emotional responses were provoking oxytocin release. In order to rule out the random neurochemical changes that are part of the brain’s housekeeping, my lab and I designed experiments that included a behavioral task. If the neurochemical changes we observed were a response to the video and not background noise, they should correlate with choices made by participants after viewing the videos. Our first study used a fundraising video we obtained with permission from St. Jude Children’s Research Hospital. We cut out two 100-second segments of a father with his two-year-old son who was dying of brain cancer. The narrative version of the video showed the father talking about how it felt to know that his son was dying. The control video showed the same father and son at the zoo. We paid people to participate and obtained blood samples before and after they viewed the video. After the second blood draw, participants had the option to donate some of their earnings to St. Jude. This was done in private so people would not feel pressured to give. The narrative version of the video caused a spike in oxytocin while the control did not. Furthermore, the increase in oxytocin correlated with the amount of empathic concern participants reported for the father and son.10 But oxytocin alone was not sufficient to predict whether participants would donate. Going into the study, we had decided to measure neurochemicals associated with arousal, knowing that very high arousal can inhibit oxytocin release. It turned out that arousal was a critical factor in determining who gave money to St. Jude. The analysis showed that, in addition to an increase in oxytocin, participants who donated showed positive arousal— initially, a rise in cortisol, and later, an increase in the faster-acting adrenocorticotropic hormone (ACTH). The data hit us with a new insight: it seemed that participants had to both pay attention to the video—i.e., be aroused—and be emotionally engaged with it to donate. In order to establish whether or not oxytocin plays a causal role in people’s decisions to donate to charity, our next study

administered synthetic oxytocin or placebo to people before they watched 16 European public service announcements (PSAs) in English. The videos warned viewers about public health issues such as heart disease and drunk driving. Many were funny, some were sad, and others simply stated facts. Participants earned $5 after watching each video and could donate to a US-based charity that worked on the highlighted problem. Sure enough, participants who received oxytocin donated 56 percent more money to 57 percent more charities and reported more concern for the people shown in the PSAs compared with placebo recipients.11 We recruited a new batch of people and had them watch one of the 16 PSAs and took blood samples before and after. As in our previous study, donations were made by those who had increases in oxytocin and ACTH. We coined the term “immersion” to denote the neurological state of attention and emotional resonance during an experience that results in an observable behavior. To more fully understand what stories such as the St. Jude video do neurologically, we needed higher-frequency data. Blood draws before and after viewing cannot capture second-by-second responses in the nervous system. In 2011, the US Defense Advanced Research Projects Agency (DARPA) had launched a program called Narrative Networks that supported neuroscience research into persuasive communications. I had met the program officer, William Casebeer, at several conferences and he invited me to submit a proposal for funding. Once funding was secured, we returned to the St. Jude video and measured myriad physiological signals including cardiac rhythms, vagus nerve activity, and electrical conductance of skin to capture arousal and emotional responses without blood draws. The data showed that the attentional response occurred first while the emotional response followed typically 10–15 seconds later. Combining arousal and the effect of oxytocin into a measure of immersion, the pattern looked like a classic narrative arc, with the intensity of immersion peaking at the video’s climax and declining as the video resolved.12 Our subsequent studies of hundreds of audio

and video stories showed that the narrative arc is an effective way to sustain immersion and motivate actions—which makes sense, as it’s been used to teach and entertain for thousands of years.13 Our contract with DARPA required that we predict with at least 70 percent accuracy who would donate after the video using only neurological data. Building statistical models from the electrical signals that constitute immersion, our predictive accuracy in 2015 was 82 percent. Modeling second-by-second data, we found that those who donated to St. Jude had a more pronounced spike in immersion at the peak of the narrative arc compared with non-donors. Measuring immersion is a way to understand, and predict, why people do what they do.

Predicting people In 2013, my Google alert for the word “oxytocin” picked up a video from Cannes, France. In it, Josy Paul, chairman of the India division of the global advertising agency BBDO, said that BBDO’s ads were so creative that “they caused the brain to make oxytocin.” I was intrigued. And skeptical. Had BBDO really measured oxytocin using blood draws? A few searches led me to Paul’s email, and I sent a query. They were “guessing” about oxytocin, he said, but they were interested in doing a test. I explained that immersion, not just oxytocin, was the best predictor of actions that I had found, and that I could measure it with wireless sensors. BBDO executives cooked up a plan to hold my feet to the fire: a blinded prediction. Here is how it went. BBDO sent me 18 TV commercials they had created for six different brands. There were three commercials each for Snickers candy bars, Cesar dog food, AT&T phone services, Visa credit cards, and two beers, Guinness and Bud Light. BBDO’s clients had already ranked the commercials by the sales bumps they had produced—information that BBDO withheld from us while we analyzed people’s immersion levels as they watched each commercial. A blinded prediction is the ultimate test of accuracy because there is no way to cherry-pick the data or do esoteric statistical analyses to improve the forecast: either

immersion predicted sales or it did not. We recruited 61 participants to watch the BBDO commercials. Immersion correctly identified the ads that produced the largest sales bump for five of the six brands. Moreover, we found a statistically significant linear relationship between immersion and sales bumps: as immersion increases, so do sales. BBDO was thrilled, as was I. The BBDO study gave me the confidence to scale up data collection. I started a company called Immersion Neuroscience and, together with my collaborators, built a software platform that allowed anyone to measure immersion. The Immersion Neuroscience software lives in cloud servers and takes the signal from popular wearables that measure cardiac activity, using algorithms we wrote to infer neural states in real time. We launched the platform in 2018, and since then, clients have used it to measure immersion in ways we had never thought of. Rather than lab experiments, Immersion’s clients are performing field studies. These studies have shown that immersion can identify top-rated reality TV shows with 88 percent accuracy and that immersion while listening to music three months prior to release had a nearly perfect correlation with post-release Spotify streams. Client usage has also found that information recall two weeks after a presentation has a high positive correlation with immersion. Since we launched our platform, a major professional services company, Accenture, has been measuring immersion during the training they provide to employees and has used immersion data to ensure all learners benefit from training. Real-time feedback on immersion is increasingly important as training and education go virtual and instructors are not in the same room with learners. I have had the privilege to take the basic science we have done on the behavioral effects of oxytocin and create a tool to predict what people are likely to do. Immersion seems to capture the value of experiences. When experiences are valued, they are remembered, acted on, and shared with others. Oxytocin is only part of the neurological process that leads to actions, but the research from my lab and many others dur-

ing the last 20 years shows it is an important signal of the value that people derive from experiences with social content. Paul J. Zak is a professor and founding director of the Center for Neuroeconomics Studies at Claremont Graduate University in California. He is also the founder and Chief Immersion Officer of Immersion Neuroscience, which launched the first “Neuroscience as a Service” platform that enables clients to predict human behavior by measuring immersion.

References 1. T.R. Insel, “The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior,” Neuron, 65:768–79, 2010. 2. P.J. Zak et al., “The neurobiology of trust,” Ann NY Acad Sci, 1032:224–27, 2004. 3. P.J. Zak et al., “Oxytocin is associated with human trustworthiness,” Horm Behav, 48:522–27, 2005. 4. M. Kosfeld et al., “Oxytocin increases trust in humans,” Nature, 435:673–76, 2005. 5. P.J. Zak et al., “Oxytocin increases generosity in humans,” PLOS ONE, 2:e1128, 2007. 6. J.A. Barraza et al., “Oxytocin infusion increases charitable donations regardless of monetary resources,” Horm Behav, 60:148–51, 2011. 7. J.A. Bartz et al., “Social effects of oxytocin in humans: context and person matter,” Trends Cogn Sci, 15:301–309, 2011. 8. K. MacDonald, T.M. MacDonald, “The peptide that binds: a systematic review of oxytocin and its prosocial effects in humans,” Harv Rev Psychiatry, 18:1–21, 2010. 9. P.J. Zak et al., “Testosterone administration decreases generosity in the ultimatum game,” PLOS ONE, 4:e8330, 2009. 10. J.A. Barraza, P.J. Zak, “Empathy toward strangers triggers oxytocin release and subsequent generosity,” Ann NY Acad Sci, 1167:182–89, 2009. 11. P.-Y. Lin et al., “Oxytocin increases the influence of public service advertisements,” PLOS ONE, 8:e56934, 2013. 12. J.A. Barraza et al., “The heart of the story: peripheral physiology during narrative exposure predicts charitable giving,” Biol Psychol, 105:138–43, 2015. 13. P.J. Zak, J.A. Barraza, “Measuring immersion in experiences with biosensors: Preparation for international joint conference on biomedical engineering systems and technologies,” in Proceedings of the 11th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2018), vol. 4, BIOSIGNALS (SCITEPRESS, 2018), 303–7, doi:10.5220/0006758203030307.

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Intimate Conversations Crosstalk between the immune system and the nervous system is proving essential for the health of both body and mind.

CREDIT © STOCKSY.COM, LINE ADDICTIVE CREATIVES

BY ASHLEY YEAGER

T

iroyaone Brombacher sat in her lab at the University of Cape Town watching a video of an albino mouse swimming around a meter-wide tub filled with water. The animal, which lacked an immune protein called interleukin 13 (IL13), was searching for a place to rest but couldn’t find the clear plexiglass stand that sat at one end of the pool, just beneath the water’s surface. Instead, it swam and swam, crisscrossing the tub several times before finally finding the platform on which to stand. Over and over, in repeated trials, the

mouse failed to learn where the platform was located. Meanwhile, wildtype mice learned fairly quickly and repeatedly swam right to the platform. “When you took out IL-13, [the mice] just could not learn,” says Brombacher, who studies the intersection of psychology, neuroscience, and immunology. Curious as to what was going on, Brombacher decided to dissect the mice’s brains and the spongy membranes, called the meninges, that separate neural tissue from the skull. She wanted to know if the nervous system and the immune

system were communicating using proteins such as IL-13. While the knockout mice had no IL-13, she reported in 2017 that the meninges of wildtype mice were chock full of the cytokine. 1 Sitting just outside the brain, the immune protein did, in fact, seem to be playing a critical role in learning and memory, Brombacher and her colleagues concluded. As far back as 2004, studies in rodents suggested that neurons and their support cells release signals that allow the immune system to passively moni1 0. 2020 | T H E S C IE N T IST 27

INTO THE BRAIN: Astrocytes (green) have long,

thin extensions called feet that line the blood vessels in the brain. Those feet contain water channels (purple) that allow cerebrospinal fluid, including the molecules within it, to move into the astrocytes and out into the brain, where it can interact directly with neurons.

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cytokines such as IL-13 spur astrocytes to release brain-derived neurotrophic factor (BDNF) and other proteins that bolster neural development and influence learning and memory. This line of work has led to rapid developments in neuroimmunology, a growing field of research that focuses on understanding the ways in which the nervous system draws on immune cells during normal function, and how that interaction plays a role in learning, memory, and social behavior, as well as neurological disease. Some researchers even propose that the immune system might be key to treating some forms of impaired cognition.

