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
Experience a Better Perspective
C

CM

MY

CY

CMY

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 OCTOBER 2020

Contents
THE SCIENTIST THE-SCIENTIST.COM VOLUME 34 NUMBER 10
© MICHELLE KONDRICH; © CATHERINE DELPHIA; © ISTOCK.COM, ENOT-POLOSKUN

Features ON THE COVER: © STOCKSY.COM, ADDICTIVE CREATIVES

18
Predicting People
Combining measures of attention and
emotional state, we are getting closer to
forecasting human behavior.
BY PAUL J. ZAK
26
Intimate Conversations
Crosstalk between the immune system
and the nervous system is proving
essential for the health of both body
and mind.
BY ASHLEY YEAGER
34
A Perfect Storm
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

1 0. 202 0 | T H E S C IE N T IST 3
 Exploring Life,
Inspiring Innovation
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FREE
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Each issue contains feature articles on hot new trends in research,

profiles of up-and-coming scientists, illustrated infographics
depicting new findings, and much, much more. The Scientist’s
website features award-winning life science news coverage, as well
as features, obituaries, scientist-written opinions, and a variety
of multimedia content.
 OCTOBER 2020

Department Contents
9
13 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

44 THE LITERATURE
44 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

47 SCIENTIST TO WATCH
Michelle Gray: Huntington’s Disease Detective
BY AMANDA HEIDT

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

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

53 READING FRAMES
Andean region, and that Monte Verde is in southern Chile,

48 Lessons About Fear from Our Deep Past

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.
By studying the diversity of antipredator
ANSWER
traits in nonhumans, we can learn to better PUZZLE ON PAGE 10
manage the tradeoffs between caution
and reward. H S A S J C
BY DANIEL T. BLUMSTEIN CO R T E X T R E P A N
L A O E N T
VO L T NUM B N E S S
56 FOUNDATIONS
C I C E
Scientist as Subject WE RN I C K E R A T S
BY AMANDA HEIDT N O L E
Z E RO MO L E CU L E
C P H O
IN EVERY ISSUE
A CQU I R E D A RMS
8 CONTRIBUTORS A L E O I E
10 SPEAKING OF SCIENCE A LWA Y S G E N E R A
54 THE GUIDE F R S S S E

1 0. 202 0 | T H E S C IE N T IST 5
 OCTOBER 2020

Online Contents

THIS MONTH AT THE-SCIENTIST.COM:

VIDEO VIDEO VIDEO

The Chemistry of Morality
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.
The Sound and the Fear
See University of California, Los
Angeles, animal behavior researcher
Dan Blumstein explain common
characteristics of vocalizations that
express fearful emotions.
The Interfacing Brain
Watch entrepreneur Connor
Russomanno talk about his work on
brain-computer interfaces.

AS ALWAYS, FIND BREAKING NEWS EVERY DAY ON OUR WEBSITE.

Coming in November
• Hundreds of gray whales are washing up along North America’s
Pacific coast. Researchers want to know why.

• As apex predators dwindle in number, the effects reverberate through

the ecosystem. Can rewilding large carnivores restore biological balance?
© ISTOCK.COM, MISSING35MM

• 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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 OCTOBER 2020

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 behav-
ior. Thereafter, it was an easy decision for him to double major in environmental conservation and environ-
mental, 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 eco-
systems 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.

Paul J. Zak may be the director of the Center for Neuroeconomics at Claremont Graduate University in California,
but it would be a mistake to paint him as just an economist. While Zak does hold bachelor’s degrees in mathe-
matics and economics from San Diego State University and a PhD in economics from the University of Pennsyl-
vania, 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
DAVI; JA-REI WANG; PAUL J. ZAK

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 com-
pany Immersion Neuroscience to help clients better predict people’s behavior.

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

F
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 conten-
tious in modern history, looms on the horizon, and some politi-
cians 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 pros-
per 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 politi-
cal 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 conscious-
ness and colors our day-to-day existence. Not even my seven-year-
old daughter is immune. “Dad, can you turn the news off?” she
recently said in the car after hearing a radio report about an eight-
year-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 relation-
ship 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
ANDRZEJ KRAUZE
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 mea-
sure 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 con-
structive ways, but not so much that we abandon our values or squan-
der 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 challeng-
ing 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

itself . . .” What followed this frequently cited phrase really drives home
FDR’s point: “. . . nameless, unreasoning, unjustified terror which par-
alyzes needed efforts to convert retreat into advance.”
Far be it from me to disagree with FDR’s famous sentiment, Editor-in-Chief
which I interpret as a call to trust in the country’s leaders in a time eic@the-scientist.com

10.2020 | T H E S C IE N T IST 9
 QUOTES

Speaking of Science
1 2 3 4 5 6 This is deadly stuff. You just
7 8
breathe the air and that’s
how it’s passed. And so that’s
a very tricky one. That’s a
9 10
very delicate one. It’s also
more deadly than even your
strenuous flu.
—US President Donald Trump, explaining his
11 12 13 14

Note: The answer grid will include every letter of the alphabet.
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
15 16 17 18 Trump voiced in public, for example, saying
at a late-February press conference that the
coronavirus was “a little bit like the flu.”

19 20 21 22
This may be the most
shameful moment in the
23 24 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
BY EMILY COX AND HENRY RATHVON risk of the virus.

ACROSS
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
DOWN
1. The present geologic epoch
2. Drug for controlling cholesterol
3. Neural impulse carrier
4. 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
© JONNY HAWKINS

24. Groups below families and above 21. Stereotypical foes of 6-Down
species
Answer key on page 5

10 T H E SC I EN TIST | the-scientist.com
 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
A
s COVID-19 wreaks havoc across the world, scien-
tists are making unparalleled, heroic strides to dis-
cover 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 pub-
licly 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
© ISTOCK.COM, FEODORA CHIOSEA
Trump administration has censored scientists, diminished
the Centers for Disease Control and Prevention’s role in lead-
ing 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 col-
lided 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 spread-
ing disinformation to understate the pandemic’s severity, dis-
credit public health experts’ advice on preventive social dis-
tancing 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 mes-
sengers. A 2019 Pew poll found that 86 percent of the more than
4,400 Americans surveyed had a great deal or fair amount of con-
fidence in scientists. The coronavirus pandemic presents an oppor-
tunity for scientists to have conversations with friends, family, col-
leagues, 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 commu-
nity 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 rac-
ist research that perpetuates falsehoods. While trust in scien-
tists 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 responsibil-
ity 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 inclu-
sive, 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 pub-
lic. Researchers can post their work on preprint servers and
publish in open access journals, pitch it to science and main-
12 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. Sci-
ence 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 infor-
mation. There is so much power in accurate information com-
municated 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 decision-
making. 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 orga-
nization, 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
Viral Invasion
F
ailure to smell fresh cut grass
or a poo-laden diaper is, at least
these days, a potential sign of
E.A. MOSEMAN ET AL., SCI IMMUNOL, 5:EABB1817, 2020
COVID-19 infection. “People say things
smell funny or they can’t smell at all,”
says Harvard University neurobiolo-
gist Sandeep Datta. Reading about peo-
ple’s experiences of anosmia, Datta won-
dered 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 olfac-
tory 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 mon-
keys—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 SARS-
CoV-2 can infect neurons in the nose and
ultimately invade the brain this way.
If the virus were able to enter olfac-
tory 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 study-
ing 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 immu-
1 0. 202 0 | T H E S C IE N T IST 1 3
 NOTEBOOK

