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Yale Scientific<br />

THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION • ESTABLISHED IN 1894<br />

DECEMBER 2022<br />

VOL. 95 NO. 4 • $6.99<br />

14<br />

RECODING IN<br />

THE BRAIN<br />

STREAMLINING THE<br />

16<br />

SEARCH FOR NEW DRUGS<br />

ON DEMAND<br />

18<br />

MEMBRANE DEFORMATION<br />

THE NEW<br />

21<br />

CIRCULAR ECONOMY<br />

LAB PROFILE:<br />

24<br />

CARDS LAB


TABLE OF<br />

VOL. 95 ISSUE NO. 4<br />

14<br />

Recoding in the Brain<br />

Elisa Howard<br />

The brain is constantly recoding itself. Researchers at Mount Sinai and Yale School of Medicine<br />

uncover details of adenosine-to-inosine (A-to-I) editing in the brain, thereby providing insight into<br />

neurodevelopment and disease.<br />

16 Streamlining the Search for New Drugs<br />

Emily Shang<br />

The research and development process of drug synthesis has always been long and arduous.<br />

Researchers of the Ellman Lab have recently synthesized a molecule capable of targeting the 5-HT 2A<br />

receptor using a novel screening technique that can expedite the drug discovery process.<br />

18 On-Demand Membrane Deformation<br />

Risha Chakraborty<br />

Studying complex cellular processes in real-time continues to prove difficult for researchers,<br />

since manipulating many biological, chemical, and physical factors simultaneously requires nearimpossible<br />

levels of precision and control. Reimagining the role of common macromolecules in the<br />

cell might just help.<br />

21 The New Circular Economy<br />

Abigail Jolteus<br />

As climate change worsens, the need for more sustainable methods to produce energy also<br />

increases. Researchers at the Yale School of Environment have investigated the potential of a new<br />

technology, bioenergy with carbon capture and storage, which could help create a sustainable<br />

and low-carbon society.<br />

24 Lab Profile: CarDS Lab<br />

Yusuf Rasheed<br />

Cardiovascular disease I'd the leading cause of death across the United States, with one affected person<br />

dying every 34 seconds. The CarDS Lab at Yale is revolutionizing how cardiovascular health is treated and<br />

managed through AI and machine learning.<br />

2 Yale Scientific Magazine December 2022 www.yalescientific.org


CONTENTS<br />

More articles online at www.yalescientific.org & https://medium.com/the-scope-yale-scientific-magazines-online-blog<br />

4<br />

6<br />

27<br />

36<br />

Q&A<br />

NEWS<br />

FEATURES<br />

SPECIALS<br />

www.yalescientific.org<br />

Does Parkinson's Smell? • Dinara Bolat<br />

Would You Trust Working With a Robot? • Jamie Seu<br />

Hidden Pandemic • Sofia Jacobson<br />

Big Tech is Always Watching • Alex Dong<br />

Optimistic Results for RSV Prevention Strategies • Madeleine Popofsky<br />

Forecasting Extinction • Evelyn Jiang<br />

It's Not All Bad • Matthew Blair<br />

The Case Against Intelligent Computer Vision • Samantha Liu<br />

The Soot Factor • William Archaki<br />

The Winding Synthetic Road to New Antibiotics • Nathan Mu<br />

Turtle Transformers • Riya Bhargava<br />

A New Approach to Cystic Fibrosis • Matthew Zoerb<br />

The Strength of Weak Ties • Eunsoo Hyun<br />

An Unexpected Marriage: Robot Drones & Flower Power • Cindy Mei<br />

Robots vs. Humans: Organic Chemistry Edition • Anya Razmi<br />

Gamer Neurons • Maya Khurana<br />

Conan the Bacterium • Kayla Yup<br />

The Golden Standard • Anavi Uppal<br />

Undergraduate Profile: Eric Sun (YC '23) • Cindy Kuang<br />

Alumni Profile: Jonathan Rothberg (GSAS '91) • Sophia Burick<br />

Science in the Spotlight: Eating to Extinction • Dinesh Bojja<br />

Science in the Spotlight: Atoms & Ashes • Ximena Leyva Peralta<br />

Counterpoint: Life on Mars Was Its Own Undoing • Crystal Liu<br />

Hidden Histories: Nettie Stevens • Anjali Dhanekula<br />

Synapse Essay Contest: Pulling Teeth • Kate Kim<br />

December 2022 Yale Scientific Magazine 3


WOULD YOU TRUST<br />

WORKING WITH A ROBOT?<br />

&<br />

DOES PARKINSON'S SMELL?<br />

By Dinara Bolat<br />

Currently, no specific diagnostic tests exist for Parkinson’s<br />

disease, a degenerative brain disorder. Instead, patients<br />

get diagnosed once they start displaying trademark<br />

symptoms like tremors, muscle stiffness, and impaired balance.<br />

However, thanks to Joy Milne, a Scottish nurse with a<br />

hypersensitive nose, this is changing.<br />

Milne came to the attention of UK scientists in 2015 when<br />

she proved her ability to detect people with Parkinson’s by their<br />

unique smell. With her help, researchers from the Universities<br />

of Edinburgh and Manchester identified specific molecules that<br />

cause ‘Parkinson’s smell.’ They identified molecules in the sebum,<br />

an oily substance on the skin surface, and found that people<br />

with Parkinson’s have altered lipid signatures compared to non-<br />

Parkinson’s patients. Using these results, they developed a skinswab<br />

test to detect this lipid signature which analyzes sebum<br />

with PS-IM-MS, a type of ion mobility mass spectrometry. This<br />

new method reveals specific compounds unique to Parkinson’s<br />

sebum samples and identifies lipid classes that are differentially<br />

secreted in patients with Parkinson’s.<br />

Scientists are hopeful that this swab test will be a key tool for earlier<br />

and faster Parkinson’s diagnosis, leading to more opportunities and<br />

options for treatment. Although there are still clinical trials and<br />

accuracy assessments required before the tests can be authorized in<br />

hospitals, scientists involved claim that the test has a greater than<br />

ninety percent accuracy. This ground-breaking technology has<br />

inspired other research teams to study the olfactory signature of<br />

other diseases, opening a new field of research yet to be explored. ■<br />

By Jamie Seu<br />

It’s a familiar trope: a well-meaning scientist invents a piece<br />

of revolutionary technology that develops consciousness<br />

and rises up to destroy the human race. Machine<br />

consciousness has long been a subject of fear and fascination,<br />

but for people who regularly interact with robots, such as those<br />

who work in the manufacturing industry, trust in automation<br />

is an incredibly pertinent issue.<br />

To better understand the nuances of trust in human-robot<br />

collaborations (HRCs), researchers at Texas A&M University<br />

designed a series of trials that allowed them to study operator<br />

trust. Participants (operators) were instructed to polish a<br />

metal surface with a robot along an S-shaped trajectory under<br />

varying levels of robot reliability and operator cognitive<br />

fatigue. Working with an unreliable robot reduced task<br />

efficiency and accuracy (deviation from the defined trajectory)<br />

but not precision (variance in deviation from the trajectory).<br />

Participants also perceived the task as more demanding than<br />

when they worked with a reliable robot. For participants<br />

experiencing cognitive fatigue, higher fatigue scores and<br />

reduced task efficiency were reported, with female participants<br />

more strongly impacted than male participants.<br />

Analyses of human factors on trust in HRCs can be utilized to<br />

create more effective worker training programs and adaptations<br />

to robot design that will maximize efficiency and workplace<br />

safety, improving and fortifying HRC systems. Robots are here<br />

to stay, and it’s on us to figure out how to work alongside them<br />

and trust them as partners. Maybe then they’ll spare us when<br />

they decide to take over the world. ■<br />

4 Yale Scientific Magazine December 2022 www.yalescientific.org


The Editor-in-Chief Speaks<br />

A FUTURE WITH SCIENCE<br />

In our final issue of the volume, we have focused on what science innovation<br />

means for the future. Novel technologies come with such great potential<br />

but almost always with caveats. While science can help lift society towards<br />

a utopia, it certainly can also do the opposite. Our duty as scientists is to<br />

prioritize the bigger picture, recognizing the ethical issues that accompany<br />

innovation. The following stories highlight science at Yale and beyond and<br />

their implications for the future of our world.<br />

Our full-length stories spotlight science’s potential in healthcare innovation.<br />

A study from the Ellman lab uses virtual screening for small molecule synthesis<br />

targeting antidepressant activity (pg. 16). The CarDS lab at the Yale School<br />

of Medicine uses data-driven strategies such as machine learning to improve<br />

cardiovascular healthcare for patients (pg. 24). Another study from the Yale<br />