Immune whispers One of the first teams to make the connection between the immune system and brain function included Jonathan Kipnis, now at the Washington University School of Medicine in St. Louis. In 2004, Kipnis and colleagues showed that mice without adaptive immune cells such as T cells had trouble remembering the location of a submerged platform while they were swimming.2 A few years later, the group

focused in on a T cell cytokine called interleukin-4 (IL-4), which helped mice with functional immune systems form long-term memories about the platform’s location. IL-4 is secreted by T cells in the body that can migrate to the meninges, and was somehow affecting the brain.3 Following up on that work, Kipnis’s then-postdoc Anthony Filiano, now an assistant professor of neurosurgery at Duke University, found that mice lacking T cells didn’t socialize with others the way normal mice did. If the immunedeficient mice got an infusion of immune cells at around four weeks of age, they became much more social, mimicking the behaviors of normal mice just a few weeks after their immune supplementation. An analysis of gene expression data collected from both sets of mice revealed that interferon gamma, a cytokine essential for the body’s defense against viral and bacterial pathogens, was associated with sociality. To see if interferon gamma had a direct effect on the brain, Filiano and his collaborators knocked out the gene for the cytokine receptor in neurons in the mouse prefrontal cortex, a region impor-

J. ILIFF AND M. NEDERGAARD

tor the brain for pathogens, toxins, and debris that might form during learning and memory-making, and that, in response, molecules of the immune system could communicate with neurons to influence learning, memory, and social behavior. Together with research on the brain’s resident immune cells, called microglia, the work overturned a dogma, held since the 1940s, that the brain was “immune privileged,” cut off from the immune system entirely. Brombacher and others are now starting to identify how communication between the nervous system and the immune system happens. In 2012, molecular imaging revealed that fluorescently labeled proteins could flow through a layer of projections, or “feet,” of neuronal support cells called astrocytes. Astrocytes are star-shaped cells that sit at the border of neural and meningeal tissues and along the blood vessels of the brain; their foot layer is the barrier that separates cerebrospinal fluid (CSF), the watery liquid that envelops the brain and spinal cord, from the neurons of the central nervous system. If those fluorescently labeled molecules could cross the astrocyte layer and move into and out of the brain, so could CSFbased immune-system proteins, which are smaller, scientists figured. Experiments have also shown that cytokines in the blood can cross the bloodbrain barrier (BBB—which, in addition to the wall of astrocyte feet, includes a tight layer of endothelial cells surrounding the brain’s vasculature—and may influence neurons. A third mode of communication, Brombacher notes, is through immune cytokines’ interactions with astrocytes themselves: it seems that the signaling molecules don’t have to penetrate neural tissue at all to influence the brain. Her work shows, for example, how

tant for social behavior. This caused mice to spend less time interacting with other mice, a sign that they were feeling less social; the result offered evidence to suggest that interferon gamma from T cells in the meninges was acting directly on the cortical neurons.4 Inspired by Kipnis and Filiano’s work, Brombacher and colleagues decided to set up a similar experiment. The team first tested IL-4 knockout mice against wildtype mice in a water maze and successfully replicated Kipnis’s original results— the immunodeficient mice were learning impaired. Then, Brombacher tried the experiment with mice lacking IL-13, which is closely related to IL-4, and got the more dramatic results: “learning was abrogated,” she says. Both cytokines clearly affected learning, but IL-13 appeared to play a more significant role than IL-4, perhaps because of some underlying biochemistry: IL-13 and IL-4 share a receptor on the surface of cells called IL-4 receptor alpha, but IL-13 can also transmit its signal using another receptor. Brombacher is now setting up experiments to remove the cell receptors and see what happens to the mice’s performance in the water maze. Evidence is also mounting for interleukin 17’s involvement in learning and sociality. In 2016, Gloria Choi of MIT’s McGovern Institute for Brain Research and colleagues linked the cytokine to signs in mouse pups similar to symptoms of autism spectrum disorder (ASD) in humans. Specifically, animals that developed infections while pregnant gave birth to babies that exhibited ASD-like behavioral traits. Interleukin 17 (IL-17) was among the immune signals secreted to help combat the pathogen, the researchers found, and baby mice born to mouse moms with infections had a higher abundance of IL-17 receptors on their brain cells than mice born to uninfected moms. Blocking those IL-17 receptors with drugs during gestation protected pups against the effects of higher maternal IL-17; the pups were born without the signature behavioral issues associated with ASD.5 Stimulating the release of IL-17 or administering the cytokine directly also

appeared to attenuate ASD-like symptoms in young and old adult mice that had been exposed to the high IL-17 levels in utero, suggesting that exposure to elevated maternal IL-17 during development also paradoxically “primes” the immune system for rescue by the cytokine in maturity.6

says. “We’re showing that you have a population of immune cells sitting outside the brain that impact neurons inside it.” In parallel with these studies demonstrating the capacity of cytokines to affect learning and memory, anxiety, and social behavior, researchers are

Turning to the immune system might be key to treating some forms of impaired cognition. Last year, neuroimmunologist Julie Ribot of the University of Lisbon and her colleagues added to the IL-17 story when they discovered that mice lacking a certain type of T cell or the cytokine had trouble making short-term memories when exploring a Y-shaped maze. 7 This is in contrast to the effects on longterm memory formation that researchers have uncovered for IL-4 and IL-13 in the water maze. The different effects of the interleukins, Ribot says, could have something to do with the fact that the gamma delta T cells that produce IL-17 reside in the meninges, where they could act within seconds during shortterm memory formation. T cells that produce IL-4 and IL-13, on the other hand, have to be recruited to the meninges from elsewhere in the body, which takes time, suggesting they support the creation of memories that take longer to form, she notes. The role of gamma delta T cells and IL-17 in cognition doesn’t end with links to memory and autism, though. The cells and their cytokine may play a role in anxiety, according to Kipnis’s latest experiments. His team recently showed that the release of IL-17 from gamma delta T cells correlates with anxiety-like behavior in mice, and that deleting the IL-17 receptor from glutamatergic neurons in cortical regions involved in threat perception and response reduced anxiety-like behaviors.8 The major takeaway from each of these IL-17 papers is the same, Kipnis

beginning to pull back the curtain on the communication channels that T cells use to talk with neurons. Although it is still unclear exactly how the two systems physically interact, several possibilities have been identified, including direct messages from T cells sent via cytokines interacting with neurons and indirect signals generated through the interaction of cytokines with astrocytes.

Communication channels Some neuroscientists remain adamant that, with the exception of some drugs, most molecules do not get through the barriers that separate the brain from the rest of the body unless there’s a rupture to the boundary layers intended to cordon off the central nervous system. But research from several groups now challenges this idea. A key study in disproving the long-held assumption that the brain is immune privileged came from the lab of neuroscientist Maiken Nedergaard of the University of Rochester Medical Center. In 2012, she and her colleagues watched fluorescent and radiolabeled tracers flow from the CSF into the brains of anesthetized mice. (See “Into the Breach,” The Scientist, November 2017.) Specifically, Nedergaard’s team recorded the movement of the tracers into and out of the animals’ cerebral cortex, the brain’s outer layer of folded gray matter, which is essential for consciousness, attention, and making memories. The researchers learned that CSF carrying cytokines and other signaling mol1 0. 202 0 | T H E S C IE N T IST 2 9

IMMUNE-NEURAL CROSSTALK

Several routes exist for immune cells and neurons to communicate, though T cells rarely come in direct contact with neural tissue. This communication can happen as cerebrospinal fluid (CSF) flows from the space surrounding blood vessels deep in the brain into neural tissue and back out again. As an animal learns new information, changing neural circuits can release signals to which the immune system responds. The immune system in the meninges, the spongy membranes that separate neural tissue from the skull, also monitors CSF coming from the brain for signs of infection or injury.

Lymphatic vessel

Meninges

Pia mater

 6

 1

Astrocyte T cell

Neuron Water channel

Cytokines

 2  3

BDNF

 4

Cellular waste and toxins

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© CATHERINE DELPHIA

Astrocyte foot

 1 The meninges’ innermost layer, the pia mater, lines the perimeter of the brain,

separating neural tissue from the surrounding fluid and tissue. But gaps in the thin, fibrous tissue allow blood vessels to extend deep into the brain.

 2

Along blood vessels in the brain, a tightly packed layer of endothelial cells, along with projections, or “feet,” from astrocytes collectively make up the bloodbrain barrier, which prevents blood from entering the organ. But CSF that sits in the space between the pia mater and upper layers of the meninges flows down around the endothelium-lined blood vessels.

 3 As arteries pulse with each beat from the heart, CSF pushes into the astrocyte feet through AQP4 water channels. This CSF can carry signals from the immune system such as cytokines IL-17, IL-4, and interferon gamma that may also talk directly with neurons.  4 Cytokines can also trigger astrocytes to release molecules such as brain-derived neurotrophic factor (BDNF), influencing learning, memory, and sociality.

 5 Once in the brain, the CSF mixes with extracellular fluid from neuronal tissue,

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sweeping up cellular waste excreted along with any toxins, pathogen-derived antigens, and debris formed as part of normal neural rewiring. This fluid is then pushed out of the brain through astrocyte feet into the perivascular space, where it can interact with gamma delta T cells. Those T cells may then respond by releasing cytokines such as IL-17 that can move right back into the brain, although this has yet to be shown.

 6 The CSF is then channeled to the lymphatic vessels in the meninges and

flushed to lymph nodes in the neck, where more T cells are waiting to scan the fluid and respond.

ecules flows from the meninges into the space surrounding the brain’s vasculature. As the arteries pulse with each beat of an animal’s heart, the blood vessels expand, and the CSF is pushed through water channels in the astrocyte feet and then into the brain. 9 The reverse flow also takes place: CSF that has entered the brain and mixed with the extracellular, or interstitial, fluid—and that now carries waste proteins ready for clearance—is pressed back through astrocytes into the space surrounding the blood vessels. “Maiken showed this very, very elegantly,” Kipnis says. It completely overthrew the dogma that the brain is immune privileged, he says. Earlier this year, Andrew Yang of Stanford University and colleagues extended this finding to specifically show that cytokines released from T cells in the blood can also reach the brains of mice. The researchers extracted blood from the animals, separated out plasma proteins, labeled them with a fluorescent tag, then injected them back into the bloodstreams of the mice they came from. In healthy young adult mice, lots of the fluorescently tagged proteins crossed the BBB to enter the interstitial fluid in the brain.10 “This finding suggests that a wide variety of neural functions . . . could be modulated by systemic protein signals,” Roeben Munji and Richard Daneman of the University of California, San Diego, wrote in a commentary accompanying Yang’s study. Cytokines in the meninges or possibly even in the blood might not have to enter the brain at all to affect the central nervous system, according to Brombacher’s studies. IL-13 and other cell signaling molecules in the CSF or blood could interact with astrocytes at the BBB or at the perimeter of the brain. In cultured astrocytes, treatment with IL-13 spurred the production of BDNF and triggered the production of glial fibrillary acidic protein (GFAP), an indication that neural connections are undergoing rewiring. Ribot’s study on IL-17 also showed that the cytokine could spur mice’s astrocytes to release BDNF into the brain. Both 1 0. 2020 | T H E S C IE N T IST 3 1

the existence of meningeal lymphatic vessels in humans and nonhuman primates.12 Understanding immune cell–neuron crosstalk—both the way T cells respond to what’s in CSF coming from the central nervous system and how they send signals into the brain—could be

Because we know that cerebrospinal fluid does go into the brain, putting therapies into that fluid will probably be a very, very efficient route for treating patients. —Jonathan Kipnis, Washington University School of Medicine

In mice, T cells residing in the meninges scan the CSF for the cellular waste generated as neuronal circuits undergo changes, whether in response to learning and memory formation or in the case of dysfunction. Then, T cells in the lymph nodes get a chance to check the CSF for potential threats such as pathogens, he says. Tracking that lymphatic system in people’s brains is much harder, but Kipnis says there’s some evidence that what scientists are finding in rodents does translate to human biology. In 2017, he and collaborators at the National Institute of Neurological Disorders and Stroke used MRI to noninvasively confirm 32 T H E SC I EN TIST | the-scientist.com

important for understanding neurological disorders, such as Alzheimer’s disease, autism, schizophrenia, and even the cognitive decline associated with aging. “With many of these neurological disorders, there’s been reports that there’s some kind of dysregulation of the immune system,” Filiano says. Identifying faulty signals from neurons in the fluid leaving the brain could lead to diagnostic tools for neurological disorders, he notes. And given that CSF can carry cytokines and other proteins to neurons, Kipnis says he suspects that “putting [immune-based] therapies into that

fluid will probably be a very, very efficient route for treating patients.”