NEURONAL ROUTE: Six days after infection,

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.

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 neu-
rons 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 con-
nect 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 dam-
age, 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 sys-
tem 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 actu-
ally kills those neurons,” says study coau- rather than against the infected neurons, don’t replenish themselves very well.”
thor Dorian McGavern, a viral immu- which also display viral bits on their Microglia are replaceable, he specu-
nologist at the National Institute of surfaces. The interaction between the lates, so losing them might be less con-
Neurological Disorders and Stroke. “But microglia and the killer T cells led the T sequential than the irreversible damage
those neurons can grow back. They can cells to release cytokines that triggered of neuronal death.
replenish the system and restore sense of the elimination of the virus from infected The work offers a glimpse at how the
smell.” Neurons farther up in the brain neurons without killing those neurons in body and brain respond to invasion of
can’t be regenerated, yet, oddly, they the process, the team found (Sci Immu- viruses such as VSV through the nose, van
didn’t appear to die after infection. nol, 5:eabb1817, 2020). “Microglia are Riel says. “If you know the way the body
Probing further, Moseman, McGav- playing an absolutely critical role here can handle an infection without causing
ern, and their colleagues revealed how in protecting neurons within the brain,” severe [brain] damage, it could lead to
those neurons that sat deeper in the McGavern says. new insights, which could lead to ther-
brain were spared. Microglia, the pri- What’s not yet clear is if the killer T apeutic strategies.” However, scientists
mary immune cells of the brain, were cells do, in fact, kill the virus-flaunting still don’t yet have a good grasp of which
SCI IMMUNOL, 5:EABB1817, 2020

gobbling up bits of the virus from
infected neurons in the olfactory bulb.
Although not getting infected them-
selves, 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,
microglia or whether the two types of
immune cells interact in some other
way to spur T cells to release the virus-
eradicating 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
viruses can enter the central nervous sys-
tem 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

14 T H E SC I EN TIST | the-scientist.com
THE FUTURE OF NEURODEGENERATION RESEARCH
 1
Fast conformational dynamics

2
Proteins involved in the onset and
progression of neurodegenerative
diseases (ND) exist in different
conformational states - as mono-
mers or oligomers. Their characteri-
zation is very challenging because
they can transition from one state to
the other very fast. Monomeric vs. oligomeric
Studying small molecule or protein
CHALLENGE interactions in ND requires working
under conditions that either favor
the monomeric or oligomeric state
of these molecules.
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. CHALLENGE
Researchers need biophysical
methods that allow them to work at
low sample concentrations to study
SOLUTION the monomeric state, and also at high
concentrations to investigate the
oligomeric state.
With NanoTemper tools, setup and
run times take only a few minutes -
so you can work with proteins
with fast conformational dynamics
with confidence.
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
Understanding and Targeting Pro
Different neurodegenerative disorders often share simila
disease, amyotrophic lateral sclerosis,
histopathological presentations, such as the abnormal re
and others, cause neuronal degradation
aggregation of certain proteins (beta-amyloid (Aβ), tau, α
and death, resulting in progressive brain TAR DNA-binding protein (TDP)-43, or polyglutamines).1
function deterioration. Although our
understanding of neurodegenerative
disease mechanisms is still in its relative Spatial awareness
infancy, scientists are shaping a clearer Recent studies have identified physical, genomic,
picture of neurodegenerative disease and proteomic spatial patterns of disease
pathogenesis and development by the progression.2 Imaging techniques such as mass
spectrometry-based molecular imaging help to
day. The characterization of several determine in situ protein, lipid, metabolite, and
prominent molecular and cellular peptide profiles.3 These patterns can also be
mechanisms common to multiple discovered through –omics-based screening of tissue
or fluid samples.2 Knowing that different elements
neurodegenerative disorders is paving are active in different brain regions at different
the way for identifying new potential times should go a long way towards shaping novel
therapeutic targets and treatment diagnostic approaches for early detection, allowing 
us to diagnose neurodegenerative disorders before
approaches.
they become symptomatic.
Prot
Heat s
regula
aggre
HSP/H
to yea

Lysos
for ne
dysfu
mTOR
in vitr
References contin

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.
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 mechanisms behind these phenomena also tend to overlap to some
egional degree. Researchers are looking into the molecular interactions that take
α-synuclein, place in these common traits to find new ways to diagnose and treat
The underlying 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, aging-
related 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. 28.J. Blesa, S. Przedborski, “Parkinson’s disease: animal models and dopaminergic cell vulnerability,” Front Neuroanat, 8:155, 2014.
at Neurosci, 18:1584-93, 2015. 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.
J Neuroinflammation, 7:56, 2010. 30. T. Saito et al., “Single App knock-in mouse models of Alzheimer’s disease,” Nat Neurosci, 17:661-63, 2014.
receptor expressed on myeloid cells-2,” J Exp Med, 201:647-57, 2005. 31. T.M. Dawson et al., “Animal models of neurodegenerative diseases,” Nat Neurosci, 21:1370-79, 2018.
Falpha and 8-isoprostane production induced by intracerebroventricular injection of LPS,” 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.
’s disease mouse models,” Nat Med, 20:1157-64, 2014. 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.
del of Parkinson’s disease,” PLoS One, 9:e97032, 2014. 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,
J Neuroinflammation, 7(56):56, 2010. 116(46):23029-39, 2019.
euroinflammation, 16:30, 2019. 36. F. Durães et al., “Old drugs as new treatments for neurodegenerative diseases,” Pharmaceuticals (Basel), 11(2):44, 2018.
Aging Neurosci, 10:395, 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.
a006320, 2012. 38. T. Martínez et al., “Silencing human genetic diseases with oligonucleotide-based therapies,” Hum Genet, 132:481-93, 2013.
3-87, 2017. 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.
:189-210, 2017.
 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 Engaging f
phosphorylation.16,17
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 gene-
or 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 detection of pro
Novel models should focus on reproducing specific aspects or features to biomarker meas
isolate and characterize related mechanisms. Multi-omic approaches will a more compreh
aid researchers in determining how well a given model matches human modalities to pro
pathogenesis and progression.31
NS or rectifying dysfunction. Our understanding of microglia remains
rse incomplete because of an inability to study the cells in their native
ion is a environment. Improving ex vivo recapitulation of local environments or
loring developing transcriptomic and epigenetic profiling is crucial to properly
ion 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
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