School of Environment investigates how to capture energy from biomass in<br />

hopes of creating a more sustainable, low-carbon society (pg. 21)<br />

Beyond academia, the promise of science can be pursued through<br />

entrepreneurship. Jonathan Rothberg, our alumni profile, describes his prolific<br />

career, founding numerous companies inspired by the ultimate goal of helping<br />

someone he loves (pg. 37).<br />

As technology becomes increasingly advanced, the ethical questions facing<br />

researchers with each successive discovery have never been more critical. For<br />

those at the forefront of artificial intelligence, should machines be held to a<br />

higher standard than humans in the context of, for example, accidents caused<br />

by a human driver versus a self-driving car? For lead geneticists, where do they<br />

draw the line for engineering traits of our offspring—should we be able to edit<br />

out diseases, to engineer in intelligence or physical traits? For those tackling<br />

aging, what are the implications of increasing human lifespan beyond several<br />

hundred years—would it broaden the distance between social classes; would it<br />

stagnate the innovations and perspectives of new generations?<br />

It has truly been an honor serving as the Editor-in-Chief of Yale Scientific,<br />

and it is an experience I will treasure forever. Thank you to the amazing 2022<br />

masthead, writers, artists, and the Yale science community. Like the amazing<br />

people behind the stories of the last calendar year, I hope to follow suit and<br />

dedicate my life to science and the benefits it creates for society. And I hope<br />

these stories continue to inspire for years to come.<br />

About the Art<br />

Jenny Tan, Editor-in-Chief<br />

Treating cardiac disease, developing<br />

pharmaceutical drug candidates,<br />

quantifying greenhouse gas<br />

emissions: today’s growing<br />

medical, environmental, and<br />

scientific concerns look towards<br />

novel methods of research such<br />

as integrated machine learning,<br />

techno-economic analysis, and<br />

DNA nanotechnology. This issue’s<br />

cover reflects the wide array of<br />

research avenues that scientists take<br />

in order to solve our world’s most<br />

poignant problems.<br />

Anasthasia Shilov, Cover Artist<br />

MASTHEAD<br />

December 2022 VOL. 95 NO. 4<br />

EDITORIAL BOARD<br />

Editor-in-Chief<br />

Managing Editors<br />

News Editor<br />

Features Editor<br />

Special Sections Editor<br />

Articles Editor<br />

Online Editors<br />

Copy Editors<br />

Scope Editors<br />

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PRODUCTION & DESIGN<br />

Production Manager<br />

Layout Editors<br />

Art Editor<br />

Cover Artist<br />

Photography Editor<br />

BUSINESS<br />

Publisher<br />

Operations Manager<br />

Advertising Manager<br />

Subscriptions Manager<br />

OUTREACH<br />

Synapse Presidents<br />

Synapse Vice President<br />

Synapse Outreach Coordinators<br />

Synapse Events Coordinator<br />

WEB<br />

Web Managers<br />

Head of Social Media Team<br />

Social Media Coordinators<br />

STAFF<br />

William Archaki<br />

Riya Bhargava<br />

Matthew Blair<br />

Dinesh Bojja<br />

Dinara Bolat<br />

Wineth De Zoysa<br />

Mia Gawth<br />

Daniel Havlat<br />

Elisa Howard<br />

Eunsoo Hyun<br />

Sofia Jacobson<br />

Evelyn Jiang<br />

Maya Khurana<br />

Jenna Kim<br />

Jessica Le<br />

Ximena Leyva Peralta<br />

Cynthia Lin<br />

Crystal Liu<br />

Samantha Liu<br />

Yurou Liu<br />

Cindy Mei<br />

Kenna Morgan<br />

Nathan Mu<br />

Victor Nguyen<br />

Avi Patel<br />

Himani Pattisam<br />

Emily Poag<br />

Madeleine Popofsky<br />

Tony Potchernikov<br />

Yusuf Rasheed<br />

Jenny Tan<br />

Tai Michaels<br />

Maria Fernanda Pacheco<br />

Madison Houck<br />

Alex Dong<br />

Sophia Li<br />

Cindy Kuang<br />

Ethan Olim<br />

Tori Sodeinde<br />

Breanna Brownson<br />

Hannah Han<br />

Kayla Yup<br />

Anna Calame<br />

Hannah Huang<br />

Meili Gupta<br />

Catherine Zheng<br />

Ann-Marie Abunyewa<br />

Brianna Fernandez<br />

Malia Kuo<br />

Anasthasia Shilov<br />

Jenny Wong<br />

Jared Gould<br />

Lauren Chong<br />

Sophia Burick<br />

Shudipto Wahed<br />

Krishna Dasari<br />

Lucy Zha<br />

Rayyan Darji<br />

Hannah Barsouk<br />

Risha Chakraborty<br />

Bella Xiong<br />

Katherine Moon<br />

Emily Shang<br />

Anavi Uppal<br />

Abigail Jolteus<br />

Elizabeth Watson<br />

Anya Razmi<br />

Alex Roseman<br />

Noora Said<br />

Jamie Seu<br />

Rishi Shah<br />

Ishani Singh<br />

Kayla Sohn<br />

Yamato Takabe<br />

Kara Tao<br />

Robin Tsai<br />

Hanwen Zhang<br />

Lawrence Zhao<br />

Matthew Zoerb<br />

The Yale Scientific Magazine (<strong>YSM</strong>) is published four times a year by Yale<br />

Scientific Publications, Inc. Third class postage paid in New Haven, CT<br />

06520. Non-profit postage permit number 01106 paid for May 19, 1927<br />

under the act of August 1912. ISN:0091-287. We reserve the right to edit<br />

any submissions, solicited or unsolicited, for publication. This magazine is<br />

published by Yale College students, and Yale University is not responsible<br />

for its contents. Perspectives expressed by authors do not necessarily reflect<br />

the opinions of <strong>YSM</strong>. We retain the right to reprint contributions, both text<br />

and graphics, in future issues as well as a non-exclusive right to reproduce<br />

these in electronic form. The <strong>YSM</strong> welcomes comments and feedback. Letters<br />

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author’s name and contact information. We reserve the right to edit letters<br />

before publication. Please send questions and comments to yalescientific@<br />

yale.edu. Special thanks to Yale Student Technology Collaborative.