A window to the brain Developing molecules to infuse into the blood or CSF to communicate with the brain requires a better understanding of how cytokines affect neurons, astrocytes, and micro-glia over the course of a lifetime. Interferon gamma, for example, appears to have two faces when it comes to influencing neuronal circuits. In Kipnis’s studies of young mice, the cytokine was essential for the animals to be social. But an analysis of the brains of old mice shows that the same cytokine might be detrimental to making new neurons in aged mice. Giving the old mice an antibody that neutralizes the immune cytokine restored neurogenesis in the animals’ brains, a team of researchers reported in 2019.13 A similar tactic might provide a novel way to treat various neuropsychiatric disorders such as schizophrenia. Analyses of immune cells in the blood of schizophrenia patients show that these individuals have higher levels of a variety of cytokines, including IL-13 and interferon gamma, than healthy individuals do. People with schizophrenia treated with anti-inflammatory and antipsychotic drugs also tend to have fewer cognitive problems than individuals treated with only antipsychotics, hinting that reducing cytokine levels could improve patients’ symptoms. While the neuronal changes that cause schizophre-

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BDNF and GFAP, which boost synaptic rewiring, are associated with learning and memory. Communication between the immune and nervous systems can also happen in the reverse direction, with signals from the brain reaching T cells of the spongy, membranous meninges and of the rest of the body. Until a few years ago, researchers agreed that the brain lacked a drainage, or lymphatic, system to clear away its waste and to transport immune cells. But to Kipnis, it just didn’t make sense that one of the most important organs in the body would not have that kind of plumbing. So he and his colleagues went looking for it, and in 2015, they found it—mice’s brains did, in fact, have lymphatic vessels that shipped waste and T cells from the meninges to deep cervical lymph nodes in the animals’ necks.11 “These structures are bona fide vessels—they express all the same markers as lymphatic vessels in every other tissue,” he told The Scientist at the time.

nia are far from clear, studies suggest that when certain neurons produce lower-thanexpected levels of dopamine, they alert T cells to a problem, and the T cells respond by releasing cytokines that prompt diseaserelated deficits in memory, learning, social behavior, and resilience to stress. Filiano and Kipnis have found evidence that a similar approach might work for helping individuals with autism. In experiments with mice lacking T cells, the researchers found that the animals not only had social deficits but also showed hyperactivity in neural circuits that often have abnormal activity in the brains of people with autism. Not only did social behavior improve when the team infused the mice with immune cells, but the animals’ abnormal neural activity subsided too. Meticulously tweaking the immune system might reverse the cognitive and social deficits of the disorder, the experiments suggest. For now, the results leave Filiano wanting to know more. He explains, “We’re really interested in how these immune

cells talk to the brain, how these signals get from the immune cells to these neural circuits, how that communication happens in health and disease.” g

References 1. T.M. Brombacher et al., “IL-13–mediated regulation of learning and memory,” J Immunol, 198:2681–88, 2017. 2. J. Kipnis et al., “T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions,” PNAS, 101:8180– 85, 2004. 3. N.C. Derecki et al., “Regulation of learning and memory by meningeal immunity: A key role for IL-4,” J Exp Med, 207:1067–80, 2010. 4. A.J. Filiano et al., “Unexpected role of interferon-γ in regulating neuronal connectivity and social behavior,” Nature, 535:425–29, 2016. 5. G.B. Choi et al., “The maternal interleukin17a pathway in mice promotes autism-like phenotypes in offspring,” Science, 351:933–39, 2016. 6. M.D. Reed et al., “IL-17a promotes sociability in mouse models of neurodevelopmental disorders,” Nature, 577:249–53, 2020.

7. M. Ribeiro et al., “Meningeal gamma delta T cell–derived IL-17 controls synaptic plasticity and short-term memory,” Sci Immunol, 4:eaay5199, 2019. 8. K.A. de Lima et al.,“Meningeal γδ T cells regulate anxiety-like behavior via IL17a signaling in neurons,” Nat Immunol, doi:10.1038/s41590-020-0776-4 2020. 9. J.J. Iliff et al., “A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β,” Sci Transl Med, 4:147ra111, 2012. 10. A.C. Yang et al., “Physiological blood–brain transport is impaired with age by a shift in transcytosis,” Nature, 583:425–30, 2020. 11. A. Louveau et al., “Structural and functional features of central nervous system lymphatic vessels,” Nature, 523:337–41, 2015. 12. M. Absinta et al., “Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI,” eLife, 6:e29738, 2017. 13. B.W. Dulken et al., “Single-cell analysis reveals T cell infiltration in old neurogenic niches,” Nature,  571:205–10, 2019. 14. D. Frydecka et al., “Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study,” Brain Behav Immun, 71:28–36, 2018.

COMMUNICATION SIGNALS

© ISTOCK.COM, NEILLOCKHART

A growing number of knock-out experiments in mice have revealed several T cell–derived cytokines that influence learning, memory, and sociability.

CYTOKINE

COGNITIVE EFFECTS

Interferon gamma

Sociality

IL-4

Learning, long-term memory

IL-13

Learning, long-term memory

IL-17

Short-term memory, anxiety

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T H E SC I ENTIST | the-scientist.com

Tiny, Illinois-based Surgisphere Corporation stunned scientists and the public earlier this year when its influential COVID-19 studies fell apart under scrutiny and the company disintegrated overnight. But the problem started long before 2020. BY CATHERINE OFFORD

I

t sounds absurd that an obscure US company with a hastily constructed website could have driven international health policy and brought major clinical trials to a halt within the span of a few weeks. Yet that’s what happened earlier this year, when Illinois-based Surgisphere Corporation began a publishing spree that would trigger one of the largest scientific scandals of the COVID-19 pandemic to date. At the heart of the deception was a paper published in The Lancet on May 22 that suggested hydroxychloroquine, an antimalarial drug promoted by US President Donald Trump and others as a therapy for COVID-19, was associated with an increased risk of death in patients hospitalized with the disease. The study wasn’t a randomized controlled trial—the gold 1 0. 2020 | T H E S C IE N T IST 3 5

standard for determining a drug’s safety and efficacy—but it did purportedly draw from an enormous registry of observational data that Surgisphere claimed to have collected from the electronic medical records of nearly 100,000 COVID-19 patients across 671 hospitals on six continents. The study was a medical and political bombshell. News outlets analyzed the implications for what they referred to as the “drug touted by Trump.” Within days, public health bodies including the World Health Organization (WHO) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) instructed organizers of clinical trials of hydroxychloroquine as a COVID19 treatment or prophylaxis to suspend recruitment, while the French government reversed an earlier decree allowing the drug to be prescribed to patients hospitalized with the virus. Before long, however, cracks started appearing in the study— and in Surgisphere itself. Scientists and journalists noted that the Lancet paper’s data included impossibly high numbers of cases— exceeding official case or death counts for some continents and coming implausibly close for others. Similar data discrepancies were also identified in two previous studies that had relied on the company’s database. Inquiries by The Scientist and The Guardian, meanwhile, failed to identify any hospital that had contributed to the registry. It also emerged that, for a company claiming to have created one of the world’s largest and most sophisticated patient databases, Surgisphere had little in the way of medical research to show for it. Founded by vascular surgeon Sapan Desai in 2008 and employing only a handful of people at a time, the company initially produced textbooks aimed at medical students. It later dabbled in various projects, including a short-lived medical journal, before shooting to fame this year with its high-profile publications on health outcomes in COVID-19 patients. The provenance of Surgisphere’s database—if it even exists, which many clinicians, journal editors, and researchers have questioned—has yet to become clear. Most of Desai’s coauthors admitted to having only seen summary data, and independent auditors tasked with verifying the database’s validity were never granted access, leading to the June 4 retractions of the Lancet study and a previous paper based on the database in The New England Journal of Medicine. Over the following days, The Scientist and other media outlets pointed out inaccurate claims made on Surgisphere’s website, which it had launched in February and gradually erased as accusations of fraud mounted. Desai, who spoke to The Scientist at the end of May, is no longer responding to requests for comment. Despite the brevity of Surgisphere’s moment in the limelight, the repercussions of the company’s actions have been far-reaching. While the WHO quickly resumed hydroxychloroquine testing following criticisms of the Lancet paper, at least one international trial was delayed more than a month. A now-removed preprint of one of the company’s earlier studies, which linked the antiparasitic medicine ivermectin to better survival in COVID-19 patients, was used by national and regional governments in Latin America 36 T H E SC I ENTIST | the-scientist.com

to help justify including the drug in clinical guidelines for disease treatment and prevention—decisions that have not been reversed since the paper disappeared. A nonprofit organization in Africa that had partnered with Surgisphere to develop diagnostic tools for COVID-19 watched months of work disintegrate after the company and its database fell into disrepute. As the initial shock faded, the medical and scientific communities sought to make sense of how something so damaging could have happened so quickly—and whether it could be prevented from happening again. While a heightened sense of urgency during the pandemic undoubtedly contributed to the problem, there were many people and institutions that theoretically could have prevented Surgisphere’s effects on science and public health, notes Rachel Cooper, the director of the Health Initiative at the nonprofit organization Transparency International. Desai’s astonishing influence on COVID-19 policy was dependent on multiple parties, Cooper notes, from the institutions that employed him to the coauthors on his research studies, the journals that published the work, and the organizations that issued public health decisions based on his research. Seen that way, the scandal represents “a perfect storm of issues that have always been there,” she says. An investigation by The Scientist points to a series of missed opportunities to halt Surgisphere’s progress—in some cases stemming from people’s failure to check implausible claims made by Desai or from a pattern of ignoring warnings of problematic data or behavior. While a few parties have since accepted some responsibility and outlined plans to avoid similar situations in the future, the majority have not.