Early Detection New Therapeutic Avenues

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
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
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
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.
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 tigate the apparent similarity between
curiosity and hunger, researchers led
was uncomfortable, but not painful. Then,
still hooked up to the electrodes, the vol-

Knowledge by Kou Murayama of the University of

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 under-
world. Despite the warning, Orpheus
glances behind him on his way out to
check whether Eurydice is indeed follow-
ing 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 informa-
tion they’re curious about can resem-
ble the drive to attain more tangible
rewards such as food—a parallel that
hasn’t been lost on scientists. To inves-
Reading in the UK recently devised an
experiment to compare how the brain
processes desires for food and knowl-
edge, 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 volun-
teers’ fingers were hooked up to electrodes
that could deliver a weak current, and
researchers calibrated the level of elec-
tricity to what each participant reported
unteers 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 “win-
ning” that round (which ranged from
1:6 to 5:6). If they accepted the gamble
and won, based on a random, computer-
generated 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 experi-
ment. 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 win-
ning, participants reported how desirable
they found either the food or the explana-
tion of the magic trick, and whether they
were willing to accept the gamble.
Not surprisingly, the chances of win-
ning and the desirability that partici-
pants assigned the food or magic reveal

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 NOTEBOOK
each correlated with their likelihood of
accepting the gamble. But the category
of the reward—food or satiated curios-
ity—was not a statistically significant
predictor of participants’ decisions.
Behaviorally, at least, the drives were
similar in how they affected the partici-
pants’ risk-taking.
The research team suspected that the
neural processes underlying the risk-tak-
ing would also be similar for the two types
of motivation. “There is a body of literature
suggesting that, as far as the neurobiologi-
cal mechanisms [go], they seem to be sim-
ilar to a certain extent,” says cognitive neu-
roscientist 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 mak-
ing their decisions inside an MRI machine
as their brains were scanned.
The patterns of blood flow revealed
by the scan indicated that the brain
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 curiosity-
inducing stimulus—which, in this func-
tional 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, particu-
larly 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 process-
ing—the nucleus accumbens, the bilateral
caudate nucleus, and the ventral tegmen-
tal area—lit up more than they did if par-
ticipants 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 interest-
ing because it investigates how curios-
ity 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 food-
related 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 mea-
sured human curiosity by asking sub-
ANDRZEJ KRAUZE
jects how much money they’d pay for
a piece of information, or having them
tell researchers how desirable the infor-
mation was to them, notes Ming Hsu,
 IRRESISTIBLE URGE: Edward Poynter’s Orpheus
and Eurydice depicts the mythical Greek hero just
before his curiosity gets the better of him.

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 process-
ing 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 tid-
bits—say, celebrity gossip—are irresistible
to many. “We can measure the amount of
a neuroeconomist at the University of ative, very novel,” he says. “And it really, I curiosity that people express,” he says. “But
WIKIMEDIA

California, Berkeley, who also was not think, underscores the point of just how what we don’t know is, why are people curi-
involved in the study. “To show this with valuable curiosity is that people are not ous about some information but not others?”
electric shock I thought was very cre- just willing to pay, say, a few cents for it, —Shawna Williams

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

BY PAUL J. ZAK
ISTOCK.COM,
CREDIT
© LINE MAKSIM TKACHENKO

18 T H E SC I EN TIST | the-scientist.com
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 uncon-
trollably as I watch the scene unfold-
ing 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 peo-
ple will do—such as whether they will be
invested enough in Hilary Swank’s char-
acter 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 organi-
zations that supply goods and services
to waste time and money offering peo-
ple 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 num-
ber one, as well as to identify learners
who have effectively understood educa-
tion and training and to drive up pro-
ductivity after virtual meetings. While
scientists are just beginning to use neu-
rological 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 pharma-
cologist and physiologist Henry Dale
in 1906, oxytocin has revealed itself to
be the quintessential mammalian pep-
tide, 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 contrac-
tion) and breasts (to initiate milk let-
down)—and as a neuromodulator, bind-
ing to receptors on neurons in the brain.
Animal research over the last 40
years has established that oxytocin medi-
ates social behaviors.1 When group-living
mammals encounter familiar conspecif-
ics, oxytocin is released in the brain and
motivates approach behaviors. The pep-
tide also plays a critical role in maternal
attachment, pair bonding, and even the
maintenance of cross-species “friendships”
that are valuable for protection, food shar-
ing, and learning through play.
Oxytocin is typically measured in cere-
brospinal fluid in animals. When I hypoth-
esized 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 prop-
erty, my lab developed a protocol to mea-
sure the change of oxytocin in blood that
would reliably reflect the change in the
brain. But oxytocin has a 3–5 minute half-
life 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, prac-
tice 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 money-
sharing tasks to document cooperation
between strangers even when there is an
incentive to cheat. The task they devel-
oped 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 deci-
sion maker 2 (DM2). After comprehen-
sive 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 cooper-
ate 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 con-
sensus view by experimental economists
is that the DM1 to DM2 transfer is a sig-
nal of trust. The DM1 transfer seems to
say, using the southern California vernac-
ular 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 cooper-
ated with strangers on this task consid-
ering that DM2s can keep all the money
without suffering any repercussions. I
suspected that our human social nature,
perhaps due to oxytocin, was the expla-
nation. I hypothesized that DM1’s trans-
fer 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 oxy-
tocin. 2,3 The magnitude of the oxyto-
cin 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 con-
dition, where the DM1-to-DM2 transfer
was determined randomly, and the par-
ticipants 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 inten-
tion of trust from DM1—reflected in the
choice of transferring money—that trig-
gered the rise in oxytocin in DM2. We
also measured nine other neurochemi-
cals known to affect the release of oxy-
tocin 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 find-
ings relating the endogenous release of
oxytocin to trustworthiness, I was con-
cerned about causation. To demonstrate
that oxytocin caused trust-related behav-
iors, I had to get oxytocin safely into
human brains. Synthetic oxytocin (trade
name Pitocin) has a very safe drug pro-
file; intravenous Pitocin is regularly used
to speed up labor. But the evidence indi-
cated that little or no intravenous oxyto-
cin enters the brain. An intranasal oxyto-
cin 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 phar-
macy 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 doc-
toral dissertation that used intranasal oxy-
tocin administration to study social stress
in humans. Heinrichs had shown that oxy- While scientists are
tocin reduced stress responses when partic- just beginning to use
ipants interacted with one another prior to
a public speaking task. Desperate to show neurological measure-
oxytocin was causally related to trust, I ments to predict what
called Markus and suggested a collabora-
tion: he had the intranasal oxytocin infus-
people will do, the
ers and I had the trust task. We put a group opportunity to improve
together and ran the study in Switzerland.
Think of synthetic oxytocin as
people’s lives holds
inducing the same physiological effect great promise.
one would experience when meeting
a friend. While in our previous exper-
iments, DM1s did not get a social sig-
nal 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 influ-
ence 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 aver-
age 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 behav-
ior. This was not entirely unexpected,
because there is already a strong desire
to reciprocate trust, as evidenced in our
previous experiments; more oxytocin, it
1 0. 202 0 | T H E S C IE N T IST 2 1
 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 exog-
enous oxytocin infusion showed that the
molecule affects many prosocial behav-
iors such as generosity toward strangers5
and charitable donations.6 These findings
were extended by other labs showing that
oxytocin administration increased empa-
thy, 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 symp-
toms, 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,