NEWS<br />

Gender Studies & Data Science / Computer Science & Law<br />

HIDDEN<br />

PANDEMIC<br />

BIG TECH IS<br />

ALWAYS<br />

WATCHING<br />

BY SOFIA JACOBSON<br />

BY ALEX DONG<br />

IMAGE COURTESY OF PIXABAY<br />

IMAGE COURTESY OF WIKIMEDIA COMMONS<br />

The pandemic drastically altered the daily tasks of many<br />

adults who, in addition to their everyday professions,<br />

took on new responsibilities in the home, including<br />

child and elder care. As many of these new duties fell mainly<br />

to women, associate research scientist Ji-Young Son and<br />

Professor of Environmental Health Michelle Bell launched a<br />

series of studies on how women and minority scientists were<br />

potentially disproportionately impacted by the pandemic.<br />

One study with the Yale School of Environment, supported<br />

by the Yale Women Faculty Forum, focused on gender<br />

disparities in submissions to academic science journals.<br />

The researchers hypothesized that the percentage of<br />

women scientists submitting articles would decrease during<br />

the pandemic. They found that there was actually an increase<br />

in women’s submissions compared to men. They examined<br />

99,114 submissions from January 2019 to July 2021. Of<br />

these, the corresponding authors were 82.1 percent male,<br />

17.8 percent female, and 0.1 percent nonbinary. Comparing<br />

the pre-pandemic time to the pandemic time, the percentage<br />

of women submitting slightly increased to 18.7 percent.<br />

However, the pandemic did have one notable effect on<br />

women’s submissions. “The rate of increase in submissions<br />

[by women] slowed during the pandemic compared to the<br />

pre-pandemic period,” Son said.<br />

There is still enormous gender disparity in the sciences.<br />

Although studies such as this one are bringing the issue to<br />

light, the problem continues—before, during, and after the<br />

COVID-19 pandemic. “More resources from universities,<br />

not [just] individual efforts, and other measures for women<br />

scientists are needed to promote equality,” Son said. ■<br />

Have you ever read Facebook’s Terms of Service after<br />

downloading the app? Chances are, probably not. While<br />

we often mindlessly click ‘accept,’ big tech companies<br />

like Meta have been known to violate user privacy without<br />

their knowledge or consent. With the rapid rise of big tech, data<br />

privacy has increasingly become a concern for both individuals<br />

and regulatory organizations.<br />

In light of this issue, Adrian Kuenzler (YLS ’15), Assistant<br />

Professor of Law at Zurich University, presents a new framework<br />

for how competition between big tech companies can promote<br />

data privacy. Kuenzler’s research draws on a variety of legal<br />

investigations, empirical economic analyses, and cognitive<br />

science studies. He proposes a new way of protecting consumer<br />

interests by integrating three strategies typically used separately.<br />

Firstly, users should be able to choose between different<br />

platforms like Google Chrome and Safari to maintain consumer<br />

sovereignty. Next, different providers must be interoperable—<br />

switching platforms and migrating data must be practical.<br />

Finally, consumer input should be considered and used to<br />

improve existing services such as feature addition and product<br />

design. Taken together, these strategies promote consumer voice<br />

and choice, giving users more authority to prioritize data privacy.<br />

Authorities typically only use a single approach, often<br />

overlooking the convergence of the three strategies when<br />

remedying data privacy issues. “It doesn’t follow that we only<br />

need one account or that a certain regulatory scheme is always<br />

appropriate,” Kuenzler said. Ultimately, using the three strategies<br />

as complements rather than substitutes enables us to better<br />

navigate data privacy concerns and leads to more effective<br />

regulatory policy decisions. ■<br />

6 Yale Scientific Magazine December 2022 www.yalescientific.org


Biology & Health / Environmental Science<br />

NEWS<br />

OPTIMISTIC<br />

RESULTS FOR<br />

RSV PREVENTION<br />

STRATEGIES<br />

FORECASTING<br />

EXTINCTION<br />

BY MADELEINE POPOFSKY<br />

BY EVELYN JIANG<br />

IMAGE COURTESY OF FLICKR<br />

IMAGE COURTESY OF FLICKR<br />

Respiratory syncytial virus (RSV), a deadly respiratory virus,<br />

has swamped hospitals globally. “Most of the [Connecticut]<br />

hospitals are packed, and they need to build tents outside<br />

some hospitals to meet [the demand of] the children who are<br />

infected for RSV,” said Zhe Zheng, a PhD candidate at the Yale<br />

School of Public Health. Critically, the virus has no vaccine or<br />

other effective, widely accessible prevention method.<br />

However, Zheng’s analysis of clinical trial results for three<br />

prevention strategies in development proves there is hope<br />

ahead. First, extended half-life monoclonal antibodies, blood<br />

proteins that counteract pathogens, already have approval<br />

in the European Union but could take another year or two<br />

to be approved in the United States. The second, a maternal<br />

immunization, has promising clinical trial results but hasn’t<br />

yet been filed for approval. According to Zheng’s findings, each<br />

could avert more than half of RSV hospitalizations in children<br />

under six months. Live-attenuated vaccines proved highly<br />

effective for children between six months and five years, though<br />

they are still in the early stages of development.<br />

An important question Zheng shed light on relating to these<br />

prevention strategies involves the efficacy of seasonal versus<br />

yearly vaccination plans. While previously reliably seasonal,<br />

COVID has made RSV’s seasons irregular, in addition to<br />

differences between seasonality in northern and southern states.<br />

“A seasonal program may provide minor [cost] advantages<br />

over a year-round [program], but the year-round would<br />

cover more children,” Zheng said. Zheng’s research compares<br />

RSV prevention methods and discusses the best method of<br />

distribution—information that could relieve overwhelmed<br />

hospitals and save children’s lives. ■<br />

While extinction is a natural phenomenon, human activity<br />

has accelerated the deterioration of ecosystems worldwide<br />

and driven an epidemic of species extinctions, leading<br />

growing numbers of scientists to search for ways to conserve the Earth’s<br />

existing natural resources for future generations. Geospatial analytical<br />

tools like range maps, which describe the geographic area a species is<br />

believed to inhabit, are essential resources for informed conservation<br />

planning. Researchers can use data from these maps to forecast future<br />

range dynamics to identify vulnerable “gaps” in protection, informing<br />

decision-making and conservation resource allocation.<br />

Traditional gap analyses tend to focus solely on threats<br />

to species’ range. However, a team of researchers led by<br />

Nyeema Harris, an associate professor at the Yale School of<br />

the Environment, has developed an innovative methodology<br />

that simultaneously analyzes positive conditions and threats to<br />

generate more comprehensive range maps.<br />

“We aggregated different layers. Some were threat layers that<br />

were detrimental to species’ range, and others were resource<br />

layers that were positive for promoting species conservation,”<br />

Harris said. “We overlapped these resources and threats to<br />

identify areas vulnerable to range contractions and that maybe<br />

aren’t receiving enough conservation and research efforts.”<br />

The researchers performed a gap analysis across the ranges of<br />

ninety-one African carnivores to determine whether existing<br />

and available conservation capacities are sufficient. The team<br />

assessed factors like hunting pressures, drought vulnerability,<br />

cultural diversity, and protected area coverage. They found<br />

that, on average, fifteen percent of a species’ range was at risk of<br />

contraction. “We hope this analysis can be used to inform future<br />

conservation and research,” Harris said. ■<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 7


FOCUS<br />

Molecular Biology<br />

IT’S NOT<br />

ALL BAD<br />

Examining the role of H-NS<br />

protein degradation in the<br />

growth of good bacteria<br />

BY MATTHEW BLAIR<br />

IMAGE COURTESY OF ISTOCK<br />

There is a common misconception that all bacteria are bad<br />

bacteria. Perhaps this narrative is bolstered by the branding<br />

of disinfectants claiming to kill 99.9 percent of all viruses<br />

and bacteria or the cartoonishly frightening drawings on the<br />

walls of doctor’s offices. This generalization is simply untrue.<br />

Bacteria play a critical role in helping humans maintain a<br />

healthy gut. Our gut is an amalgamation of trillions of bacteria<br />

that form unique interactions and express various genes essential<br />

to their colonization of the gut. This bacterial colonization helps<br />

humans to maintain a balanced gut and, consequently, a healthy<br />

body. Already, questions abound. How do organisms “decide”<br />

which genes to express? Are there genes whose expression<br />

is more desirable than others? It is just these questions that<br />

Jeongjoon Choi, an associate research scientist in the Department<br />

of Genetics at the Yale School of Medicine, focused on answering.<br />

Specific genes are expressed when they receive the direction<br />

to do so from regulatory and signaling proteins. “But what I was<br />

kind of surprised by is even when you give such an inducing<br />

signal, some genes are not expressed under certain conditions,”<br />

Choi said. Interestingly, many unexpressed or silenced genes<br />

were of a specific variety: horizontally transferred genes<br />

(HTGs), also called foreign genes. HTGs are important as they<br />

drive bacterial evolution by introducing foreign DNA, and thus<br />

new traits, to the recipient organism.<br />

The silencing of foreign genes is done by the heat-stable<br />

nucleoid structuring protein (H-NS). Nucleoid structuring<br />

refers to how this protein upholds the basic structure of DNA.<br />

Building on this function, H-NS represses foreign genes by<br />

specifically binding to the corresponding DNA. In some<br />

instances, gene silencers like H-NS are beneficial. The laissezfaire<br />

expression of all foreign genes at once would be fatal.<br />

Unfortunately, however, H-NS can suppress the expression of<br />

important HTGs. For foreign genes to be expressed, they must<br />

overcome gene repression by the silencer H-NS.<br />

Choi’s study provides new insight into how organisms can<br />

overcome foreign gene repression by silencers such as H-NS.<br />

It has been a dogma in the field that H-NS amounts remain<br />

constant regardless of the conditions. Choi made the groundbreaking<br />

discovery that the abundance of H-NS varies in<br />

different conditions, such as acidic and neutral conditions.<br />

Additionally, in some conditions, H-NS is degraded. “Because<br />

H-NS amounts were believed to stay constant, overcoming<br />

foreign gene silencing was largely ascribed to anti-silencing<br />

proteins,” Choi said. Thanks to Choi’s research, there is a new<br />

understanding that both anti-silencing proteins and H-NS<br />

degradation work collaboratively to overcome gene silencing by<br />

H-NS and control foreign gene expression.<br />

The study focused on Escherichia coli, an example of a “good”<br />

type of bacteria. Choi found that for the E. coli to grow in the<br />

guts of mice and express HTGs, H-NS had to be degraded. The<br />

silencing effect of H-NS can be overcome in two steps. Firstly,<br />

the DNA binding regulatory protein PhoP—a protein impacting<br />

the expression of certain parts of DNA displaces H-NS, making<br />

it susceptible to degradation. Then, the protease Lon—an enzyme<br />

that breaks down proteins—targets specific regions of H-NS to<br />

degrade it. With H-NS degraded, E. coli can grow.<br />

“This is basic molecular biology, and I like basic science, but<br />

if the basic science wants to change the word, then we need to<br />

transfer it, making it more applicable for treatment or another<br />

purpose,” Choi said. The impacts of this finding are far-reaching,<br />

potentially changing how we address many ailments, from minor<br />

bacterial infections to tuberculosis. The possibilities of Choi’s<br />

discovery lie in the manipulation of H-NS. “By manipulating H-NS<br />

degradability, we can cause our bacteria, not our good bacteria but<br />

those big, bad bacteria, to be more susceptible to environmental<br />

changes. This will prevent harmful bacteria from causing much of<br />

a problem,” Choi said. This approach could work in tandem with<br />

antibiotics commonly prescribed to remove harmful bacteria. In<br />

cases of intense antibiotic resistance, H-NS manipulation could be<br />

the solution: where antibiotics do not work, causing the bacteria to<br />

be more vulnerable to the natural processes of our body can make<br />

these harmful bacteria unable to cause disease.<br />

Choi’s research done in the guts of mice can be extrapolated, with<br />

some caveats, to human health, making leaps in our understanding<br />

of how bacteria can be regulated and how we can work to maintain<br />

a healthy gut through the development of “good” bacteria. ■<br />

8 Yale Scientific Magazine December 2022 www.yalescientific.org


Computer Science / Biology<br />

FOCUS<br />

THE CASE AGAINST<br />

INTELLIGENT<br />

COMPUTER VISION<br />

Neural networks are lagging behind<br />

human brains in visual perception<br />

BY SAMANTHA LIU<br />

IMAGE COURTESY OF FLICKR<br />

Convolutional neural networks, or CNNs, are deep learning<br />

networks trained with millions of images. Designed to imitate<br />

primate brains, they proved highly adept at object recognition,<br />

sparking media excitement over the future of computer vision—the use<br />

of AI to interpret visual input. Moreover, researchers hoped CNNs could<br />

offer a shortcut to studying the primate brain. Rather than undertake<br />

copious MRI scans and patient trials, scientists could run a simulation<br />

through a CNN to predict how the human brain would respond.<br />

But the research of Yaoda Xu, a senior research scientist at Yale,<br />

proves otherwise. Ten years ago, when a perfect visual recognition<br />

system and its manifold implications—think! driverless cars!—loomed<br />

on the brink of discovery, those possibilities now seem distant as ever.<br />

“People got excited about using the CNN to model the brain,” Xu said.<br />

“But my findings have been that, no, it doesn’t look like the brain. It’s<br />

maybe a primitive, overdeveloped, early visual area of the brain.”<br />

As her recent paper published in NeuroImage clarifies, where CNNs<br />

fail is in the realm of identifying transformation tolerant representations.<br />