A clear path From the time he founded Surgisphere in 2008 as a surgical resident at Duke University, Desai spent 12 years working as a vascular surgeon in various US states. The Scientist learned of serious concerns about Desai’s integrity and his conduct as a physician spanning that time. After he left Duke in 2012, Desai trained or worked at the University of Texas Health Science Center, Southern Illinois University (SIU), and Northwest Community Hospital (NCH) in suburban Chicago. At the latter two institutions, he held senior positions: director of a new surgical skills lab and vice chair of research for surgery at SIU, and director of performance improvement at NCH, which he joined in 2016. While vascular surgery was not the focus of Surgisphere’s work during the pandemic, Desai emphasized his background as a doctor in press materials and interviews, calling the company “physician-led.” The Scientist has since spoken to five of Desai’s former colleagues—ranging from medical trainees to supervisors—spanning his medical career. The colleagues, who asked to remain anonymous for fear of repercussions, recount similar concerns about Desai during the time they had worked with him. All five describe experiences of Desai making exaggerated claims about his personal achievements, and three people at two separate institutions say they had firsthand experiences of Desai providing inaccurate information

about patients. They accuse him of describing patient data that didn’t match patient charts, for example, or saying he’d attended to a patient when nurses and other staff confirmed he hadn’t. Those three also indicate that Desai’s unreliability was an open secret, with staff members regularly checking the veracity of his claims with other members of the institution. Asked why concerns about Desai’s conduct hadn’t been followed up on, some former colleagues say they’d felt too junior or hadn’t had enough proof to make a formal complaint. Others reference the risk of Desai pursuing legal action, or of retaliation from their institutions, which might have suffered reputational damage should those concerns be made public. Some say complaints were made internally at their institutions, but weren’t acted upon. By the time Desai left NCH this February, he’d been accused of medical malpractice in at least three lawsuits—two of which involved permanent damage following surgery and one that involved a patient death. Those cases are ongoing and Desai told The Scientist earlier this year that he deemed any lawsuit naming him to be unfounded.

second, published on May 1 in NEJM, reported an association between cardiovascular disease and COVID-19 patient mortality, but no elevated risk associated with certain heart drugs feared to be harmful in patients hospitalized with the virus. For the three studies, Desai had collaborated with various combinations of six other people—five who would later say they had not seen the raw data on which the studies were based, and three who received (but didn’t act upon) warnings from other researchers about possible problems with Surgisphere’s data. Weeks before the Lancet study was published, data scientist Joe Brew and medical researcher Carlos Chaccour—both of whom are involved in a clinical trial at ISGlobal in Barcelona testing ivermectin’s use to reduce COVID-19 transmission—wrote to Desai and his preprint coauthors, Mandeep Mehra of Brigham and Women’s Hospital and Harvard Medical School, David Grainger of the University of Utah, and Amit Patel, who formerly held a teaching post at Utah, about discrepancies in the ivermectin data. These discrepancies were similar to those that would later be raised for the Lancet paper—specifically, there appeared to be more cases in the Surgisphere dataset than official records captured, suspiciously high

Despite the brevity of Surgisphere’s moment in the limelight, the repercussions of the company’s actions have been far-reaching. Contacted by The Scientist, most people in charge of departments where Desai worked declined to comment. NCH, which continued to list Desai in its online physician directory until June, tells The Scientist in a statement that Desai had left voluntarily for “personal reasons.” Desai, who is still registered with the American Board of Surgery and has an active medical license in Illinois, told The Scientist in May that he would consider returning to clinical practice in the future, although his former colleagues say that after what’s happened he’d be unlikely to find a job in vascular surgery at a major institution.

Helping hands Surgisphere went through many guises and was repeatedly reregistered in different states as Desai moved from institution to institution during his medical career. Only in the last couple of years did the company begin redefining itself as a data analytics firm. It was in this capacity that Surgisphere would soon claim it had amassed a medical database of almost unprecedented proportions and complexity, one that could offer crucial insights during this year’s pandemic. By the time of the Lancet publication, Surgisphere had provided data for two other studies of COVID-19 patients. The first, posted as a preprint on SSRN in early April, linked ivermectin to improved outcomes in hospitalized COVID-19 patients. The

numbers of hospitalizations on continents where electronic medical records are rarely used, and surprisingly large effect sizes given what was known of the drugs in question. Mehra—who, along with Patel, would coauthor all three Surgisphere studies—responded to Brew and Chaccour that he shared doubts about the “implausibly high” effect size and forwarded their concerns to Desai and Patel. Desai also replied but did not assuage the researchers’ concerns, Brew and Chaccour tell The Scientist. Asked about the exchange, Grainger tells The Scientist in a statement that Mehra handled all the correspondence about data sourcing and that he’d never been in contact with Surgisphere. Mehra tells The Scientist in a statement that he wasn’t aware of potential discrepancies in the dataset before the Lancet paper was published, and that all correspondence on the preprint should be directed to first author Patel. Patel, who the Lancet study stated had “full access to all the data in the study” and who revealed on Twitter that he is related to Desai “by marriage,” did not reply to specific questions by The Scientist on this issue. Desai’s remaining three collaborators, like Grainger, each worked on only one paper. Frank Ruschitzka of University Hospital Zurich, a coauthor on the Lancet study, says in a statement that Mehra had recruited him at the “manuscript stage in this Harvardled registry analysis” and that he had no role in data acquisition. 1 0. 202 0 | T H E S C IE N T IST 37

Actions taken by Surgisphere and its founder, Sapan Desai Collaborations and publications Fallout from the company’s actions MAY 30 The Lancet posts a correction notice on the hydroxychloroquine paper noting that the study authors have updated the paper to resolve the discrepancies in the Australian data and to present raw rather than adjusted data. The journal states that the study’s conclusions remain unchanged.

*Timeline scale adjusted in some places for fit.

JUNE 3 Surgisphere’s website is edited to remove mentions of collaborations with the University of Minnesota and other institutions after the university contacts the company in response to inquiries by The Scientist. The WHO resumes the hydroxychloroquine arm of the Solidarity Trial.

MAY 31 The preprint on ivermectin disappears from SSRN. Mehra will later tell The Scientist that he requested the removal because he “felt further analysis was needed to consider additional confounding factors.”

JUNE 26 MHRA allows COPCOV to resume recruitment to its trial of hydroxychloroquine as prophylactic in healthcare workers.

JUNE 5 The AFEM issues a statement withdrawing its recommendation of the COVID-19 diagnostic tools developed in collaboration with Surgisphere, and halts plans for a clinical trial to test them. AFEM founder Lee Wallis tells The Scientist the nonprofit will work through the end of the year to develop, test, and roll out a replacement.

JUNE 8 MHRA formally suspends the COPCOV trial despite the retraction of the Lancet paper and a response from organizers with reasons the study should continue.

MOREIRA; WIKIMEDIA, THE WORLD HEALTH ORGANIZATION

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Surgisphere’s COVID-19 diagnostic tools are removed from the company’s website hours after The Scientist publishes a story about researchers’ criticism of them.

JUNE 4 The Lancet and NEJM retract the papers based on Surgisphere’s database after independent auditors tasked with checking its validity are refused access. JUNE 2 A second open letter, this time addressed to NEJM and the authors on that study, details further discrepancies in Surgisphere’s database evident from this paper. After making inquiries in the US states hit hardest by COVID-19, The Scientist reports that it’s unable to find any health systems that contributed data to Surgisphere’s registry. Within hours of each other, NEJM and The Lancet issue expressions of concern on the papers based on Surgisphere’s database.

JUNE 12 Surgisphere’s website is suspended.

JUNE 7 Mehra distances himself from Desai and Surgisphere in statements to multiple news organizations. He later tells The Scientist that he didn’t become aware of potential discrepancies in the company’s database until after the publication of the Lancet study.

JUNE 19 The Pan American Health Organization, a regional office of the WHO, circulates a document warning that there is a lack of clinical evidence of ivermectin’s efficacy in COVID-19 patients and that the drug should not be used to treat the disease. Still, many Latin American countries now recommend ivermectin as treatment and as prophylaxis.

JUNE 17 The WHO drops hydroxychloroquine from the Solidarity Trial, this time because interim data indicate a lack of efficacy in hospitalized COVID-19 patients.

The Scientist also contacted authors of the NEJM paper, which included the statement that “all the authors reviewed the manuscript and vouch for the accuracy and completeness of the data provided.” SreyRam Kuy did not respond, and her institution, Baylor College of Medicine, tells The Scientist that she is unavailable for comment. Timothy Henry of Christ Hospital in Cincinnati acknowledges he hadn’t seen Surgisphere’s data when the team submitted the NEJM paper, but tells The Scientist in an interview that it’s common practice for coauthors on clinical research to review only summary data, and that there was nothing suspicious about Surgisphere’s dataset at the time. He says he doesn’t believe the data were fabricated and that he thinks NEJM retracted the paper too quickly, adding that the paper’s conclusions have since been “proven to be correct,” suggesting that the problems lie with the data source rather than “data accuracy.” The scientific community is often unclear on how to treat the coauthors of researchers accused of fraud or other misconduct, says Stefan Eriksson, who directs the Centre for Research Ethics and Bioethics at Uppsala University in Sweden. But the situation is more black-and-white for authors who formally vouch for a published study, as all five NEJM authors did and as Patel did on the Lancet paper. “You can’t escape your responsibility” in this case, Eriksson says. By assuring journals of the veracity of the dataset without having taken the necessary steps to confirm it, a researcher has effectively “betrayed the publishing culture, and science in a sense, as much as if you were part in the making up of data.” The University of Utah terminated Patel’s employment as an unpaid adjunct member of faculty in early June. Asked whether Mehra was under investigation, Harvard Medical School tells The Scientist that it is “fully committed to upholding the highest standards of ethics and to rigorously maintaining the integrity of our research. Any concerns brought to our attention are reviewed thoroughly in accordance with our institutional policies and applicable regulations.”

A peer-reviewed platform In the 13 days between publication and retraction of the hydroxychloroquine study, The Lancet faced intense criticism—initially for allowing the paper to remain online after flaws were uncovered in the database, and later for having allowed the paper to be published at all. Many scientists, including Brew and Chaccour, wrote to the journal within days of the paper’s publication highlighting concerns about the patient numbers and the formidable challenges of collecting high-quality electronic medical data from hundreds of hospitals in such a short time. Those concerns were also discussed by researchers in blog posts and on PubPeer. On May 28, statistician James Watson of the Bangkok-based Mahidol Oxford Tropical Medicine Research Unit (MORU), which was involved in one of the hydroxychloroquine trials suspended following the paper’s publication, posted an open letter to the journal and the study authors on behalf of more than 100 signatories, listing 10 major concerns about the study’s methods and 40 T H E SC I EN TIST | the-scientist.com

data. (He later organized a second letter listing concerns about the NEJM study.) On May 30, The Lancet issued a brief correction, in which the authors revised data from Australia—where the paper’s recorded deaths had exceeded official counts—and modified one of the paper’s supplementary data tables. The Lancet told The Scientist in an emailed statement that the study’s conclusions were unchanged. But on June 2, both The Lancet and NEJM published expressions of concern, and just two days later, after independent auditors failed to obtain access to Surgisphere’s dataset, both of the studies were retracted. Some scientists expressed frustration that the journals didn’t act sooner; Watson wrote in an email to The Scientist at the end of May that “by allowing the authors to post [a] correction and not address any of the other concerns, The Lancet appear to [be] stating that so far they are not worried about the reliability of the study.”

The Lancet study had rapid, widespread effects, partly due to the dramatic responses of organizations overseeing hydroxychloroquine research.

Editor-in-chief Richard Horton has repeatedly defended the journal’s actions, telling The Scientist that editors followed proper editorial processes and that the journal acted swiftly to evaluate and then retract the paper. As for whether The Lancet should have prevented Surgisphere’s work from being published at all, he notes that “peer review is not an effective system for detecting fraud,” because editors and reviewers typically trust that they’re reviewing genuine research. He denied that hype around hydroxychloroquine had unduly influenced the editorial process for this study. The Lancet and NEJM have both said that they’ll aim to improve paper acceptance procedures. “We strive not to repeat mistakes,” NEJM tells The Scientist in a statement. “As occurs with every retraction, we make changes to our system, test them, then reevaluate to see if they’re having an impact.” For example, the journal plans to include reviewers with better expertise in “big data” for similar studies in the future, a NEJM spokesperson tells The Guardian. At The Lancet, part of the response will entail including questions about possible breaches of research integrity as part of peer review, Horton says, as well as asking authors more-specific questions about the data’s accuracy and reliability. “You’re trying to tack

between learning the lessons but also not overresponding, because you don’t want to impose another layer of bureaucracy on science that actually makes it more difficult either to do science or to publish science,” Horton says. “You’re trying to minimize harm and maximize the efficiency of the system—that’s a very difficult balance.”