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

© MICHELLE KONDRICH

22 T H E SC I EN TIST | the-scientist.com
 nous testosterone, known to inhibit oxy-
tocin 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 trig-
ger 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 sit-
ting 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.

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

CREDIT LINE


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
 that elicited such emotional responses
were provoking oxytocin release.
In order to rule out the random neuro-
chemical changes that are part of the brain’s
housekeeping, my lab and I designed experi-
ments 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 ver-
sion of the video showed the father talk-
ing 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
Think of synthetic people to participate and obtained blood
oxytocin as inducing samples before and after they viewed the
the same physiological video. After the second blood draw, par-
ticipants had the option to donate some of
effect one would their earnings to St. Jude. This was done
experience when in private so people would not feel pres-
sured to give. The narrative version of the
meeting a friend. 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 par-
ticipants 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 adrenocorti-
cotropic hormone (ACTH). The data hit
us with a new insight: it seemed that par-
ticipants had to both pay attention to the
video—i.e., be aroused—and be emotion-
ally engaged with it to donate.
In order to establish whether or not
oxytocin plays a causal role in people’s deci-
sions to donate to charity, our next study
24 T H E SC I EN TIST | the-scientist.com
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 char-
ity 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 experi-
ence that results in an observable behavior.
To more fully understand what sto-
ries such as the St. Jude video do neuro-
logically, we needed higher-frequency data.
Blood draws before and after viewing can-
not 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 neuro-
science research into persuasive communi-
cations. I had met the program officer, Wil-
liam 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 myr-
iad physiological signals including car-
diac 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 nar-
rative 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 mod-
els from the electrical signals that constitute
immersion, our predictive accuracy in 2015
was 82 percent. Modeling second-by-sec-
ond 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 pre-
dict, why people do what they do.
Predicting people
In 2013, my Google alert for the word “oxyto-
cin” picked up a video from Cannes, France.
In it, Josy Paul, chairman of the India divi-
sion 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 com-
mercials each for Snickers candy bars,
Cesar dog food, AT&T phone services,
Visa credit cards, and two beers, Guin-
ness and Bud Light. BBDO’s clients had
already ranked the commercials by the
sales bumps they had produced—infor-
mation 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 statisti-
cal 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. More-
over, we found a statistically significant lin-
ear relationship between immersion and
sales bumps: as immersion increases, so
do sales. BBDO was thrilled, as was I.
The BBDO study gave me the confi-
dence 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 Neu-
roscience 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 immer-
sion in ways we had never thought of.
Rather than lab experiments, Immer-
sion’s clients are performing field studies.
These studies have shown that immer-
sion 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 per-
fect correlation with post-release Spotify
streams. Client usage has also found that
information recall two weeks after a pre-
sentation 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 pro-
vide to employees and has used immersion
data to ensure all learners benefit from
training. Real-time feedback on immer-
sion 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 pre-
dict what people are likely to do. Immer-
sion seems to capture the value of experi-
ences. When experiences are valued, they
are remembered, acted on, and shared with
others. Oxytocin is only part of the neuro-
logical process that leads to actions, but the
research from my lab and many others dur-
ing the last 20 years shows it is an impor-
tant 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 Neu-
roscience, which launched the first “Neuro-
science as a Service” platform that enables
clients to predict human behavior by mea-
suring 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.
1 0. 2020 | T H E S C IE N T IST 2 5
 CREDIT LINE

26 T H E SC I EN TIST | the-scientist.com
 Intimate
Conversations
Crosstalk between the immune system and the nervous system
is proving essential for the health of both body and mind.

BY ASHLEY YEAGER

T
iroyaone Brombacher sat in her
lab at the University of Cape Town
watching a video of an albino mouse
ADDICTIVE CREATIVES
mouse failed to learn where the platform system were communicating using pro-
was located. Meanwhile, wildtype mice teins such as IL-13. While the knockout
learned fairly quickly and repeatedly swam mice had no IL-13, she reported in 2017

swimming around a meter-wide tub filled
with water. The animal, which lacked an
immune protein called interleukin 13 (IL-
13), 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
STOCKSY.COM,
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
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 criti-
cal role in learning and memory, Brom-
bacher and her colleagues concluded.

water’s surface. Instead, it swam and swam, brains and the spongy membranes, called As far back as 2004, studies in
LINE

crisscrossing the tub several times before the meninges, that separate neural tis- rodents suggested that neurons and their
CREDIT

finally finding the platform on which to sue from the skull. She wanted to know support cells release signals that allow
stand. Over and over, in repeated trials, the if the nervous system and the immune the immune system to passively moni-
©

1 0. 2020 | T H E S C IE N T IST 27
 tor the brain for pathogens, toxins, and
debris that might form during learn-
ing and memory-making, and that, in
response, molecules of the immune sys-
tem 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 communica-
tion between the nervous system and the
immune system happens. In 2012, molec-
ular imaging revealed that fluorescently
labeled proteins could flow through a layer
of projections, or “feet,” of neuronal sup-
port 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 cerebro-
spinal 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 CSF-
based immune-system proteins, which are
smaller, scientists figured.
Experiments have also shown that
cytokines in the blood can cross the blood-
brain 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 influ-
ence neurons. A third mode of commu-
nication, Brombacher notes, is through
immune cytokines’ interactions with
astrocytes themselves: it seems that the
signaling molecules don’t have to pene-
trate neural tissue at all to influence the
brain. Her work shows, for example, how
cytokines such as IL-13 spur astrocytes to
release brain-derived neurotrophic factor
(BDNF) and other proteins that bolster
neural development and influence learn-
ing 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 con-
nection 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 with-
out 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 lack-
ing T cells didn’t socialize with others
the way normal mice did. If the immune-
deficient 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 supplementa-
tion. An analysis of gene expression data
collected from both sets of mice revealed
that interferon gamma, a cytokine essen-
tial 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

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.