The process sounds complex, but it’s something humans carry out every<br />

day: when a person walks toward a table and sees it enlarge in their field<br />

of vision, they know it’s the same table as before. The same goes for<br />

objects viewed from different perspectives or positions—even as altered<br />

representations, the brain maps them onto the same visual identity.<br />

This intuitive procedure proves much more challenging for neural<br />

networks. In her project, Xu took images of eight real-world objects,<br />

ranging from a pair of scissors to an elephant, and distorted them in<br />

various ways. Some she geometrically transformed, moving up and<br />

down or dilating on the page. Others she subjected to non-Euclidean<br />

transformations, changing the contrast and resolution. In each case,<br />

when tested on eight different CNNs, the neural networks showed<br />

weaker consistency and tolerance for these images.<br />

The implication is striking: a process trivial for primate brains<br />

remains elusive for the complex, pre-trained machines meant to<br />

model them. Xu attributes this discrepancy to the mechanics of<br />

human cognition versus machine learning. The primate brain<br />

processes visual information through two streams: dorsal, which<br />

recognizes the object’s spatial location (the “where”), and ventral,<br />

www.yalescientific.org<br />

which recognizes the object’s identity (the “what”). Though<br />

seemingly redundant, the ability to identify the same object in<br />

different contexts arises from these two systems.<br />

The CNN, in contrast, employs a sub-optimal approach. “In<br />

my view, it basically has a huge amount of memory,” Xu said. “It<br />

memorizes each instance of each object it was exposed to, without<br />

making a connection among these different objects.” Scientists are<br />

unsure how this algorithm works precisely, thus creating a “black box.”<br />

But Xu is hopeful about cracking it—if only the scientific community<br />

reframes its approach. She plans to delve deeper into neuroscience<br />

research, seeing where and how primate vision diverges from neural<br />

networks, to shed light on the CNN algorithm and identify stages<br />

for improvement. Importantly, she believes the key lies in crafting<br />

a comprehensive biological understanding of vision rather than<br />

tackling the problem unilaterally through computer engineering.<br />

She compared this pursuit to trying to replicate flight: someone can<br />

blindly tweak the wing, fold a new flap, and throw everything against<br />

the wall until something flies or falls off a cliff. But someone can also<br />

investigate how flight works, learning the fundamental aerodynamics<br />

and physics which drive movement to find inspiration for an airplane.<br />

“What is vision trying to achieve? What is the problem you’re trying<br />

to solve?” Xu asked. She expressed aversion toward the trial-anderror<br />

experimentation employed by many computer science labs. “I’m<br />

showing you that, hey, this is the algorithm and computation that’s<br />

happening in the brain. If the system you’re building can have the same<br />

principles, maybe you can do a lot better than what you have right now.”<br />

Xu looks towards a future where artificial networks could perfectly<br />

mimic human vision. She recalled how, as a student growing up in<br />

China, she spent entire weekends hand-washing her clothes. When<br />

the laundry machine mechanized the process, her free time could be<br />

put toward more valuable endeavors — like advancing her research<br />

career. “There’s a lot of human potential that is untapped,” Xu said. “If<br />

some of our boring tasks can be done by a machine efficiently with<br />

this kind of visual intelligence, it could lead to another leap in human<br />

development. We could have the creativity to be who we want or to<br />

be the best version of ourselves.” ■<br />

December 2022 Yale Scientific Magazine 9


FOCUS<br />

Environmental Chemistry<br />

THE SOOT<br />

FACTOR<br />

Picking the sustainable<br />

jet fuel of the future<br />

BY WILLIAM ARCHACKI<br />

IMAGE COURTESY OF FLICKR<br />

Next time you’re cruising at forty thousand feet in the<br />

air, think about how amazing it is that a few hundred<br />

tons of metal can whisk you between two distant cities<br />

in just a few hours. For the seasoned flier, air travel is so simple<br />

it almost feels like magic. Behind that magic, though, lie many<br />

technological innovations—one of the most important being the<br />

jet fuel that keeps the engines running.<br />

Most aircraft engines today burn petroleum fuels that emit large<br />

volumes of carbon dioxide, the primary pollutant behind rising<br />

global temperatures. To reduce these emissions and make aviation<br />

more sustainable, biofuels may be a necessary replacement. Biofuels<br />

consume carbon dioxide from the atmosphere in production,<br />

balancing the amount they emit when burned. Because they<br />

have similar physical and chemical properties to petroleum fuels,<br />

biofuels could easily power existing jet engines. However, with<br />

thousands of possible biofuels competing for a single spot in<br />

the future of aviation, it’s hard to say which one to use. Thus, it’s<br />

necessary to consider a key piece of data: the soot factor.<br />

Soot is the black residue left behind by burnt organic matter.<br />

When dispersed in the atmosphere, it absorbs solar energy and<br />

contributes to climate change alongside carbon dioxide. Under<br />

some circumstances, it can even induce the growth of high-altitude<br />

cirrus clouds that absorb solar radiation more strongly than carbon<br />

dioxide. When inhaled, soot can lead to the development of heart<br />

disease and certain cancers, adding to the public health risk of air<br />

pollution. To minimize the burden of soot emissions on the climate<br />

and human health, researchers must select biofuels that burn<br />

without releasing harmful amounts of soot.<br />

In an effort to improve available data about soot emissions, the<br />

Pfefferle Lab Group at Yale developed a new method to measure<br />

a fuel’s “sooting tendency” and then examined two dozen biofuel<br />

candidates. Earlier techniques for calculating sooting tendency<br />

required researchers to burn large volumes of fuels to observe the<br />

complex properties of the flames. The Pfefferle group’s new method<br />

reduced the amount of fuel necessary to generate data. They opted<br />

to calculate sooting tendency by measuring the luminosity, or<br />

brightness, of the fuels’ flames when burning individual drops—<br />

the brighter the flame, the sootier the fuel.<br />

The biofuel candidates subjected to this new test all fall under<br />

the category of terpenes, which are combustible chemicals<br />

found in organisms ranging from redwood trees to algae.<br />

Charles McEnally, a chemical engineering research scientist at<br />

the Pfefferle lab, explained that terpenes are of special interest<br />

as candidates because of their diversity.<br />

“What’s interesting about terpenes is that the biochemistry that<br />

makes them is always the same, and the input molecule is always<br />

the same: its isoprene,” McEnally said. “Depending on exactly how<br />

the chemistry works, you can get an enormous number of different<br />

outputs. There are tens of thousands of terpenes that are known.”<br />

Out of the twenty-four terpene biofuels that the Pfefferle group tested,<br />

seven were produced through a process known as hydrogenation, in<br />

which the chemical structure is modified to include more hydrogen<br />

atoms and fewer double bonds. These hydrogenated options<br />

outperformed their unmodified competitors for soot reduction,<br />

posting lower numbers on the sooting index that the Pfefferle group<br />

developed. Hydrogenation—as well as other chemical processes that<br />

are broadly referred to as “upgrading”—have the potential to further<br />

improve the properties of biofuel candidates.<br />

“We have all of organic chemistry at our disposal, so we’re no longer<br />

limited to the molecules that are in petroleum. Almost certainly, out of<br />

all of organic chemistry, there are other molecules that will make better<br />

fuels than the ones that happen to be in petroleum,” McEnally said.<br />

In their paper regarding terpene biofuels, the authors note that<br />

large-scale production of terpenes could shift toward bioreactors in<br />

the future. By genetically engineering microorganisms like E. coli<br />

to synthesize terpenes in bioreactors, the aviation industry could<br />

find a path to a simple and sustainable fuel source.<br />

The Pfefferle group’s measurements for terpenes add to an evergrowing<br />

set of data about biofuel candidates. Their simplified method<br />

for determining sooting tendency provides a starting point for further<br />

research. With the group’s work, a biofuel alternative to petroleumbased<br />

jet fuel may eventually be what takes you to the skies. ■<br />

10 Yale Scientific Magazine December 2022 www.yalescientific.org


Biochemistry<br />

FOCUS<br />

THE WINDING<br />

SYNTHETIC ROAD<br />

TO NEW<br />

ANTIBIOTICS<br />

BY NATHAN MU<br />

PHOTOGRAPHY BY MATTHEW ZOERB<br />

Since the very first use of antibiotics, researchers have known<br />

about antibiotic resistance in bacteria. However, it takes a<br />

large investment of time and resources to discover novel<br />

antibiotics, which must be made cheaply available for patients.<br />

Therefore, the pharmaceutical industry has turned away from<br />

antibiotic development due to the immense input required and<br />

limited opportunity for profit, allowing antibiotic resistance to rise<br />

and our ability to fight infections to fall.<br />

Olivia Goethe and Mikaela DiBello, former and current<br />

graduate student researchers in Professor Seth Herzon’s lab in<br />

the Yale Department of Chemistry, tackled this issue by seeking<br />

to create new antibiotics from one core molecule, pleuromutilin.<br />

Pleuromutilin is naturally produced by fungi, and its derivatives<br />

have been used clinically as antibiotics for skin infections and<br />

community-acquired pneumonia. Herzon’s lab has also previously<br />

worked with pleuromutilins.<br />

Their recent paper, published in Nature Chemistry, presents a<br />

new total synthesis pathway to create pleuromutilin derivatives.<br />

This pathway is an improvement upon Herzon’s previous method<br />

published in 2017, as well as pre-existing semisynthesis pathways,<br />

which rely on bacteria to synthesize products rather than commonly<br />

available chemical reagents. “Our [new] synthetic route can access<br />

[unique] chemical modifications, like changing functional groups<br />

and changing ring sizes. But through semisynthesis, you’re kind of<br />

blocked in. You can only modify the easily accessible functionality,”<br />

Goethe said. Essentially, this new pathway allows for infinite new<br />