International fallout The Lancet study had rapid, widespread effects, partly due to the dramatic responses of organizations overseeing hydroxychloroquine research. Within hours of its publication on May 22, the head of MHRA’s clinical trials unit, Martin O’Kane, wrote to organizers of COPCOV—a large international trial investigating hydroxychloroquine and the related molecule chloroquine as a preventive therapy for health workers exposed to COVID-19—saying that trial organizers were expected to “immediately cease recruitment.” Three days later, the WHO publicly announced it was suspending the hydroxychloroquine arm of its Solidarity Trial, which was testing several potential treatments for hospitalized COVID-19 patients, in light of the safety concerns. Although both organizations responded quickly to the Lancet study’s publication, the WHO was swifter to react as concerns about the paper were raised. On June 3, after The Lancet issued an expression of concern but before the paper’s retraction, the agency reinstated recruitment to the hydroxychloroquine arm after finding “no reasons to modify the trial protocol,” the WHO’s director-general Tedros Adhanom Ghebreyesus told reporters at the time. The study would subsequently conclude that the drug was ineffective in hospitalized COVID-19 patients; citing interim data, the WHO dropped the hydroxychloroquine arm for good on June 17. By then, another large study, the UK RECOVERY trial—which had continued testing hydroxychloroquine in late May and early June— had reported similar findings. The WHO did not respond to repeated requests for comment. The COPCOV trial was plagued by greater delays, despite pleas from the research community. Scientists running COPCOV had responded to MHRA’s May 22 communication with pages of documents explaining why the trial shouldn’t be suspended, why the Lancet study was flawed, and how organizers could implement additional safety precautions. Nevertheless, MHRA proceeded with a formal suspension of the trial on June 8, days after the Lancet paper had been retracted. It wasn’t until June 26, more than a week after MHRA received the trial organizers’ formal response to the June 8 suspension, that the agency allowed COPCOV to resume. By then, other studies had been published on the issue, including a small trial from researchers at the University of Minnesota that reported on June 3 that hydroxychloroquine was ineffective as postexposure prophylaxis, although it hadn’t detected any safety issues. COPCOV organizers note that the five-week delay—not to mention the decrease in active cases and the negative pub-

lic opinion about hydroxychloroquine that developed in the interim—may have permanently hobbled the trial. MORU’s Nick White, COPCOV’s co-principal investigator, says he was surprised at MHRA’s lightning fast action to suspend research on hydroxychloroquine as a preventive therapy based on observational findings in hospitalized patients. The agency “didn’t follow their normal principles,” White says. Noting similarly dramatic responses to the Lancet study by regulators in other countries, he adds, “I think they all bent under the intense political pressure and the natural media hype.” MHRA defended its decisions in a statement to The Scientist. “When presented with a body of evidence—even after retraction of the Lancet paper—that represented a fine balance between the potential risks and potential benefits of hydroxychloroquine, MHRA rightly made regulatory decisions [with participant protection] as our prime concern.” It added that “the situation surrounding the publication and subsequent retraction of the Lancet study . . . is unfortunate, and there will be lessons learnt across the research system.” It did not provide further detail about what those lessons were or whether the agency would be implementing any new measures.

Not the end Many questions about Surgisphere have yet to be answered, such as how the company’s data were assembled and what motivated Desai, who has not admitted to wrongdoing, to produce the studies in the first place. Now that public interest in the company has subsided, with debates on other scientific and political issues taking center stage, those questions may never be answered. Some scientists have since argued that some amount of flawed research is an inevitable, even acceptable, price to pay for the accelerated pace of science during the pandemic. Others have argued the opposite, saying that what’s needed right now is more-rigorous science and science-based decision making—an opinion echoed in a July editorial in The Lancet Global Health. For the people directly affected by Surgisphere’s actions, the discussion is far from academic. In July, Lee Wallis of the African Federation for Emergency Medicine, the nonprofit that partnered with Surgisphere to develop COVID-19 diagnostic aids for clinicians in low-resource settings, told The Scientist the organization’s work had been delayed by at least six months, a cost that would be felt by African patients. Meanwhile, Patricia García, a Solidarity Trial investigator and the former health minister of Peru—one of the countries in which the ivermectin preprint has been widely cited in recommendations for COVID-19 treatment—expressed anger that Surgisphere had been able to damage public trust in scientists at a time when scientific expertise is needed most. “Now people are so confused about what science can give you— whether hydroxychloroquine works, it doesn’t work, it’s fake, it’s not fake—that it’s going to be very difficult for us scientists then to use any type of article or publication,” says García. “Now that they know scientists can lie, who will believe us again?” g 1 0. 2020 | T H E S C IE N T IST 41

ONDEMAND

The Structure and Functions of the p53 Pathway: Information Acquisition, Redundancy, and Connectivity

Since its discovery by Arnold Levine in 1979, the tumor protein p53 has transformed the field of cancer research. p53 signaling plays a key role in regulating the cell cycle, maintaining genome stability, and preventing mutations caused by stress or DNA damage. In fact, more than 50% of human cancers have a mutation in the p53 gene. Today, scientists continue to make new discoveries regarding p53 signaling and its role in cancer. In this webinar brought to you by The Scientist and sponsored by IsoPlexis, Arnold Levine from the Institute for Advanced Study will discuss his groundbreaking discovery of p53 and the evolution of the field since then. Jon Chen from IsoPlexis will discuss the use of single-cell phosphoproteomics in identifying changes in key signaling networks including p53, and how signaling alterations can affect treatment resistance in glioblastoma.

ARNOLD LEVINE, PhD Professor Emeritus Simons Center for Systems Biology Institute for Advanced Study

ORIGINALLY AIRED TUESDAY, JUNE 30, 2020 WATCH NOW! www.the-scientist.com/p53SignalingandCancer TOPICS COVERED • The foundational discovery of p53 and its recent advances

JON CHEN Technology Co-Inventor IsoPlexis

• The effect of signaling networks on cancer therapy resistance • Using single-cell phosphoproteomics to identify key signaling events in glioblastoma

WEBINAR SPONSORED BY

ONDEMAND

• How changes in MDM2-p53 signaling affect the timing and development of tumors

• Altering signaling coordination to mitigate adaptive resistance

A Little Help From My Friends: Lessons Learned From Microbiome Metagenomics

Metagenomic analyses of the human microbiome reveal novel functions of our constant companions, from genes for antibiotic resistance to cancer risk and susceptibility to treatment. These novel functions play an important role in human health and disease. In this webinar brought to you by The Scientist and sponsored by Bio-Techne, Heather Jordan and Jennifer Wargo will discuss how metagenomics studies help uncover new and medically relevant functions of the human microbiome.

HEATHER R. JORDAN, PhD Associate Professor Department of Biological Sciences Mississippi State University

JENNIFER A. WARGO, MD, MMSC Professor, Surgical Oncology & Genomic Medicine Program Director for PRIME TR MD Anderson Cancer Center

WEBINAR SPONSORED BY

ORIGINALLY AIRED THURSDAY, JULY 16, 2020 WATCH NOW! www.the-scientist.com /rnai-mechanisms-in-neurodegenerative-disease-therapy TOPICS COVERED • Autopsy sampling to uncover human resistome diversity • The role of the microbiome in cancer therapy

ONDEMAND

RNAi Mechanisms in Neurodegenerative Disease Therapy

The overexpression of certain proteins leads to neurotoxicity in diseases such as Parkinson’s, Alzheimer’s, and Huntington’s. While scientists do not fully understand the mechanisms for these disorders, knocking down gene expression using RNA interference (RNAi) has become a promising area of therapeutic research. In this webinar brought to you by The Scientist and sponsored by 10x Genomics, Nandakumar Narayanan will discuss how RNAi modulates gene new RNAi methods for treating neurodegenerative diseases.

NANDAKUMAR NARAYANAN, MD, PhD Juanita J. Bartlett Professor in Neurology Research Associate Professor and Vice Chair for Basic and Translational Research, Neurology Associate Director, Iowa Neuroscience Institute Assistant Director, Clinical Neuroscience Training Program Carver College of Medicine at The University of Iowa

ORIGINALLY AIRED WEDNESDAY, JULY 15, 2020 WATCH NOW! www.the-scientist.com/microbiome-metagenomics TOPICS COVERED • Advancing viral-based RNAi as a therapy for neurological disease

WEBINAR SPONSORED BY

ONDEMAND

Direct Capture of Guide RNAs Enables Scalable and Combinatorial Single-Cell CRISPR Screens

Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. Recently, multiple techniques have emerged that pair CRISPR screens with high-throughput single-cell RNA sequencing (scRNA-seq), resulting in high resolution, information-rich readouts. In this webinar brought to you by The Scientist and sponsored by 10x Genomics, Dina Finan will introduce the 10x Genomics product portfolio, including new targeted gene expression panels. Joining Dina will be Joseph Replogle who will discuss how this technology helped him and his colleagues to develop direct capture Perturb-seq, a new single cell CRISPR screening technique that greatly expands accessibility, scalability, and flexibility of single cell CRISPR experiments.

JOSEPH REPLOGLE, MD/PhD TRAINEE Weissman lab UCSF/MI

ORIGINALLY AIRED FRIDAY, JULY 17, 2020 WATCH NOW! www.the-scientist.com/Chromium-Single-Cell-Perturb-seq TOPICS COVERED

DINA FINAN, PhD Product Manager 10x Genomics

WEBINAR SPONSORED BY

• Streamlining pooled single-cell CRISPR screens with combinatorial perturbation libraries • Improving efficacy of CRISPR interference and activation by targeting individual genes with multiple sgRNAs • Applying direct capture Perturb-seq to study the genetic interactions (GIs) between cholesterol biosynthesis and DNA repair genes • Leveraging hybridization-based target enrichment gene panels to decrease sequencing costs by up to 90%

EDITOR’S CHOICE PAPERS

The Literature NEUROSCIENCE

Corticospinal tracts

Buff Neurons THE PAPER

I.S. Glover, S.N. Baker, “Cortical, corticospinal, and reticulospinal contributions to strength training,” J Neurosci, 40:5820– 32, 2020.