28 T H E SC I EN TIST | the-scientist.com
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 sug-
gest 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 wild-
type mice in a water maze and success-
fully 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: “learn-
ing was abrogated,” she says. Both cyto-
kines 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 per-
formance in the water maze.
Evidence is also mounting for interleu-
kin 17’s involvement in learning and social-
ity. In 2016, Gloria Choi of MIT’s McGov-
ern Institute for Brain Research and
colleagues linked the cytokine to signs in
mouse pups similar to symptoms of autism
spectrum disorder (ASD) in humans. Spe-
cifically, animals that developed infections
while pregnant gave birth to babies that
exhibited ASD-like behavioral traits. Inter-
leukin 17 (IL-17) was among the immune
signals secreted to help combat the patho-
gen, 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 unin-
fected moms. Blocking those IL-17 recep-
tors with drugs during gestation protected
pups against the effects of higher mater-
nal 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 symp-
toms 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 sys-
tem for rescue by the cytokine in maturity.6
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 memo-
ries when exploring a Y-shaped maze. 7
This is in contrast to the effects on long-
term memory formation that research-
ers 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 short-
term memory formation. T cells that
produce IL-4 and IL-13, on the other
hand, have to be recruited to the menin-
ges 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 corre-
lates 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
says. “We’re showing that you have a pop-
ulation of immune cells sitting outside
the brain that impact neurons inside it.”
In parallel with these studies dem-
onstrating the capacity of cytokines
to affect learning and memory, anxi-
ety, and social behavior, researchers are
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 interac-
tion 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 bound-
ary layers intended to cordon off the cen-
tral nervous system. But research from sev-
eral groups now challenges this idea. A key
study in disproving the long-held assump-
tion that the brain is immune privileged
came from the lab of neuroscientist Mai-
ken Nedergaard of the University of Roch-
ester Medical Center. In 2012, she and her
colleagues watched fluorescent and radio-
labeled 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 cor-
tex, the brain’s outer layer of folded gray
matter, which is essential for conscious-
ness, attention, and making memories.
The researchers learned that CSF carry-
ing cytokines and other signaling mol-
1 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 sepa-
rate neural tissue from the skull, also monitors CSF coming from the brain for signs of infection or injury.

Lymphatic
6

vessel

1

Meninges Pia mater

Astrocyte

T cell

Neuron
Water
channel

Cytokines
2


3


BDNF

4
 Cellular waste
and toxins 5

Astrocyte
foot
© CATHERINE DELPHIA
 ecules flows from the meninges into the
space surrounding the brain’s vascula-
ture. 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 extracel-
lular, or interstitial, fluid—and that now
carries waste proteins ready for clear-
ance—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 pro-
teins, labeled them with a fluorescent tag,
then injected them back into the blood-
streams of the mice they came from. In
healthy young adult mice, lots of the flu-
1 The meninges’ innermost layer, the pia mater, lines the perimeter of the brain,
 orescently tagged proteins crossed the
separating neural tissue from the surrounding fluid and tissue. But gaps in the thin, BBB to enter the interstitial fluid in the
fibrous tissue allow blood vessels to extend deep into the brain.
brain.10 “This finding suggests that a wide
2
 Along blood vessels in the brain, a tightly packed layer of endothelial cells,
variety of neural functions . . . could be
along with projections, or “feet,” from astrocytes collectively make up the blood- modulated by systemic protein signals,”
brain barrier, which prevents blood from entering the organ. But CSF that sits in the Roeben Munji and Richard Daneman of
space between the pia mater and upper layers of the meninges flows down around the University of California, San Diego,
the endothelium-lined blood vessels. wrote in a commentary accompanying
Yang’s study.
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
Cytokines in the meninges or possi-
system such as cytokines IL-17, IL-4, and interferon gamma that may also talk bly even in the blood might not have to
directly with neurons. enter the brain at all to affect the central
nervous system, according to Brombach-
4 Cytokines can also trigger astrocytes to release molecules such as brain-derived
 er’s studies. IL-13 and other cell signal-
neurotrophic factor (BDNF), influencing learning, memory, and sociality. ing molecules in the CSF or blood could
interact with astrocytes at the BBB or at
5 Once in the brain, the CSF mixes with extracellular fluid from neuronal tissue,

sweeping up cellular waste excreted along with any toxins, pathogen-derived anti-
the perimeter of the brain. In cultured
gens, and debris formed as part of normal neural rewiring. This fluid is then pushed astrocytes, treatment with IL-13 spurred
out of the brain through astrocyte feet into the perivascular space, where it can the production of BDNF and triggered
interact with gamma delta T cells. Those T cells may then respond by releasing the production of glial fibrillary acidic
cytokines such as IL-17 that can move right back into the brain, although this has yet protein (GFAP), an indication that neu-
to be shown.
ral connections are undergoing rewiring.
CREDIT LINE

6 The CSF is then channeled to the lymphatic vessels in the meninges and
 Ribot’s study on IL-17 also showed that
flushed to lymph nodes in the neck, where more T cells are waiting to scan the the cytokine could spur mice’s astrocytes
fluid and respond. to release BDNF into the brain. Both