pleuromutilin derivatives to be produced by changing, removing, and<br />

rearranging atoms in a way that other synthesis methods could not.<br />

This total synthesis pathway is a powerful tool for learning about the<br />

properties of various pleuromutilin derivatives.<br />

Another key advancement was the ability to produce pleuromutilin<br />

derivatives in higher yields. Having enough product is vital for testing<br />

antibiotic activity. Obtaining viable yields of products was not an easy<br />

process, however. Each step in the synthesis pathway must be executed<br />

properly to give the correct molecule with the correct orientation or<br />

stereochemistry. Otherwise, subsequent reactions will result in little<br />

www.yalescientific.org<br />

to no yield of product. This was one of the most challenging parts<br />

of the research process. It took Goethe months of going through the<br />

available literature and experimenting with different reactions to<br />

obtain the desired product in a reaction that initially gave the wrong<br />

stereochemistry. “I had to have the right stereochemistry in order to<br />

make a usable amount of [the pleuromutilin derivative], which is why<br />

I definitely had to fix this, or I was screwed,” Goethe said.<br />

Out of all the pleuromutilin derivatives tested for antibiotic<br />

activity, many were surprisingly inactive, including many of the<br />

core derivatives proposed to improve metabolic stability, which<br />

would help the overall antibiotic effect. The most successful<br />

derivative contained a halogen, which was somewhat unexpected.<br />

“If you went into the ribosome site [of the bacteria], there wasn’t<br />

really any indication that including a halogen there would be<br />

helpful,” Goethe said. Successful pleuromutilin antibiotics usually<br />

bind to sites on bacterial ribosomes, but the chloride group had an<br />

unexpected effect that is worth more exploration. Work can also be<br />

done to find more compounds and, eventually, test the stability of<br />

pleuromutilin antibiotics once they enter the body. “It seems like,<br />

to me, medical chemistry is just a numbers game. You just need to<br />

make a ton of compounds and study them to get trends. There’s a<br />

lot of interest in studying pleuromutilins, and we’re contributing to<br />

the information available about what we can do to this molecule,”<br />

Goethe said. Ideally, this research will lead to the straightforward<br />

synthesis of novel, cheap, and accessible antibiotics.<br />

Goethe found this research for her PhD to be extremely rewarding.<br />

“I think that it’s really cool, just something you made with your<br />

hands from stock materials can be used to kill bacteria,” Goethe<br />

said. Now, Goethe works at Gilead Sciences, a biopharmaceutical<br />

company. She works in process chemistry, preparing materials for<br />

clinical phase trials, which test previously experimental treatments<br />

in human participants. “I think that my ideal dream [job] would be<br />

that I’ll combine the experience that I get here [at Gilead] in drug<br />

development with the passion I had for antibiotics, and maybe once<br />

I get a couple of years of experience, I can help antibiotic companies<br />

actually start to make some more drugs,” Goethe said. ■<br />

December 2022 Yale Scientific Magazine 11


FOCUS<br />

Robotic Engineering<br />

TURTLE<br />

TRANSFORMERS<br />

Reshapeable multienvironment<br />

robots and<br />

the future of soft robotics<br />

BY RIYA BHARGAVA<br />

IMAGE COURTESY OF JOKO DIAZ<br />

Pictured above is a baby leatherback turtle, a deep-diving<br />

reptile that lives in the ocean for years but migrates to<br />

the land to lay eggs. Leatherbacks have sleek, paddlelike<br />

forelimbs to navigate the seas, claws to walk on sand,<br />

and a mosaic of breathable cartilage for a shell. Many such<br />

adaptations have made turtles the masters of their niche<br />

between the land and the sea for over 200 million years.<br />

Accordingly, when engineers Robert Baines and Sree Kalyan<br />

Patiballa sat down to ideate a multi-environment mobile robot,<br />

they drew inspiration from turtle body plans and kinematics<br />

and named their robot the Amphibious Turtle Robot, or ART.<br />

“The importance of the paper is that we are showcasing<br />

how you can have robots that have adaptive components—<br />

components that change shape, and how this design paradigm<br />

can improve their efficiency and effectiveness,” says Baines, a<br />

PhD student researcher in Rebecca Kramer-Bottiglio’s lab at<br />

Yale, describing the lab’s recent Nature publication. ART is a<br />

quadruped with a streamlined shell, weighs nine kilograms,<br />

and has a body amalgamating soft materials that respond to<br />

external stimuli and traditional, rigid robotics components.<br />

The most remarkable feature of the robot is its morphing<br />

limbs that undergo adaptive morphogenesis—the limbs can<br />

alter their gait or shape in response to a stimulus, adopting<br />

morphologic features that best suit aquatic and terrestrial<br />

locomotion. For example, the limbs can morph into the<br />

streamlined flippers of a sea turtle when in water and the<br />

columnar legs of a land-faring tortoise when walking.<br />

While rigid-bodied robots can be programmed to perform<br />

a single task efficiently, they do not afford the same body<br />

compliance needed to design bio-inspired robots with<br />

muscle-like actions. Soft materials also have move-andhold<br />

operability–these materials can retain changes in shape<br />

without the constant application of external force, enhancing<br />

the overall energy efficiency of the robot.<br />

The best metric for ART’s performance was the Cost of Transport<br />

(COT), which measures the effectiveness of robot locomotion in<br />

terms of energy efficiency. ART had a minimum COT of three and<br />

ten for aquatic and terrestrial locomotion, respectively–a number<br />

that equals or outperforms other famous unimodal quadrupeds<br />

like EPFL’s Cheetah Cub and the Titan V-III.<br />

However, many improvements must be made before the<br />

robot is put to commercial use, especially when it comes to<br />

untethering. “One of the things we’re moving forward with is<br />

putting additional sensors on the robot to understand how it’s<br />

moving in the environment,” Baines said. “This way, it would<br />

know, for example, if it were in choppy water or still water, or<br />

if it were going down a hill and stumbling versus being stable<br />

and standing on flat ground.” The lab is also working to find<br />

better gaits for the robot.<br />

Even with such challenges, Baines foresees several important<br />

applications of such robots in the near future. Robots such as<br />

ART can be used to monitor ecosystems less invasively. “Such<br />

a platform is unique because it is bio-inspired. It would have<br />

less disturbance on the environment and the animals living in<br />

it,” Baines said. Instead of using turbulent propellers, the turtle<br />

robot swims using streamlined flippers. This design paradigm<br />

also foreshadows advances in disaster relief distribution,<br />

security, and the study of animal locomotion physics. ■<br />

12 Yale Scientific Magazine December 2022 www.yalescientific.org


Biology / Medicine<br />

FOCUS<br />

A NEW<br />

APPROACH TO<br />

CYSTIC FIBROSIS<br />

BY MATTHEW ZOERB<br />

IMAGE COURTESY OF FLICKR<br />

The possibility of rewriting genetic code has given hope to<br />

the 35,000 Americans suffering from cystic fibrosis (CF). In<br />

individuals with CF, a mutated gene causes a specific protein<br />

called the cystic fibrosis transmembrane conductance regulator<br />

(CFTR) to malfunction, wreaking havoc on the respiratory system.<br />

In each breath, dust, allergens, and pathogens enter our lungs<br />

and become trapped in a thin layer of mucus. This mucus must be<br />

constantly replenished to clean our airways and digest food, but<br />

without the properly functioning CFTR protein, mucus becomes<br />

viscous and thick, trapping contaminants in the lungs. The<br />

symptoms of CF manifest as coughing fits, frequent lung infections,<br />

and other discomforts. However, with the advent of gene editing,<br />

there is hope for a treatment for CF and other genetic diseases.<br />

A recent study by Yale postdoctoral research fellow Alexandra<br />

Piotrowski-Daspit and Marie Egan, a professor at the Yale<br />

School of Medicine, investigated a novel gene editing approach<br />

to restore the function of the mutated CF gene in mice. They<br />

targeted a specific mutation, the F508del mutation, responsible<br />

for about ninety percent of CF cases. To edit the mutated gene,<br />

the researchers encapsulated peptide nucleic acids (PNAs) and<br />

an unmutated “donor” version of the CFTR gene into polymeric<br />

nanoparticles. PNAs are synthetic nucleic acids with a similar<br />

structure to DNA and the same complementary base pairs, which<br />

allow them to bind to target sites in genomic DNA. Once inside<br />

the cell, the PNA molecules form complexes around the mutated<br />

DNA, leveraging the cell’s natural repair mechanisms to insert<br />

the corrected sequence using the donor DNA as a template.<br />

There are several key differences between PNA and CRISPR/<br />

Cas9 gene editing. CRISPR/Cas9 uses nucleases to “cut”<br />

genomic DNA, which reliably enables genetic modification,<br />

but may accidentally damage DNA in regions other than the<br />

target site. PNA-based editing reduces the possibility of offtarget<br />

effects by harnessing the cell’s existing, non-mutagenic<br />

repair mechanisms to incorporate the correct DNA sequence.<br />

This makes them an attractive choice since they reduce the<br />

likelihood of accidentally harming other systems in complex<br />

living organisms.<br />

The experiment demonstrated that gene editing has the<br />

potential to treat CF, which affects multiple organs throughout<br />

the body. “It’s kind of the holy grail of gene editing—to be able<br />

to effectively deliver gene editing agents systemically,” lead<br />

researcher Piotrowski-Daspit said. Even though the percent of<br />

cells edited in the treatment was less than the estimated five to<br />

fifteen percent needed to match healthy individuals, a partial<br />

restoration of function in the affected organs was observed<br />

without any off-target effects.<br />

Looking beyond the specific F508del mutation that served as<br />

the focus of this study, new PNAs will need to be synthesized<br />

to target other mutations responsible for CF, for which<br />

no treatments are currently available. Piotrowski-Daspit’s<br />

personal goal is to improve delivery efficiency and restore<br />

function to a higher percentage of cells. These advances may<br />

eventually translate into treatments that can cure CF and other<br />

genetic diseases in humans. ■<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 13