44 T H E SC I EN TIST | the-scientist.com

Reticulospinal tracts

LIFT, AND LOWER: Over the course of two months, researchers trained macaque monkeys to lift more and more weight, until they were able to do the equivalent of a one-armed pull-up. When the researchers stimulated a bundle of nerves in the spinal cord known as the reticulospinal tract (RST), they saw increases in the resulting neuronal electrical signals in the monkeys’ arm muscles as training progressed, while they did not see the same consistent upward trend in the muscles’ responses to stimulation of the corticospinal tract (CST). The results suggest that RST connectivity may play a critical role in muscle strengthening.

training continued. By the end of training, responses had increased by about 50 percent. The team continued to track the strength of the neural connections for two weeks after training was complete and found that the increased connectivity persisted. The muscles’ responses to CST stimulation did not show the same steady increase during training, however, and in one monkey, CST connectivity appeared to decrease. After the training, the monkeys were killed, and looking inside their spinal cords, Baker and Glover found further evidence of the RST’s role in weight training: the connections on the trained (right) side were stronger than on the untrained (left) side, as evidenced by greater electrical responses of neurons in the spinal cord to stimulation of the brain stem. “It’s as if the volume was turned up on the trained side,” Baker says. There was no difference between the two sides for the CST. “The most interesting [part] to me was the spinal cord result,” says Timothy Carroll, a neuroscientist at the Univer-

sity of Queensland in Australia who was not involved in the research. “It’s a level of analysis that just hasn’t been attempted for this type of exercise before.” He agrees with Baker that the RST is “underappreciated,” noting that “there is a really strong overemphasis on the cortex in controlling movement.” The new study, he adds, “is a nice example that there’s probably a lot going on in the brain stem and probably the spinal cord” during movement. In the future, Baker is interested in understanding how increased connectivity of the RST relates to how the body heals after injury and how to help accelerate the process. For example, a study he published with colleagues earlier this year found that noninvasive brain stimulation could speed the recovery of hand function in stroke patients (Neurorehabil Neural Repair, 34:600–608, 2020). “We’re very interested in using targeted stimulation of the RST to improve recovery after damage,” he says. —Jef Akst

© KELLY FINAN

Of the two major neural highways that carry messages about movement down the spinal cord, one—the reticulospinal tract—is decidedly less fashionable, according to neuroscientist Stuart Baker of Newcastle University in the UK. In contrast to the corticospinal tract (CST), which evolved more recently and helps control complex, uniquely human movements such as playing the piano, the reticulospinal tract (RST) is associated with “boring” functions such as posture and walking, Baker says. But he suspects that the RST plays a bigger role in our movements than researchers currently appreciate. To test for the RST’s possible contribution to strength training, Baker’s PhD student Isabel Glover, now a postdoc at University College London, taught two macaque monkeys to grasp and pull a handle attached to a pulley with their right paws. Feeding the monkeys fruit, nuts, or bits of chocolate as rewards for successful reps, she gradually increased the weight on the other end of the pulley. After a couple of months, the animals were able to pull their own body weight. Prior to the weight training, the researchers had implanted electrodes in the monkeys’ brain stems and arm muscles. This allowed the scientists to stimulate the CST or the RST and measure the electrical response in the muscles. Glover did this as the monkeys pulled an unweighted lever each morning before training began. Then she and Baker looked at how the neural connections changed over the course of the experiment. They found a marked uptick in the muscles’ response to RST stimulation as weight

Spinal cord

COMING TOGETHER: Functional MRI scans show higher connectivity in

BRAIN WAVES: Patterns of neural activity known as alpha waves, often recorded via electroencephalography, may stem from the visual cortex.

NEUROSCIENCE

NEUROSCIENCE

Non-Concussive Microdamage

Alpha Wave Origins

the brains of rugby players in the off-season (top row) compared with noncontact athletes (bottom row).

THE PAPER

NEUROLOGY, 95:E402–12, 2020; © ISTOCK.COM, UNDEFINED UNDEFINED

K.Y. Manning et al., “Longitudinal changes of brain microstructure and function in nonconcussed female rugby players,” Neurology, 95:e402–12, 2020. Conversations about injuries in high-impact sports, such as football, hockey, and rugby, typically center around concussions, brain injuries that can affect memory, cognition, and balance. But not every collision yields a concussion, and even repeated, seemingly harmless impacts can alter the microstructure of white matter, myelinated neurons located deep in the brain, researchers reported in Neurology in July. The study followed 104 female collegiate athletes in rugby, swimming, and rowing. Athletes wore headband sensors to measure the force of collisions during practices and games. None of the hits experienced by any athlete caused a concussion. Still, MRI and other imaging techniques showed differences in the white matter of rugby players who suffered low-impact collisions compared with the white matter of swimmers and rowers who didn’t suffer head hits. The differences were most noticeable in the corpus callosum, a nerve bundle that facilitates communication between the brain hemispheres, says study coauthor Ravi Menon, a neuroscientist at Robarts Research Institute in Canada. Specifically, imaging during and after the athletes’ competitive seasons showed altered axon placement and increased functional connectivity among white matter neurons in the brains of the rugby players. Such neural rewiring, previous research suggests, could be a way for the brain to compensate for an injury. Following athletes in the off-season is novel, says Pashtun Shahim, a physician at the National Institutes of Health Clinical Center who was not involved with the work. But, he cautions, “whether these changes in functional connectivity or white matter integrity are transient or persist over a long time is unclear.” Blood biomarkers that can be tracked noninvasively over longer periods of time, Shahim suggests, would be a more practical way to identify potential axon disruption in college athletes. —Lisa Winter

THE PAPER

R.D. Traub et al., “Layer 4 pyramidal neuron dendritic bursting underlies a post-stimulus visual cortical alpha rhythm,” Commun Biol, 3:230, 2020. Groups of neurons firing in sync produce predictable and measurable brainwave patterns, including the alpha rhythm, which dominates when we’re relaxed and our eyes are closed. While researchers have long suspected the alphas originate in a brain region called the thalamus, the waves’ definitive source and function remain elusive, says Roger Traub, a mathematical neurologist with IBM. Experimenting with slices of rat brain tissue, Traub’s colleagues inserted electrodes into a piece of visual cortex and used drugs to chemically induce a stable alpha rhythm. This rhythm, the team found, emanated from pyramidal neurons in the fourth layer of the visual cortex. People think that because there aren’t many pyramidal neurons in that fourth layer, they aren’t important, but those neurons appear to generate alpha waves, Traub says. Comparing a model of neurons’ electrical firing to the team’s experimental data, he confirmed the cortex as the source of the alpha waves. The waves form when pyramidal neurons fire in sync, and the model suggested that the period of the resulting oscillation (the time it takes to complete one cycle) was determined by synaptic excitation, as opposed to the synaptic inhibition common in other brain waves. When excited, pyramidal cell activity oscillates at a different frequency (the number of waves per second) than nearby sensory neurons, possibly interrupting the flow of information throughout the cortex. The findings are “very convincing,” says University of Salzburg neuroscientist Wolfgang Klimesch, who was not involved in the study. He questions, however, whether the result will translate into humans. The alpha frequency in a rodent, for example, may be different than in a human. “It’s a very questionable assumption” that the frequencies in different animals are the same, Klimesch says. —Amanda Heidt 1 0. 202 0 | T H E S C IE N T IST 4 5

Announcing The Scientist’s annual Top 10 Innovations Competition We showcase the best of this year’s cutting-edge, life-science technology, as determined by a panel of expert judges. The winners will be the subject of a feature article in the December 2020 issue of The Scientist. • An “innovation” is defined as any product that life-science researchers use in a lab: machines, instruments, tools, cell lines, custom-made molecular probes and labels, software, apps, etc. • Products released on or after October 1, 2019 are eligible. • Tune in to The Scientist to see which products won! For further information, email: [email protected]

SCIENTIST TO WATCH

Michelle Gray: Huntington’s Disease Detective Associate Professor of Neurology and Neurobiology, University of Alabama at Birmingham BY AMANDA HEIDT

LEXI COON/UNIVERSITY OF ALABAMA AT BIRMINGHAM

M

ichelle Gray says her mother knew never to tell her a story unless she could account for every detail. “If you told me one sentence, I was going to ask you another question,” Gray says. “I was always in pursuit of more knowledge.” Gray grew up in Alabama and attended Alabama State University, earning her bachelor’s degree in biology in 1997. She then headed to Ohio State University for her PhD and chose to work alongside neurobiologist Christine Beattie on the startle response of zebrafish. Gray and Beattie’s experiments showed that the neural circuits involved in the response are malleable, which might have been essential in the evolution of predator avoidance (J Neurosci, 23:8159– 66, 2003). Having studied the development of neurons, Gray realized that she wanted to apply her knowledge to study the other end of the cell cycle: neurodegeneration. The topic was quite a pivot from developmental biology, she explains, so much so that she didn’t know any researchers to contact. Before she finished her PhD in 2003, she began attending neurology conferences and emailing neuroscientists. One of the researchers she contacted was neuroscientist X. William Yang. He had just started his own lab at the University of California, Los Angeles, after helping to pioneer the development of the bacterial artificial chromosome (BAC), a molecular tool used to clone chunks of DNA up to 300,000 base pairs long. Yang planned to use BACs to create transgenic mice for the study of neurodegeneration in Huntington’s disease, a fatal brain disorder. He agreed to take Gray on as a postdoc to help develop the Huntington’s mouse model. “I give her a lot of credit . . . for being very bold,” Yang says. “I was proposing to do things that hadn’t actually been done before.” Huntington’s disease is caused by a dominant mutation in the huntingtin gene. Together, Yang and Gray created a mouse model, called BACHD, which included the

full-length mutant human huntingtin gene along with a molecular switch to reduce the expression of the gene in individual cell types. That was important because no one knew which cells were most important to the disease, Gray says. After the model was made, it fell to Gray to characterize BACHD by detailing the behavioral, cognitive, and muscular changes the mice experience when expressing the human form of huntingtin (J Neurosci, 28:6182–95, 2008). Because it takes more than a year for the animals to show a full suite of symptoms, the work could be frustratingly slow, she says, but her diligence paid off: BACHD mice are now widely used in Huntington’s disease research. “For cell type–specific effects, the BACHD is really the best model out there,” Mahmoud Pouladi, a neurogeneticist at the National University of Singapore, tells The Scientist. Pouladi uses BACHD to study the disease’s effect on neuronal support cells called oligodendrocytes. When it comes to the types of questions this model

can answer, Pouladi says, “the limitation is only our imagination.” Using the model, Gray and her colleagues showed that reducing huntingtin expression in cortical neurons led to a partial improvement in the animals’ motor and behavioral deficits. Reducing gene expression in both the cortex and the striatum, however, provided even more dramatic results; it led to a reversal of every symptom afflicting the diseased mice, prevented brain atrophy, and bolstered the repair of neuronal connections linking the two brain regions (Nat Med, 20:536–41, 2014). The results, Yang says, informed current efforts to develop treatments for Huntington’s disease, including a drug now in a Phase 3 clinical trial that reduces levels of the mutant protein. After wrapping up her postdoc, Gray started her own lab at the University of Alabama at Birmingham in 2008. There, she decided, she’d study the role of neuronal support cells called astrocytes in Huntington’s. When Gray first mentioned the line of research to Yang, he says he remembers thinking it was risky, “because at the time very few people thought astrocytes could be important.” Taking the risk paid off. Gray and other biologists at the university’s Center for Glial Biology in Medicine showed that BACHD mice with reduced human huntingtin expression in their astrocytes don’t decline as quickly as BACHD mice with normal expression levels, suggesting that astrocytes play some role in the disease’s progression. Through her work with the Huntington’s Disease Society of America, Gray has witnessed that progression in human patients, she says. That’s when “you fully appreciate that [your research] is really going to be instrumental in people’s lives.” g

1 0. 202 0 | T H E S C IE N T IST 47

BIO BUSINESS

Reading Minds A nascent but growing consumer market is driving the development of sleek new tools for decoding brain activity. BY JEF AKST

C

48 T H E SC I EN TIST | the-scientist.com

a rare form of dementia, and a close friend suffered a temporarily paralyzing neck injury. Russomanno realized that portable EEG devices that feed information about brain activity into a computer, if done well, could have all sorts of applications, including monitoring brain health and assisting people with disabilities; the technology could “be applied in so many ways beyond my personal curiosity.” There were already a handful of mobile EEG devices on the market and several more on the way, driven partly by neuroscientists’ desire to make the technology more practical for use in healthcare and other settings, and partly by the tech industry’s interest in develop-

NEXT-GEN MIND READER: Neurosity’s Notion

headset, released in 2019, is one of a handful of consumer brain-computer interface devices that scientists are adapting for their EEG research.