1 0. 2020 | T H E S C IE N T IST 3 1
 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 Kip-
nis, 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 ves-
sels—they express all the same markers as
lymphatic vessels in every other tissue,” he
told The Scientist at the time.
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 gener-
ated as neuronal circuits undergo changes,
whether in response to learning and mem-
ory formation or in the case of dysfunc-
tion. 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
the existence of meningeal lymphatic ves-
sels 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 cen-
tral nervous system and how they
send signals into the brain—could be
important for understanding neuro-
logical disorders, such as Alzheimer’s
disease, autism, schizophrenia, and even
the cognitive decline associated with
aging. “With many of these neurologi-
cal disorders, there’s been reports that
there’s some kind of dysregulation of the
immune system,” Filiano says. Identify-
ing faulty signals from neurons in the
fluid leaving the brain could lead to diag-
nostic tools for neurological disorders,
he notes. And given that CSF can carry
cytokines and other proteins to neu-
rons, Kipnis says he suspects that “put-
ting [immune-based] therapies into that
fluid will probably be a very, very effi-
cient 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 influenc-
ing 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 mak-
ing 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 dis-
orders such as schizophrenia. Analyses of
immune cells in the blood of schizophre-
nia 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-inflam-
© ISTOCK.COM, PEEPO
matory and antipsychotic drugs also tend
to have fewer cognitive problems than indi-
viduals treated with only antipsychotics,
hinting that reducing cytokine levels could
improve patients’ symptoms. While the
neuronal changes that cause schizophre-

nia are far from clear, studies suggest that
when certain neurons produce lower-than-
expected levels of dopamine, they alert T
cells to a problem, and the T cells respond
by releasing cytokines that prompt disease-
related deficits in memory, learning, social
behavior, and resilience to stress.
Filiano and Kipnis have found evi-
dence 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 hyper-
activity 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’ abnor-
mal neural activity subsided too. Meticu-
lously tweaking the immune system might
reverse the cognitive and social deficits of
the disorder, the experiments suggest.
For now, the results leave Filiano want-
ing to know more. He explains, “We’re
really interested in how these immune
COMMUNICATION SIGNALS
A growing number of knock-out experiments in mice have revealed several T cell–derived cytokines
that influence learning, memory, and sociability.
© ISTOCK.COM, NEILLOCKHART
cells talk to the brain, how these signals
get from the immune cells to these neu-
ral circuits, how that communication hap-
pens 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 interleukin-
17a 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.
CYTOKINE
Interferon gamma
IL-4
IL-13
IL-17
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 IL-
17a 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.
COGNITIVE EFFECTS
Sociality
Learning, long-term memory
Learning, long-term memory
Short-term memory, anxiety
33
 ISTOCK.COM,
CREDIT
© LINE ENOT-POLOSKUN

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 anti-
malarial 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 dis-
ease. 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 elec-
tronic 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 COVID-
19 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 Guard-
ian, meanwhile, failed to identify any hospital that had contrib-
uted to the registry.
It also emerged that, for a company claiming to have created
one of the world’s largest and most sophisticated patient data-
bases, 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 jour-
nal, before shooting to fame this year with its high-profile publi-
cations 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 Sci-
entist and other media outlets pointed out inaccurate claims
made on Surgisphere’s website, which it had launched in Feb-
ruary 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 fol-
lowing 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 antipara-
sitic 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 commu-
nities 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 dur-
ing 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 pub-
lished the work, and the organizations that issued public health deci-
sions 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 oppor-
tunities 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 resi-
dent at Duke University, Desai spent 12 years working as a vascular
surgeon in various US states. The Scientist learned of serious con-
cerns about Desai’s integrity and his conduct as a physician span-
ning 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 improve-
ment 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 supervi-
sors—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 achieve-
ments, 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 fol-
lowed 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 retalia-
tion from their institutions, which might have suffered repu-
tational 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.
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 depart-
ments 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 Ameri-
can 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 vascu-
lar surgery at a major institution.
Helping hands
Surgisphere went through many guises and was repeatedly reregis-
tered in different states as Desai moved from institution to institu-
tion 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 pro-
vided 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
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 ivermec-
tin’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 Uni-
versity of Utah, and Amit Patel, who formerly held a teaching post
at Utah, about discrepancies in the ivermectin data. These discrep-
ancies were similar to those that would later be raised for the Lan-
cet paper—specifically, there appeared to be more cases in the Sur-
gisphere dataset than official records captured, suspiciously high
numbers of hospitalizations on continents where electronic medi-
cal 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 Surgi-
sphere 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 Hospi-
tal Zurich, a coauthor on the Lancet study, says in a statement that
Mehra had recruited him at the “manuscript stage in this Harvard-
led 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 *Timeline scale adjusted in some places for fit.
in the Australian data and to present
raw rather than adjusted data. The jour-
nal states that the study’s conclusions
remain unchanged.
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 JUNE 5 JUNE 26

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 con-
founding factors.”
The AFEM issues a statement withdrawing its MHRA allows COPCOV to
recommendation of the COVID-19 diagnostic resume recruitment to its trial of
tools developed in collaboration with Surgisphere, hydroxychloroquine as prophy-
and halts plans for a clinical trial to test them. lactic in healthcare workers.
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.