FOCUS<br />

Neuroscience<br />

RECODING IN<br />

THE BRAIN<br />

Applying A-to-I editing in human<br />

neurodevelopment and disease<br />

BY ELISA HOWARD<br />

The human brain is constantly recoding<br />

itself. Adenosine-to-inosine (A-to-I)<br />

editing, a form of RNA modification,<br />

occurs at more than one hundred million<br />

sites in the human transcriptome, diversifying<br />

RNA sequences of the human brain.<br />

In a recent paper published in Cell Reports,<br />

researchers at Icahn School of Medicine at<br />

Mount Sinai and the Yale School of Medicine<br />

investigated the spatiotemporal and genetic<br />

regulation of A-to-I editing over the course<br />

of human brain development. Their work<br />

catalogs A-to-I editing sites throughout<br />

human brain maturation, enhancing current<br />

understandings of neurodevelopment and<br />

underlying mechanisms of neurological<br />

diseases. “RNA editing is dysregulated in<br />

neurodevelopmental disorders,” said Winston<br />

Cuddleston, a PhD candidate at the Icahn<br />

School of Medicine and lead researcher<br />

of the study. “We are trying to get a better<br />

understanding of which RNA editing sites<br />

PHOTO COURTESY OF HANNAH HAN VIA WINSTON CUDDLESTON<br />

Postdoctoral fellow Winston Cuddleston, the<br />

first author of the paper published by the Breen<br />

Lab, poses for a photograph while running<br />

biocomputational analyses.<br />

are dynamically regulated across brain<br />

development to realize which cellular and<br />

molecular processes are being affected.”<br />

The Science of RNA Editing<br />

According to the central dogma of molecular<br />

biology, coined by biophysicist Francis Crick,<br />

the expression of protein-coding genes<br />

involves the flow of genetic information from<br />

DNA to RNA to protein. A gene’s DNA is<br />

copied into RNA through transcription, and<br />

that RNA specifies an amino acid sequence for<br />

protein synthesis in the translation process.<br />

In eukaryotes, primary RNA transcripts<br />

undergo diverse post-transcriptional<br />

modifications, resulting in mature RNA<br />

molecules prior to protein production. These<br />

modifications diversify the transcriptome, the<br />

collection of an organism’s RNA transcripts.<br />

A-to-I editing is a post-transcriptional<br />

modification involving adenosine conversion<br />

to inosine nucleosides. This conversion process<br />

is catalyzed by a family of enzymes called<br />

adenosine deaminase acting on RNA (ADAR)<br />

and occurs most prominently in the central<br />

nervous system (CNS). These modifications<br />

affect neuronal genes, including those involved<br />

in synaptic transmission and signaling.<br />

In protein-coding regions, A-to-I editing can<br />

result in amino acid substitutions at locations<br />

known as recoding sites. These recoding sites<br />

are necessary for normal neurodevelopment,<br />

given their involvement in modulating calcium<br />

permeability, desensitization recovery rates,<br />

and cytoskeletal organization at excitatory<br />

synapses, alongside other functions.<br />

Investigation of A-to-I Sites in the Brain<br />

Millions of individual A-to-I<br />

editing modifications have been<br />

found in humans—many in the brain.<br />

Nevertheless, according to this study’s senior<br />

author Michael Breen, assistant professor<br />

of psychiatry, genetics, and genomic<br />

sciences at Mount Sinai, only a small<br />

subset of these modifications appears<br />

to be functional. “Those sites that<br />

are functional have precise temporal<br />

patterns across time: their editing efficiency<br />

changes throughout age and development in<br />

the brain,” Breen said.<br />

Breen and colleagues took a systematic<br />

look at A-to-I editing sites across<br />

prenatal and postnatal stages of human<br />

brain maturation. The researchers<br />

collected RNA sequencing data from<br />

brain samples of the dorsolateral<br />

prefrontal cortex (DLPFC), cerebrum,<br />

and cerebellum. They also analyzed<br />

RNA-sequencing data from in vitro<br />

models of neuronal maturation, postmortem<br />

cortical samples from late stages of aging, and<br />

murine and non-human primate models of<br />

brain development. In doing so, the researchers<br />

collected brain RNA sequencing data covering<br />

the human lifespan.<br />

“RNA editing is dynamically<br />

regulated in the brain during<br />

aging, and this is a unique<br />

property of RNA editing in the<br />

brain compared to other tissues<br />

in the body,” Cuddleston said. In<br />

their paper, Breen, Cuddleston, and<br />

14 Yale Scientific Magazine December 2022 www.yalescientific.org


Neuroscience<br />

FOCUS<br />

colleagues provide an atlas of A-to-I<br />

sites that are spatiotemporally and<br />

genetically regulated throughout brain<br />

maturation while uncovering key features of<br />

RNA editing throughout neurodevelopment.<br />

In particular, A-to-I editing is enriched in<br />

repetitive sequences known as Alu elements.<br />

Using an Alu editing index (AEI) to quantify<br />

modification levels, Breen and fellow<br />

researchers observed that global Alu editing<br />

steadily increases across all stages of brain<br />

development and neuronal maturation. This<br />

editing peaks around thirty to fifty-nine years<br />

of age, while advanced aging stages do not<br />

exhibit dynamic regulation.<br />

The researchers identified thousands of<br />

editing sites that are temporally regulated<br />

and increase in editing levels throughout<br />

neurodevelopment. The majority exist in the<br />

three prime untranslated regions (3' UTRs)<br />

of genes critical for neurodevelopment.<br />

The minority of spatiotemporally<br />

regulated editing sites exist within<br />

protein-coding regions, and thirtyseven<br />

RNA-recoding sites appear<br />

to change in editing levels<br />

across maturation.<br />

The researchers<br />

also describe trends<br />

in hyper-editing. As<br />

opposed to A-to-I<br />

editing at individual<br />

adenosine nucleosides,<br />

hyper-editing refers to<br />

modifying many adjacent adenosines along<br />

an extended region. The results indicate that<br />

hyper-editing is enriched in advanced stages<br />

of aging with the function of stabilizing RNA<br />

secondary structures.<br />

A-to-I Editing in Neurodevelopmental<br />

Disorders<br />

Editing rates increase globally throughout<br />

brain development. “Global increase is<br />

dynamic in different neurological diseases,<br />

so it could be looked at as a predictor of<br />

brain health,” Breen said. The researchers<br />

asked whether sites displaying increased<br />

editing throughout brain development<br />

are affected in neurodevelopmental<br />

disorders. Their results suggest that<br />

A-to-I sites disrupted in postmortem<br />

brain tissue from individuals with<br />

schizophrenia and autism spectrum<br />

disorder are temporally regulated,<br />

exhibiting an increase in editing levels<br />

www.yalescientific.org<br />

PHOTO COURTESY OF HANNAH HAN VIA MICHAEL BREEN<br />

The Breen Lab, headed by principal investigator<br />

Michael Breen at the Icahn School of Mount Sinai,<br />

poses for a photograph on a rooftop at sunset.<br />

across maturation. “Knowing what we think<br />

these sites do in typical brain development,<br />

[i.e.,] modulating the ability of micro-RNAs to<br />

regulate host gene expression, and that these<br />

sites are disrupted in neurodevelopmental<br />

diseases gives an immediate avenue towards<br />

trying to understand what these sites might be<br />

doing in these disorders,” Breen said.<br />

Recoding sites where A-to-I editing results<br />

in amino acid substitutions provide further<br />

insight into neurodevelopmental diseases. “A<br />

handful of recoding sites have been described<br />

as dynamically regulated in Alzheimer’s,<br />

schizophrenia, and other neurological<br />

disorders,” Breen said. “We know that these<br />

sites are important for synaptic transmission,<br />

and their editing efficiencies are altered in<br />

these different diseased states.”<br />

Additionally, hyper-editing data enhances<br />

the current understanding of the aging brain.<br />

Only a handful of prior studies investigate<br />

RNA hyper-editing, and none consider the<br />

developmental regulation of hyper-editing<br />

in the brain. Breen and fellow researchers<br />

discovered that hyper-editing increases in the<br />

aging brain and appears to affect transcript<br />

stability rather than directly regulating gene<br />

ABOUT THE AUTHOR<br />

expression. Considering all study datasets,<br />

the normalized hyper-editing signal steadily<br />

rises across brain development periods and<br />

peaks into advanced aging stages. “While<br />

site-selective editing peaks in terms of its<br />

rate of change in mid-fetal development,<br />

hyper-editing continues to accumulate all the<br />

way into advanced aging,” Cuddleston said.<br />

“This is really important for aging research.”<br />

RNA hyper-editing may provide insight<br />

into Alzheimer’s disease, for instance, which<br />

Cuddleston aims to investigate in the future.<br />

The Prospects of RNA Biology<br />

In Cell Reports, Breen and colleagues<br />

provide an atlas of spatiotemporally and<br />

genetically regulated A-to-I sites in the brain<br />

throughout human neurodevelopment while<br />

unearthing key features of RNA editing<br />

throughout the lifespan. These findings not<br />

only improve current understandings of<br />

human brain development at the RNA level<br />

but also provide an avenue for learning more<br />

about the foundations of neurodevelopmental<br />

disorders. “We know very little about RNA<br />

modifications and what those might mean<br />

for disease pathology,” Breen said. “We<br />

are just starting to paint that picture.” It is<br />

through understanding such diseases at<br />

the neurobiological level that progress can<br />

be made toward treatment development.<br />

“Understanding which RNA editing events<br />

are functionally relevant for disease is how we<br />

are going to get closer to therapeutics that we<br />

can use in the clinic,” Cuddleston said.<br />

With thousands of temporally regulated<br />

RNA editing sites, the brain is a fascinating<br />

organ of continual change. How is your<br />

brain recoding itself? ■<br />

A R T B Y E V E L Y N J I A N G<br />

ELISA HOWARD is a junior Neuroscience major in Berkeley College. While a senior staff writer for<br />