ing EEG-based consumer BCI applications. Accordingly, companies selling the devices typically fell into one of two groups: those targeting researchers, with high-quality but extremely expensive equipment, and those targeting tech developers with low-cost hardware, usually with only a few electrodes and sometimes with fees to access the raw data. Russomanno saw an opportunity to democratize a technology that, at

STEVE GONG

onor Russomanno hadn’t stopped wondering about the effects of the multiple concussions he’d suffered playing football and rugby at Columbia University. In 2011, less than a year after his last severe hit, he had passed a neurologist’s standardized test of cognition, but he still wasn’t himself, at least not all the time. “My mind [was] definitely different than it was before,” he says. “I was really, really amped and self-motivated and confident on certain days, and then I would hit these extreme lows on other days.” The following year, as Russomanno was pursuing a master’s degree in design in New York City, a friend offered to sell him a MindFlex—a cutting-edge toy from Mattel that allowed users to make a ball hovering on an air jet rise and fall by concentrating on it—and pointed him to an online tutorial on how he could hack the toy to create a brain-computer interface (BCI). Russomanno jumped at the opportunity to figure out what was going on inside his brain. He deconstructed the toy and fitted it to a baseball cap with its single electroencephalogram (EEG) electrode resting on his forehead. He added a Bluetooth transmitter on the brim that allowed the device to communicate with his smartphone and built an app into which he could enter his activities and moods. Then Russomanno wore the hat one day while walking around New York City. “I wanted to start seeing if I [could] quantitatively track my habits and routines and stitch them to my emotions and internal states,” he explains. Russomanno’s device was just a prototype, and one day’s worth of data was not enough to answer the questions he had about his own mind. But his tinkering opened his eyes to the potential of BCI and the technology it’s based on. Around that time, his grandmother was diagnosed with

© MUSE BY INTERAXON INC.

the time, was largely limited to big companies and well-funded labs. In December 2013, he and Joel Murphy, his physical computing professor at Parsons School of Design, launched a Kickstarter campaign that promised to deliver an open-source, reasonably priced BCI device that could amplify and convert analog EEG signals into digital data to be streamed wirelessly to a computer. In less than two months, 947 backers pledged more than $215,000. In early 2014, Russomanno and Murphy founded a company, OpenBCI; they started shipping their first product—a small box that amplified the analog brain signals from up to eight EEG electrodes and sent the translated digital data to a computer—by the end of the year. The timing couldn’t have been better. The consumer BCI industry was just beginning to blossom. In September 2014, Toronto-based InteraXon launched Muse, one of the first EEG-based devices truly targeted at consumers: a headband with four electrodes that communicated with smartphone or computer apps, designed to improve mindfulness and meditation by giving users auditory feedback on their cognitive state. A few years later, Paris and San Francisco–based Rythm (now called Dreem) launched the Dreem headband with six electrodes and apps to help consumers sleep. Since then, several new electrode headsets—and the hardware and software needed to process their recorded neural activity—have come on the market. (See table on page 50.) From health and wellness to gaming and virtual reality, the BCI market—which Brandessence Market Research valued in 2019 at $980 million and predicted would double in value in the next 15 years—is mainly driven by consumer demand. But the BCI industry also has an eye toward research, and with neuroscientists striving to make EEG mobile, consumer BCI wearables may be just what the field needs. “The consumer market is creating these devices that didn’t exist . . . devices that open doors for researchers,” says Olav Krigolson, a University of Victoria neuroscientist. “It’s a new emerging tech-

nology and researchers are slowly figuring out the things you can do with it.”

EEG goes mobile Although EEG took a back seat in neuroscience with the advent of magnetic resonance imaging (MRI) in the 1970s and ’80s, the technology has been making a comeback in recent years, says Krigolson, thanks in no small part to the fact that it can be taken on the go. The first “mobile” EEG setups involved packing traditional equipment into backpacks, an approach that was cumbersome and produced noisy data. In the late 2000s and early 2010s, at least half a dozen companies sprang up to offer more-practical setups. These products were expensive, with price points in the thousands or tens of thousands of dollars. The equipment was designed with researchers, not consumers, in mind. But soon, the first low-cost devices began to hit the market. In 2009, San Francisco– based EMOTIV launched its first headset, which had 14 electrodes—still far fewer than the 32 or 64 of a traditional EEG cap—and cost researchers just $750. That same year, NeuroSky released MindSet, a pair of consumer-targeted headphones with an arm that positioned a single electrode on the forehead—for $199. (MindFlex and another EEG-based toy—Uncle Milton’s Force Trainer, which similarly allowed users to control a ball by concentrating while hearing instructions from Yoda—were also released in 2009 and used chips sold by NeuroSky.) And in 2014, InteraXon launched Muse.

The consumer market is creating these devices that didn’t exist . . . devices that open doors for researchers. —Olav Krigolson, University of Victoria

With four electrodes and a price of $150, it became the first consumer product to make real inroads into research. Researchers were initially skeptical about the quality of the EEG data that Muse and other low-cost devices could yield. Krigolson, for example, worried that the noise generated from muscle movements and other sources would wash out any signal that the device recorded from the brain. “Picking up muscle activity is very easy; it’s orders of magnitude bigger” than the neural signal, he notes. But when Krigolson and his colleagues, who have no financial ties to InteraXon, put it to the test a few years ago, they found that Muse did yield data of sufficient quality to detect event-related potentials (ERPs)—patterns of neural activity in response to a stimulus. Enthused, Krigolson and his colleagues designed a protocol to detect cognitive fatigue and successfully tested it first on hospital workers and miners, and then on themselves during a weeklong expedition to the Mars Habitat at the Hawaii Space Exploration Analog and Simulation. Other researchers also started using Muse; on its website, InteraXon lists

MEDITATION EEG: The original Muse headset, released in 2014, was one of the first consumer devices to make inroads into the research community.

BIO BUSINESS nearly 200 publications on diverse topics including pain and post-traumatic stress disorder (PTSD) that have used data collected by the headband. “People have been using Muse for research for a long time now, as a recording device, as a therapeutic device, and everything in between,” says Subash Padmanaban, a research engineer at the company. Still, the data from Muse and other mobile devices are not as pristine as data retrieved from research-grade equipment,

notes Anthony Ries, a research psychologist at the US Army Research Laboratory who was part of a team that compared researchtargeted mobile EEG technologies with conventional EEG systems. “Generally, there is a tradeoff between data quality and mobility,” he tells The Scientist by email. Thea Radüntz of the Federal Institute for Occupational Safety and Health in Berlin, Germany, agrees. She has compared devices from EMOTIV, NeuroSky, and others, and found that EEG setups with fewer electrodes often

produce messier data and limit researchers’ ability to triangulate the source of the electrical activity being recorded. But for many applications, just one or a few electrodes may be sufficient. Strong, brain-wide responses, for example, are “pretty easy to record with one of these mobile systems,” says Scott Burwell, a neuroscientist currently wrapping up a postdoc at the University of Minnesota who has used Muse and an EMOTIV headset for his research. “And in

CONSUMER BCI PRODUCTS In addition to several companies that offer mobile electroencephalography (EEG) equipment specifically designed for researchers, a number are developing EEG-based brain-computer interface (BCI) devices for the consumer market. Here are a few:

Company

Headquarters

Year company launched first product

NeuroSky

San Jose, California

2009

MindWave Mobile 2 headband with a single electrode

Gaming and development

$99

Free

OpenBCI

New York City

2014

Various BCI components sold a la carte or as kits for creating simple wearables

Broadly accessible BCI technology

Ultracortex headset sells for $350

Free

2014

Muse 2 and Muse S headbands with four electrodes, plus sensors to measure heart rate, movement, and breathing

Meditation and mindfulness

$250–$350

$4/month (but can be hacked for free)

$499 for consumer version; $599 for research version, which gives access to the raw data

Free with research version

InteraXon

Dreem (formerly Rythm)

Toronto

Paris, New York City, and Taiwan

Latest Product(s)

Primary application

Cost

Access to raw data

2017

Dreem 2 headband with six electrodes, plus sensors to measure heart rate, movement, and breathing

Sleep improvement

Decode motor intention; productivity, flow for software developers

$899

Free; processed on device for security

Decode visual attentional focus; gaming, AR/VR

$399

Not available

Neurosity

New York City

2019

Notion 2 headset with eight electrodes, plus a sensor to measure movement and breathing and two haptic motors to generate vibrational feedback

NextMind

Paris

2020

NextMind headset with eight electrodes

5 0 T H E SC I EN TIST | the-scientist.com

SINGULAR ELECTRODE: NeuroSky’s Mind-

Set headset, released in 2009, was one of the first consumer BCI products on the market. Its underlying technology was used in two toys that year that allowed users to hover a ball over a stream of air by concentrating.

the clinical setting especially, people are just interested in registering that brain response, and you can do that with relatively few channels.”

NEUROSKY, INC.

Open for tinkering The consumer BCI industry continues to grow, with established companies launching upgraded and novel products and a handful of new competitors entering the market with low-priced devices. While the BCI-enabling products primarily focus on consumer applications, these companies are also paying mind to research applications of the technology. In 2019, Neurosity launched Notion, a headset with eight electrodes that sells for $899, with raw data freely available to users. Like Muse, Notion comes with neurofeedback software, but instead of encouraging a meditative state, it’s used to maximize focus and productivity, with the primary market so far being software coders, says Neurosity cofounder Alex Castillo. Notion has an on-board computer so that the data can be stored and later retrieved directly, and thus does not have to be streamed, something Castillo argues is critical for data fidelity and security. The device also comes preloaded

with an app that can learn to interpret the user’s imagined motor commands, for applications in gaming and artificial reality/virtual reality (AR/VR). Castillo says that Notion’s potential in health and wellness applications is never far from his mind. His brother has epilepsy, and at the end of 2019, researchers published a study that suggested it may be possible to predict an epileptic seizure up to one hour before it starts using EEG data and machine learning. “Maybe people who suffer from epilepsy can use this technology and predict this is going to happen and maybe not go for a drive,” he speculates. “Our device, it is for consumers, but it is clinical grade. We made it so you can use it for research, because we’re also looking to the future and this new generation of neuroscientists [who] are going to use it to develop their own research.”

For many applications, just one or a few electrodes may be sufficient.