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.
MOREIRA; WIKIMEDIA, THE WORLD HEALTH ORGANIZATION

JUNE 4
© ISTOCK.COM, BORISLAV; © ISTOCK.COM, EDEVARDE_

The Lancet and NEJM retract the JUNE 19

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 fur-
ther discrepancies in Surgisphere’s database
evident from this paper.
After making inquiries in the US states hit hard-
est by COVID-19, The Scientist reports that it’s
unable to find any health systems that contrib-
uted data to Surgisphere’s registry.
Within hours of each other, NEJM and The Lan-
cet 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 dis-
crepancies in the company’s
database until after the publi-
cation of the Lancet study.
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 manu-
script 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 unavail-
able for comment. Timothy Henry of Christ Hospital in Cincin-
nati 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 noth-
ing 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 conclu-
sions 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 pub-
lished 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 high-
est standards of ethics and to rigorously maintaining the integ-
rity 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 hydroxy-
chloroquine study, The Lancet faced intense criticism—initially
for allowing the paper to remain online after flaws were uncov-
ered 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 con-
cerns 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 dis-
cussed 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 fol-
lowing the paper’s publication, posted an open letter to the jour-
nal and the study authors on behalf of more than 100 signato-
ries, 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 Scien-
tist 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 reliabil-
ity 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 edito-
rial 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 retrac-
tion, 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 stud-
ies in the future, a NEJM spokesperson tells The Guardian.
At The Lancet, part of the response will entail including ques-
tions about possible breaches of research integrity as part of peer
review, Horton says, as well as asking authors more-specific ques-
tions 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 hydroxy-
chloroquine 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 mole-
cule chloroquine as a preventive therapy for health work-
ers 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 hydroxy-
chloroquine arm of its Solidarity Trial, which was testing sev-
eral 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 hydroxy-
chloroquine arm after finding “no reasons to modify the trial
protocol,” the WHO’s director-general Tedros Adhanom Ghe-
breyesus told reporters at the time. The study would subse-
quently 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 con-
tinued 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 COP-
COV had responded to MHRA’s May 22 communication with
pages of documents explaining why the trial shouldn’t be sus-
pended, why the Lancet study was flawed, and how organiz-
ers could implement additional safety precautions. Neverthe-
less, 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 suspen-
sion, 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 ineffec-
tive 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 obser-
vational 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 politi-
cal 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 pub-
lication and subsequent retraction of the Lancet study . . . is unfor-
tunate, 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 inter-
est in the company has subsided, with debates on other scien-
tific 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 accept-
able, 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, Patri-
cia García, a Solidarity Trial investigator and the former health
minister of Peru—one of the countries in which the ivermec-
tin 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
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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
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 EDITOR’S CHOICE PAPERS
The Literature
NEUROSCIENCE
Buff Neurons
THE PAPER
I.S. Glover, S.N. Baker, “Cortical, cortico-
spinal, and reticulospinal contributions to
strength training,” J Neurosci, 40:5820–
32, 2020.
Of the two major neural highways that carry
messages about movement down the spinal
cord, one—the reticulospinal tract—is decid-
edly less fashionable, according to neurosci-
entist 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 walk-
ing, 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 contribu-
tion to strength training, Baker’s PhD stu-
dent Isabel Glover, now a postdoc at Uni-
versity 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 research-
ers 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 mon-
keys pulled an unweighted lever each morn-
ing 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 mus-
cles’ response to RST stimulation as weight
44 T H E SC I EN TIST | the-scientist.com
Corticospinal
tracts
Spinal cord
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, sity of Queensland in Australia who was
responses had increased by about 50 percent. not involved in the research. “It’s a level of
The team continued to track the strength of analysis that just hasn’t been attempted for
the neural connections for two weeks after this type of exercise before.” He agrees with
training was complete and found that the Baker that the RST is “underappreciated,”
increased connectivity persisted. The mus- noting that “there is a really strong overem-
cles’ responses to CST stimulation did not phasis on the cortex in controlling move-
show the same steady increase during train- ment.” The new study, he adds, “is a nice
ing, however, and in one monkey, CST con- example that there’s probably a lot going on
nectivity appeared to decrease. After the in the brain stem and probably the spinal
training, the monkeys were killed, and look- cord” during movement.
ing inside their spinal cords, Baker and In the future, Baker is interested in
Glover found further evidence of the RST’s understanding how increased connectivity
role in weight training: the connections on of the RST relates to how the body heals after
the trained (right) side were stronger than injury and how to help accelerate the pro-
on the untrained (left) side, as evidenced by cess. For example, a study he published with
greater electrical responses of neurons in the colleagues earlier this year found that non-
spinal cord to stimulation of the brain stem. invasive brain stimulation could speed the
“It’s as if the volume was turned up on the recovery of hand function in stroke patients
trained side,” Baker says. There was no differ- (Neurorehabil Neural Repair, 34:600–608,
© KELLY FINAN
ence between the two sides for the CST. 2020). “We’re very interested in using tar-
“The most interesting [part] to me geted stimulation of the RST to improve
was the spinal cord result,” says Timothy recovery after damage,” he says.
Carroll, a neuroscientist at the Univer- —Jef Akst
 COMING TOGETHER: Functional MRI scans show higher connectivity in
the brains of rugby players in the off-season (top row) compared with non-
contact athletes (bottom row).
NEUROSCIENCE
Non-Concussive
Microdamage
THE PAPER
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
NEUROLOGY, 95:E402–12, 2020; © ISTOCK.COM, UNDEFINED UNDEFINED
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
BRAIN WAVES: Patterns of neural activity known as alpha waves, often
recorded via electroencephalography, may stem from the visual cortex.
NEUROSCIENCE
Alpha Wave Origins
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: innovate2020@the-scientist.com
 SCIENTIST TO WATCH
Michelle Gray: Huntington’s Disease Detective
Associate Professor of Neurology and Neurobiology, University of Alabama at Birmingham
BY AMANDA HEIDT
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 evolu-
tion of predator avoidance (J Neurosci, 23:8159–
66, 2003).
Having studied the development of neu-
rons, 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 devel-
opment of the bacterial artificial chromosome
(BAC), a molecular tool used to clone chunks
LEXI COON/UNIVERSITY OF ALABAMA AT BIRMINGHAM
of DNA up to 300,000 base pairs long. Yang
planned to use BACs to create transgenic mice
for the study of neurodegeneration in Hunting-
ton’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 hun-
tingtin 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 expres-
sion 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 expe-
rience when expressing the human form of hun-
tingtin (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 Pou-
ladi, a neurogeneticist at the National Univer-
sity of Singapore, tells The Scientist. Pouladi uses
BACHD to study the disease’s effect on neuro-
nal 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 cur-
rent efforts to develop treatments for Hun-
tington’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 Ala-
bama at Birmingham in 2008. There, she
decided, she’d study the role of neuronal
support cells called astrocytes in Hunting-
ton’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 expres-
sion in their astrocytes don’t decline as
quickly as BACHD mice with normal expres-
sion levels, suggesting that astrocytes play
some role in the disease’s progression.
Through her work with the Huntington’s Dis-
ease 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
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 neurol-
ogist’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 con-
fident 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). Rus-
somanno jumped at the opportunity to fig-
ure out what was going on inside his brain.
He deconstructed the toy and fitted
it to a baseball cap with its single electro-
encephalogram (EEG) electrode resting on
his forehead. He added a Bluetooth trans- a rare form of dementia, and a close friend NEXT-GEN MIND READER: Neurosity’s Notion
mitter on the brim that allowed the device to suffered a temporarily paralyzing neck headset, released in 2019, is one of a handful of
consumer brain-computer interface devices that
communicate with his smartphone and built injury. Russomanno realized that por-
scientists are adapting for their EEG research.
an app into which he could enter his activ- table EEG devices that feed information
ities and moods. Then Russomanno wore about brain activity into a computer, if
the hat one day while walking around New done well, could have all sorts of applica-
York City. “I wanted to start seeing if I [could] tions, including monitoring brain health ing EEG-based consumer BCI appli-
quantitatively track my habits and routines and assisting people with disabilities; the cations. Accordingly, companies sell-
and stitch them to my emotions and internal technology could “be applied in so many ing the devices typically fell into one of
states,” he explains. ways beyond my personal curiosity.” two groups: those targeting research-
Russomanno’s device was just a proto- There were already a handful of ers, with high-quality but extremely
type, and one day’s worth of data was not mobile EEG devices on the market and expensive equipment, and those target-
enough to answer the questions he had several more on the way, driven partly by ing tech developers with low-cost hard-
about his own mind. But his tinkering neuroscientists’ desire to make the tech- ware, usually with only a few electrodes
STEVE GONG

opened his eyes to the potential of BCI and nology more practical for use in health- and sometimes with fees to access the
the technology it’s based on. Around that care and other settings, and partly by raw data. Russomanno saw an opportu-
time, his grandmother was diagnosed with the tech industry’s interest in develop- nity to democratize a technology that, at