<strong>YSM</strong>, she researches axon regeneration using stimulated emission depletion (STED) microscopy in<br />

the Strittmatter Lab at the Yale School of Medicine. She is the Donor Outreach Coordinator for the<br />

American Red Cross at Yale, the Mentorship Chair for the Yale Neuroscience Education Undergraduate<br />

Research Organization (YNEURO), and the creator/head of Yale Volunteers at Downtown Evening Soup<br />

Kitchen (DESK). She is also a member of the Yale Collegiate Figure Skating Club and volunteers for<br />

Connecticut Hospice.<br />

THE AUTHOR WOULD LIKE TO THANK Michael Breen and Winston Cuddleston for their time and<br />

enthusiasm about their research.<br />

FURTHER READING<br />

ELISA HOWARD<br />

Slotkin, W., & Nishikura, K. (2013). Adenosine-to-inosine RNA editing and human disease. Genome<br />

Medicine, 5(11), 105. https://doi.org/10.1186/gm508<br />

December 2022 Yale Scientific Magazine 15


FOCUS<br />

Chemistry / Pharmacology<br />

STREAMLINING<br />

THE SEARCH<br />

FOR NEW<br />

DRUGS<br />

Discovering promising molecules<br />

with antidepressant activity<br />

BY EMILY SHANG<br />

Have you ever wondered how scientists<br />

synthesize drugs? Everything, from<br />

the Advil you take to alleviate a<br />

headache to the Vitamin C gummies you eat<br />

to strengthen your immune system, needs<br />

to undergo rigorous scientific testing and<br />

scrutiny to ensure that it is safe for human<br />

consumption. The process of efficiently finding<br />

and synthesizing drugs is especially challenging<br />

for those treating specific medical maladies<br />

since the drug’s functional mechanism must<br />

be investigated. Drugs often function by<br />

targeting specific receptors in our bodies and<br />

either block the effects of the receptor’s typical<br />

function (antagonism) or activate the receptor<br />

to create a response (agonism).<br />

The Challenge of Synthesizing Drugs<br />

that designing a drug that is specific, effective,<br />

and safe is no easy task: it’s why the research<br />

and development process, not to mention the<br />

process of clinical trials and safety testing, is so<br />

long and arduous.<br />

But recently, in a collaboration between<br />

the Ellman Lab at Yale University, the Irwin<br />

and Shoichet Labs at the University of<br />

California San Francisco, the Wetsel Lab at<br />

Duke University, the Skiniotis Lab at Stanford<br />

University, and the Roth Lab at the University<br />

of North Carolina, researchers have been able<br />

to use a novel virtual screening technique<br />

to streamline the beginning stages of drug<br />

discovery by finding promising molecules that<br />

bind potently and selectively to the 5-HT 2A<br />

receptor. This receptor is a serotonin receptor<br />

involved in producing both the negative<br />

(hallucinations, delusions) and positive effects<br />

(alleviation of anxiety, depression) of the<br />

psychedelic drug lysergic acid diethylamide<br />

(LSD) and its affiliates in the brain.<br />

When synthesizing new drugs, researchers<br />

have a lot of metrics to satisfy and a lot of<br />

factors to consider. First, the specificity and<br />

favorability of the drug to the drug target: are<br />

the pieces of the receptor and drug compatible,<br />

and is there a possibility for off-target binding?<br />

Second, the size of the drug: will its molecular<br />

weight hinder its ability to get where it needs to<br />

be in the body? Third, the molecular kinetics of<br />

the drug: how many of the bonds are rotatable,<br />

and how stable and likely is the conformation<br />

it takes on to bind the receptor? It’s no secret<br />

PHOTOGRAPHY BY EMILY POAG<br />

Representations of organic molecules are scrawled across the sash of a fume hood in the Ellman Lab.<br />

16 Yale Scientific Magazine December 2022 www.yalescientific.org


Chemistry / Pharmacology<br />

FOCUS<br />

The virtual screening process started with a<br />

broad analysis of the commonalities between<br />

the chemical structures of a variety of FDAapproved<br />

drugs. Researchers found that the<br />

most often-observed structures included<br />

the six-membered nitrogen heterocycles<br />

piperidine and pyridine. Thus, they began<br />

looking into using a virtual library technique<br />

to create a tetrahydropyridine (THP) drug, a<br />

much less investigated subclass of the kinds<br />

of structural molecules described above.<br />

This structure also produces some obstacles<br />

for synthesis, which made it an interesting<br />

candidate for virtual screening and analysis of<br />

molecular docking and binding.<br />

Creating a Database of THP Molecules<br />

Using the THP structure as a foundation,<br />

the researchers created a database of 75<br />

million THP molecules. The contents of this<br />

database were limited to synthetic chemistry<br />

techniques available to the Ellman Lab using<br />

three different types of starting materials:<br />

an amine, enal/enone, and alkyne. The<br />

researchers also implemented a molecular<br />

weight limit of 350 grams per mole to<br />

increase the likelihood that the compounds<br />

would have effective delivery in animals.<br />

They also considered a cationic property of<br />

the molecule that would help the molecule<br />

competitively bind to G-coupled protein<br />

receptors such as the 5-HT 2A<br />

receptor, as well<br />

as eliminate chiral starting materials that<br />

would have resulted in mixtures of THPs with<br />

different three-dimensional structures, for a<br />

simplified single-conformation output.<br />

Narrowing Down the Search<br />

These 75 million THP molecules were then<br />

pared down using computational molecular<br />

binding techniques. Since the structure<br />

of the 5-HT 2A<br />

receptor was unknown, the<br />

researchers composed one thousand models<br />

of the receptor bound to LSD in the hopes of<br />

analyzing the dynamics of the binding and<br />

finding a competitive molecule. Using this<br />

refined structure of the 5-HT 2A<br />

receptor, the<br />

binding of the 75 million THP molecules was<br />

evaluated, and thirty molecules were selected<br />

as most likely to bind to the receptor. From the<br />

thirty molecules, seventeen molecules were<br />

able to be synthesized using commercially<br />

available materials. Four of these molecules<br />

were identified to bind to 5HT 2A<br />

receptors,<br />

and two of these molecules exceeded preset<br />

binding thresholds in testing. Based upon<br />

www.yalescientific.org<br />

the initial THPs that bound to the receptor,<br />

the team then designed, synthesized, and<br />

tested numerous additional analogs to obtain<br />

compounds that were potent and selective<br />

5-HT 2A<br />

receptor agonists.<br />

“While you can dock to predict binding, at<br />

this stage, you cannot predict if a compound<br />

is going to be an agonist or an antagonist.<br />

Virtual screening is just a foot in the door;<br />

afterwards, you really need chemistry for<br />

synthesizing a lot of compounds, testing a<br />

lot of compounds, critical analysis of data,<br />

and many iterations,” said Jonathan Ellman,<br />

principal investigator of the Ellman Lab.<br />

The 5-HT 2A<br />

receptor can undergo two<br />

different pathways once activated. The first<br />

is the beta arrestin pathway, which has been<br />

linked to undesired psychedelic effects,<br />

and the second is the G-protein mediated<br />

pathway. “Our molecules are more biased<br />

towards the G-protein mediated pathway,<br />

and we didn’t see the psychedelic effects,”<br />

James Kweon, one of the lead researchers<br />

from the Ellman group, explained. While<br />

it’s very hard to predict just by looking<br />

at a chemical structure which signaling<br />

pathway will be favored, the molecules<br />

synthesized by the Ellman Lab are able to<br />

bias the receptor towards the G-protein<br />

mediated pathway rather than the beta<br />

arrestin pathway, which can then separate<br />

the psychedelic function of the receptor<br />

from the antidepressant function.<br />

Looking Into the Future<br />

The next steps for the Ellman Lab and<br />

their collaborators include using the same<br />

virtual screening approach to find more<br />

complex molecules to selectively target<br />

a new receptor: this time, a pain receptor<br />

that is targeted by opioid drugs such as<br />

morphine. They hope to separate the harsh<br />

respiratory distress associated with opioid<br />

use by synthesizing a molecule with great<br />

IMAGE COURTESY OF CREATIVE COMMONS<br />

A schematic depicts the virtual screening process<br />

to look for promising molecules.<br />

functional selectivity that can separate<br />

these negative effects from the painrelieving<br />

positive effects. “We’re basically<br />

trying to demonstrate that virtual screening<br />

really can be used as a tool for even more<br />

complex molecules,” Kweon said.<br />

The kinds of molecules they’re synthesizing<br />

have a three-dimensional component which<br />

opens up more complex levels of docking<br />

analysis and will show that the technique<br />

of virtual screening is capable of taking on<br />

complex problems and solutions. Given its<br />

efficacy in successfully finding possible drug<br />

molecules fast, it’s likely this virtual screening<br />

technique will become increasingly important<br />

for the discovery of new drugs. ■<br />

ABOUT THE AUTHOR EMILY SHANG<br />

EMILY SHANG is a sophomore in Timothy Dwight College studying Molecular Biophysics and<br />