This July, another new competitor, NextMind, began presales of its $399 headset. This device also uses eight electrodes but specifically targets the visual cortex, located at the back of the brain. The company has developed software it calls the NextMind engine, which ascertains visual attention and translates that into digital commands, allowing developers, particularly in the gaming and AR/VR industries, to get creative. “We are basically offering the platform to the industry such that the industry will be

able to build on top of it,” says NextMind founder Sid Kouider. NextMind does not currently offer access to raw data, but Kouider says the team would consider doing so in the future. “By addressing this broader market we expand the potential of neuro-technology,” he writes in an email, adding that it “should help us to reach a scale never achieved so far” and thereby benefit research. While these latest devices have yet to undergo stringent tests by independent labs, they’re already being adopted by researchers. Kouider says that most buyers so far are developers, but some are academic researchers or consumers. And the University of Minnesota’s Burwell was all too happy to try out Notion after Neurosity cofounder and CEO AJ Keller, formerly of OpenBCI, reached out to him. Burwell is launching a company based on software he’s developing to detect neural biomarkers of drug craving, and had been using Muse to monitor patients’ brain activity. But now he says he’s leaning toward taking his work forward with Notion. He says Muse has done well for him, but it has some limitations—if wearers move their heads or scrunch their foreheads, for example, the electrical activity of the facial muscles can “swamp out the EEG signals.” Notion sits on the crown of the head, where there are fewer muscles to interfere. Burwell is now on the list to receive the Notion 2 headset, which began shipping this summer, and Neurosity has written support letters for Burwell’s grant applications for research using their equipment. “Up until maybe five years ago, this stuff wasn’t ready for prime time yet,” says Burwell. Even now, many neuroscientists remain cautious, largely sticking to EEG setups designed for researchers. But consumer-oriented technology is starting to prove itself, and Burwell says he expects that as it continues to improve, the research community will come to accept at least some of these devices as valid research tools. “We’re kind of at a really critical period here.” g 1 0. 202 0 | T H E S C IE N T IST 51

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READING FRAMES

Lessons About Fear from Our Deep Past By studying the diversity of antipredator traits in nonhumans, we can learn to better manage the tradeoffs between caution and reward. BY DANIEL T. BLUMSTEIN

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umans have many unique behaviors among animals. For instance, we have a formal language that permits unparalleled communication about things that exist in the past, present, and future. We can be especially jealous and can feel schadenfreude. Yet we share at least one fundamental emotion with many other species: fear. That primordial emotion, as I describe in my latest book, The Nature of Fear, binds us to our past. We are the descendants of a long lineage of successful individuals who got their risk assessments right. While many evolutionary psychologists focus solely on our hominin ancestors to understand why we act as we do, I suggest that we go much farther back in time and beyond our branch on the tree of life. All animals, past and present, must assess life-threatening predation risks and make decisions to avoid or otherwise manage those risks. It’s a delicate balance: being too fearful is costly if caution means that you miss out on acquiring food, mates, or other important resources. Being too brazen could end very poorly indeed. Successful individuals are those that get these tradeoffs right, and because of this, leave relatively more offspring. Despite some differences in the precise neurochemicals that modulate fear, the neurophysiological mechanisms associated with fear in humans are readily seen across vertebrates. Controlled laboratory studies in rodents and humans have identified identical regions of the brain and “fear circuits.” But to really understand our fears we have to get outside to study how animals assess and manage predation risk in the wild. This is because context influences all decisions. If you’re hungry, it’s wise to take more risks lest you starve. And, if you’re dominant and can steal food from

others at will, perhaps it’s OK to be a bit more cautious. My students and I have spent more than 35 years studying the antipredator and social behavior in giant clams, fishes, skinks and other lizards, as well as in several species of birds and mammals. I’ve studied and researched antipredator behavior in marmots and wallabies in depth. We’ve even explored antipredator behavior in plant species that rapidly close their leaves when threatened. One of the main lessons I’ve learned is that risk is ubiquitous, and that it’s impossible to completely eliminate it. Fear is a natural emotion and a potent motivator. Indeed, humans share with many animals a tendency to overestimate risk (it’s better to be safe than sorry!). This makes us vulnerable to politicians with malevolent intentions who make compelling advertisements that efficiently tap into our well-honed neurophysiological fear systems. Once they stoke our fear, they tell us that their proposed policies will guarantee our safety. But think for a moment before you support such fearmongers. Ultimately, we must learn to manage our risks. Trustworthy politicians lead us down a path of efficient risk management and recognize that uncertainty is both natural and ubiquitous. In The Nature of Fear, I describe how natural expressions of this emotion influence the structure of ecological communities, and I review studies that show how the removal of predators changes entire ecosystems. We know this, in part, because of remarkable experiments where we restore predators to locations where they have been extirpated. To manage predatory risks, animals modify their activity patterns, habitat selection, and their diet. Fear of predators can also reduce an individual’s reproductive success. All of

Harvard University Press, September 2020

these fear-induced modifications can have a profound influence on both the environment and the distribution and abundance of many species. Fear, it turns out, is an essential ingredient in healthy ecosystems and helps maintain biodiversity. I find it comforting to know that my fear comes from a long line of my ancestors, both human and nonhuman. It is an inherited treasure, a powerful ally. Yet, it is also an annoying and sometimes intolerable companion. It is a compass that, when calibrated properly, guides us away from danger and toward opportunity. Coopted and mutated, it can lead us down destructive paths that often endanger our own humanity. g Daniel T. Blumstein is an ethologist and conservation biologist. He is a professor in the Department of Ecology and Evolutionary Biology, as well as a professor in the Institute of the Environment and Sustainability, at the University of California, Los Angeles. Read an excerpt of The Nature of Fear at the-scientist.com. 1 0. 202 0 | T H E S C IE N T IST 53

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STATEMENT OF OWNERSHIP, MANAGEMENT, AND CIRCULATION (Required by 39 U.S.C. 3685) for THE SCIENTIST (ISSN 00890-3670) Filed on August 31, 2020, published monthly (except January/February which is a bimonthly) at 1000 N West St Suite 1200 Wilmington, DE 19801. The number of issues published annually is 10. The annual individual subscription price is $39.95. The general business offices of the publisher are 334 King St, Unit 2 Midland, ON, Canada L4R 3M8. The name and address of the Publisher is Robert S. D’Angelo, LabX Media Group, 1000 N West St Suite 1200 Wilmington, DE 19801. The name and address of the Editor is Robert Grant, LabX Media Group, 1000 N West St Suite 1200 Wilmington, DE 19801. THE SCIENTIST is owned by LabX Media Group/Bob Kafato, 334 King St, Unit 2 Midland, ON, Canada L4R 3M8. The known bondholders, mortgagers and other security holders owning or holding 1 percent or more of the total amount of bonds, mortgages, or other securities are none. Publication Title: THE SCIENTIST. The issue date for circulation data below (actual): September 2020. The average number of copies of each issue during the preceding 12 months are: (A) Total number of copies printed: 30,580. (B1) Paid/Requested outside-county mail subscriptions stated on form 3541: 25,783. (B2) Paid in-county subscriptions stated on form 3541: none. (B3) Sales through dealers and carriers, street vendors, counter sales, and other non-USPS paid distribution: 179. (B4) Other classes mailed through the USPS: none. (C) Total paid and/or requested circulation: 25,962. (D1) Outside county nonrequested copies stated on PS form 3541: 4,174. (D2) In-county nonrequested copies stated on PS Form 3541: none. (D3) Nonrequested copies Distributed thought the USPS: none. (D4) Nonrequested distribution outside the mail: 72. (E) Total nonrequested distribution: 4,246. (F) Total distribution: 30,209. (G) Copies not distributed: 371. (H) Total: 30,580. (I) Percent paid and/or requested circulation: 85.9%. The actual number of copies of single issue published nearest to filing date are: (A) Total number of copies printed 28,000. (B1) Paid/Requested outside-county mail subscriptions stated on form 3541: 22,002. (B2) Paid in-county subscriptions stated on form 3541: none. (B3) Sales through dealers and carriers, street vendors, counter sales, and other non-USPS paid distribution: 658. (B4) Other classes mailed through the USPS: none. (C) Total paid and/or requested circulation: 22,660. (D1) Outside county nonrequested copies stated on US Form 3541: 5,024. (D2) In-county nonrequested copies stated on PS Form 3541: none. (D3) Nonrequested copies Distributed thought the USPS: none. (D4) Nonrequested distribution outside the mail: none (E) Total nonrequested distribution: 5,024. (F) Total distribution: 27,684. (G) Copies not distributed: 316. (H) Total: 28,000. (I) Percent paid and/or requested circulation: 81.9%. Electronic Copy Circulation. The average number of copies of each issue during the preceding 12 months are: (A) Requested and paid electronic copies: 26,580. (B) Total requested and paid print copies + requested/paid electronic copies: 52,812. (C) Total requested copy distribution + requested/paid electronic copies: 57,058. (D) Percent paid and/or requested circulation (both print & electronic copies): 93%. The actual number of copies of single issue published nearest to filing date are: (A) Requested and paid electronic copies: 28,594. (B) Total requested and paid print copies + requested/paid electronic copies: 51,254. (C) Total requested copy distribution + requested/paid electronic copies: 56,278. (D) Percent paid and/orrequested circulation (both print & electronic copies): 91%. I certify that all information on this statement is true and complete: Robert S, D’Angelo, Publisher August 31, 2020.

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WHAT’S OLD IS NEW:

Tasked with finding a cure for malaria in the early 1970s, Institute of Chinese Materia Medica researcher Tu Youyou scoured texts spanning thousands of years for traditional remedies. Tu successfully derived a drug called artemisinin from sweet wormwood and tested it in animals. She and two colleagues then tested the treatment on themselves to make sure it wasn’t toxic before they began clinical trials. The work earned her a Nobel Prize in 2015.

end of the 19th century during the Spanish-American war to study the disease, which killed 13 soldiers for every one killed in battle. To establish how the virus was transmitted, three of Reed’s colleagues intentionally exposed themselves and a handful of volunteer soldiers to mosquitoes that had previously fed on victims of yellow fever. Three of the volunteers got sick, and one, Jesse Lazear, subsequently died. In 1930, Max Theiler, a virologist with the Rockefeller Foundation, began developing a yellow fever vaccine that he first tested on himself. For his discovery, he was awarded the 1951 Nobel Prize in Physiology or Medicine. Nowadays, in the US, selfexperimentation isn’t explicitly forbidden, and researchers can put themselves forward as candidates for treatments just as anyone else might. However, Lederer notes that many people now “look askance” at scientists

who subject themselves and their families to unregulated treatments. As Allen Weisse, a retired cardiologist and medical historian, explains in a 2012 article, “The trend in recent years toward collaborative studies, often on a massive scale, makes selfexperimentation by a single individual, tucked away in his laboratory, seem almost quaint, a relic of the past.” Still, the last Nobel Prize awarded for work involving self-experimentation was only five years ago, when Tu Youyou was honored for developing an anti-malaria drug that she first tested on herself in the 1970s. Lederer says it’s likely that self-experimentation more often goes unreported nowadays, even as it still happens—including in pursuit of a vaccine to prevent COVID-19. g A longer version of this article appears on The Scientist’s website under the title “SelfExperimentation in the Time of COVID-19”

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ong before there were rumors of COVID parties, there were “filth parties,” and the guest lists were exclusive. Joseph Goldberger, an infectious disease expert in the US Public Health Service, was tasked in 1914 with determining the cause of pellagra, a deadly systemic disease. Many physicians of the time believed pellagra stemmed from an unknown microbe, but Goldberger felt strongly, and correctly, that it was the result of a nutritional deficiency. To prove it, he and his wife Mary held small gatherings in multiple cities during which they and a few brave volunteers injected themselves with the blood of pellagra victims and ingested capsules filled with the scabs, nasal secretions, feces, and urine of living patients. History is spattered with sometimes-gruesome examples of medical self-experimentation, some of which have netted notoriety and awards. Self-experimentation “has certainly been a well-recognized tradition,” says Susan Lederer, a professor of the history of medicine and bioethics at the University of Wisconsin–Madison. “I would argue . . . it was almost required. The fact that you would risk it on your own body, or on your own children, was a sign of your good faith.” In one of the more famous examples, Jonas Salk, a virologist at the University of Pittsburgh, first tested his polio vaccine on himself and his children in 1952. Four years earlier, virologist Hilary Koprowski and his assistant had tested their own rudimentary polio vaccine—this one made of liquefied rat brain and spinal cord—by drinking it themselves. Research into yellow fever  inspired greater personal sacrifice. A research team led by US Army physician Walter Reed arrived in Cuba at the

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