48 T H E SC I EN TIST | the-scientist.com
 the time, was largely limited to big com-
panies and well-funded labs.
In December 2013, he and Joel Mur-
phy, 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 dig-
ital 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 Mur-
phy 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 bet-
ter. 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 head-
band 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
© MUSE BY INTERAXON INC.
to make EEG mobile, consumer BCI wear-
ables 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 figur-
ing out the things you can do with it.”
EEG goes mobile
Although EEG took a back seat in neuro-
science with the advent of magnetic res-
onance 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 prod-
ucts were expensive, with price points in
the thousands or tens of thousands of dol-
lars. 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 con-
sumer-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 move-
ments 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 col-
leagues designed a protocol to detect
cognitive fatigue and successfully tested
it first on hospital workers and miners,
and then on themselves during a week-
long 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 origi-
nal Muse headset, released in
2014, was one of the first con-
sumer 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 col-
lected by the headband. “People have been
using Muse for research for a long time
now, as a recording device, as a therapeu-
tic 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 research-
targeted mobile EEG technologies with con-
ventional EEG systems. “Generally, there is
a tradeoff between data quality and mobil-
ity,” he tells The Scientist by email. Thea
Radüntz of the Federal Institute for Occupa-
tional 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 elec-
trical activity being recorded.
But for many applications, just one
or a few electrodes may be sufficient.
Strong, brain-wide responses, for exam-
ple, are “pretty easy to record with one
of these mobile systems,” says Scott Bur-
well, a neuroscientist currently wrapping
up a postdoc at the University of Minne-
sota who has used Muse and an EMO-
TIV 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:

Year
Access
company Primary
Company Headquarters Latest Product(s) Cost to raw
launched application
data
first product

San Jose, MindWave Mobile 2 headband Gaming and

NeuroSky 2009 $99 Free
California with a single electrode development

Various BCI components sold a la Broadly Ultracortex

OpenBCI New York City 2014 carte or as kits for creating simple accessible BCI headset sells Free
wearables technology for $350
Muse 2 and Muse S headbands $4/month
with four electrodes, plus sensors Meditation and (but can
InteraXon Toronto 2014 $250–$350
to measure heart rate, movement, mindfulness be hacked
and breathing for free)
$499 for
consumer
version; $599
Dreem Dreem 2 headband with six elec- Free with
Paris, New York Sleep for research
(formerly 2017 trodes, plus sensors to measure research
City, and Taiwan improvement version,
Rythm) heart rate, movement, and breathing version
which gives
access to the
raw data
Notion 2 headset with eight elec- Decode motor
Free; pro-
trodes, plus a sensor to measure intention; pro-
cessed on
Neurosity New York City 2019 movement and breathing and two ductivity, flow $899
device for
haptic motors to generate vibra- for software
security
tional feedback developers
Decode visual
NextMind headset with eight Not
NextMind Paris 2020 attentional focus; $399
electrodes available
gaming, AR/VR

5 0 T H E SC I EN TIST | the-scientist.com

the clinical setting especially, people are
just interested in registering that brain
response, and you can do that with rela-
tively few channels.”
Open for tinkering
The consumer BCI industry continues
to grow, with established companies
launching upgraded and novel products
and a handful of new competitors enter-
ing the market with low-priced devices.
While the BCI-enabling products pri-
marily 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 com-
puter so that the data can be stored and
NEUROSKY, INC.
later retrieved directly, and thus does
not have to be streamed, something Cas-
tillo argues is critical for data fidelity and
security. The device also comes preloaded
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.
with an app that can learn to interpret
the user’s imagined motor commands, for
applications in gaming and artificial real-
ity/virtual reality (AR/VR).
Castillo says that Notion’s poten-
tial 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 sug-
gested 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 look-
ing to the future and this new genera-
tion 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 elec-
trodes but specifically targets the visual
cortex, located at the back of the brain.
The company has developed software it
calls the NextMind engine, which ascer-
tains visual attention and translates that
into digital commands, allowing devel-
opers, 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 con-
sider doing so in the future. “By address-
ing 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 indepen-
dent labs, they’re already being adopted
by researchers. Kouider says that most
buyers so far are developers, but some
are academic researchers or consum-
ers. 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 crav-
ing, and had been using Muse to moni-
tor 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 limi-
tations—if wearers move their heads or
scrunch their foreheads, for example,
the electrical activity of the facial mus-
cles can “swamp out the EEG signals.”
Notion sits on the crown of the head,
where there are fewer muscles to inter-
fere. Burwell is now on the list to receive
the Notion 2 headset, which began ship-
ping 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 neurosci-
entists remain cautious, largely sticking
to EEG setups designed for research-
ers. 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
H
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 fun-
damental 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 trade-
offs right, and because of this, leave rela-
tively more offspring.
Despite some differences in the pre-
cise neurochemicals that modulate fear,
the neurophysiological mechanisms asso-
ciated with fear in humans are readily
seen across vertebrates. Controlled lab-
oratory 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 fearmon-
gers. 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 nat-
ural 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 ances-
tors, 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 opportu-
nity. Coopted and mutated, it can lead us
down destructive paths that often endan-
ger 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
The Guide
Working with Stem Cells? Continuous Measurements
Primary Enzyme Producer Opens the Potential
of Cell Monolayer Barrier
for Innovation with New Digital Stem Cell Function (TEER) in
Research Products Catalog Multiple Wells.
Learn More:
• Collagenase Products, Activities and Applications The TEER 24 System electrically monitors
• STEMxyme ® Collagenase/Neutral Protease Blends, the barrier function of cells grown in culture C

Animal Free upon permeable membrane substrates. The new TEER 24

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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
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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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 FOUNDATIONS
Scientist as Subject
BY AMANDA HEIDT
L
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
5 6 T H E SC I ENTIST | the-scientist.com
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, self-
experimentation 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
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.
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 self-
experimentation 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
XINHUA NEWS AGENCY / CONTRIBUTOR
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 “Self-
Experimentation in the Time of COVID-19”
Read The Scientist on your iPad!
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