Biochemistry. In addition to managing the website at <strong>YSM</strong>, she loves to play chess and perform research<br />

at the Yale School of Medicine.<br />

THE AUTHOR WOULD LIKE TO THANK Dr. Jonathan Ellman and James Kweon of the Ellman lab for<br />

their cooperation and contributions to this article.<br />

FURTHER READING<br />

ART BY<br />

MALIA KUO<br />

Kaplan, A.L., Confair, D.N., Kim, K. et al. Bespoke library docking for 5-HT2A receptor agonists with<br />

antidepressant activity. Nature 610, 582–591 (2022). https://doi.org/10.1038/s41586-022-05258-z<br />

December 2022 Yale Scientific Magazine 17


FOCUS<br />

Nanotechnology<br />

ON DEMAND<br />

MEMBRANE<br />

Using DNA nanostructures to understand and control the cell membrane<br />

BY RISHA CHAKRABORTY<br />

ART BY MALIA KUO<br />

Scientists learn more about the cell<br />

every day. From taking microscopic<br />

pictures to performing biochemical<br />

tests on pellets of harvested cells, biologists<br />

are able to determine the organization and<br />

interactions of major cellular components,<br />

including organelles, proteins, and nucleic<br />

acids. But understanding what these interactions<br />

look like in real-time is much more<br />

difficult than capturing fluorescent images,<br />

which offer a freeze-frame snapshot<br />

of the cell, and biochemical assays, which<br />

offer only a general understanding of molecular<br />

interactions but are often limited<br />

by the experimenter’s ability to manipulate<br />

the reacting biomolecules in space<br />

and time. In a recent article in Science Advances,<br />

Yale Professor of Cell Biology and<br />

Biomedical Engineering Chenxiang Lin<br />

and postdoctoral fellow Longfei Liu pioneer<br />

a unique way to study cell biology by<br />

harnessing the power of DNA as a molecule<br />

with a highly controllable structure to<br />

study the interactions of proteins and the<br />

cell membrane in real-time.<br />

Students typically learn that DNA is the<br />

genetic code of the cell, responsible for encoding<br />

the information eventually converted<br />

to the proteins responsible for cellular functions.<br />

But Lin offers an alternate perspective<br />

on DNA: that DNA itself has unique structural<br />

and chemical properties that can guide the<br />

assembly of other biomolecules and modulate<br />

how they interact. The DNA contained within<br />

our cells’ nuclei is in the traditional double-stranded<br />

helix because this conformation<br />

keeps DNA stable and relatively easy to<br />

transcribe. But scientists can now control the<br />

sequence of short single-stranded DNA molecules,<br />

called oligonucleotides, such that they<br />

spontaneously form nanoscale assemblages<br />

of precisely defined shapes. And because<br />

DNA oligonucleotides are easier to synthesize<br />

and chemically modify than molecules not<br />

found in nature or even proteins, they form<br />

nanostructures desirable for biochemical and<br />

biophysical experiments, where scientists<br />

want to study the finest details of molecular<br />

organization, dynamics, and function. The<br />

programmability and self-assembling nature<br />

of the DNA structures allow scientists to repeat<br />

such experiments many times and with<br />

all kinds of permutations. “This bottom-up<br />

approach is very powerful since all you need<br />

to do is design the DNA molecules correctly.<br />

The DNA strands can find each other and<br />

self-assemble into larger structures, with precise<br />

experimenter control.” Lin explained.<br />

History of DNA Nanotechnology<br />

According to Lin, the idea to use DNA as<br />

a structural macromolecule for more than<br />

IMAGES COURTESY OF FLICKR<br />

18 Yale Scientific Magazine December 2022 www.yalescientific.org


Nanotechnology<br />

FOCUS<br />

just encoding genetic material harkens<br />

back forty years to New York University<br />

Professor Ned Seeman. Seeman imagined<br />

DNA nanostructures completely conceptually<br />

before creating them was even possible.<br />

DNA nanotechnology began to materialize<br />

upon creating a stable four-way<br />

DNA junction in a test tube resembling the<br />

Holliday junction, a somewhat complicated<br />

three-dimensional arrangement of single-stranded<br />

DNA pieces that forms during<br />

a type of DNA repair called homologous recombination.<br />

Scientists then began experimenting<br />

with combining multiple small,<br />

single-stranded DNA oligonucleotides into<br />

“tiles” and harnessing the symmetry of<br />

these tiles to build two-dimensional lattices<br />

or three-dimensional crystalline structures.<br />

In 2006, Paul Rothemund at the California<br />

Institute of Technology invented a new<br />

technology called DNA origami. He folded<br />

a single-stranded DNA extracted from<br />

viruses into shapes like smiley faces with<br />

the help of tens to hundreds of oligonucleotides.<br />

Importantly, these helper strands<br />

could each carry additional modifications<br />

to attach other molecules to the DNA origami<br />

structure at precise locations.<br />

Scientists sought to create domains in the<br />

DNA nanostructure that would change<br />

in conformation in response<br />

to some physiologically<br />

relevant signal, such as changes in<br />

pH, visible light, or UV radiation. These<br />

DNA nanostructures can mimic proteins<br />

to study how changes in these proteins’<br />

structures would impact their biochemical<br />

activities. DNA structures containing<br />

regions of non-conventional motifs, such<br />

as four stacked cytidine bases (one of four<br />

nitrogen-containing cyclic molecules that<br />

comprise the inside of the DNA helix),<br />

change in conformation in acidic environments,<br />

which are characteristic of cancerous<br />

cells. Similarly, chemically joining an<br />

azo-benzene group (two hexagonal carbon<br />

rings connected by two nitrogen atoms) to<br />

the DNA backbone allows DNA to change<br />

conformation in response to a visible or UV<br />

light source. Such trigger-responsive DNA<br />

structures allow engineers to build nanorobots<br />

under users’ command by adding a<br />

drop of a chemical or simply by shining a<br />

light. This is also very useful for mimicking<br />

the dynamic activity of some proteins that<br />

act as enzymatic molecular switches.<br />

Studying Membrane Dynamics<br />

Unfortunately, while DNA nanotechnology<br />

has seen some traction in studying soluble,<br />

cytoplasmic proteins, proteins embedded<br />

in the cell’s<br />

membranes<br />

are harder to manipulate. Membrane<br />

proteins are crucial for many of the cell’s most<br />

basic functions, such as motion, regulating<br />

molecular traffic through the membrane,<br />

and interacting with pathogens, all of which<br />

require the membrane proteins to respond<br />

to changes in the membrane landscape and<br />

sometimes actively remodel the membrane.<br />

However, the membrane proteins are often<br />

involved in very complex interactions with<br />

lipids, other membrane proteins, and the cytoskeleton,<br />

scaffolding proteins that give cells<br />

their shape. Because this system is so complicated,<br />

Lin and Liu aimed to build a highly reductionist<br />

cell membrane model to contain<br />

only some features or proteins of interest. In<br />

their article, the proteins were foregone and<br />

replaced with mimics made of DNA. “These<br />

DNA structures were designed to look like<br />

a membrane-remodeling protein and work<br />

like one,” Lin said. “By tweaking them and<br />

observing how they behave on membrane,<br />

we may learn a thing or two about how the<br />

protein works in cells.” This system enabled<br />

them to study cell membranes as a platform<br />

and create artificial environments relevant to<br />

biological problems.<br />

One of the most important membrane<br />

dynamics researchers have attempted to<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 19


FOCUS<br />

Nanotechnology<br />

model is membrane<br />

tubulation, whereby<br />

one part of a membrane<br />

pokes out from an existing<br />

piece of a membrane but<br />

remains in close contact, essentially<br />

creating an extended “tube” of the membrane.<br />

This process is ubiquitous across<br />

the cell, involved in organelle and cell division,<br />

as well as packaging molecules for<br />

transport in membrane-enclosed vesicles.<br />

The interaction requires exquisite molecular<br />

machinery to change the membrane<br />

curvature and actually pinch the membrane<br />

destined to be separated from the<br />

old membrane (budding).<br />

Liu and Lin were able to understand the<br />

key factors required for membrane vesicle<br />

formation to occur using DNA nanostructures.<br />

The DNA nanostructures in their<br />

study mimicked the proteins that integrate<br />

into the membrane, contributing to membrane<br />

curvature. This allowed them to study<br />

the proteins’ properties and their effect<br />

on tubulation and vesiculation. The DNA<br />

nanostructures they integrated into their<br />

cell membrane model were initially set in an<br />

open state with high internal tension. Releasing<br />

such tension caused the DNA structures<br />

to buckle and adopt a closed, highly curved<br />

conformation (imagine a spring-loaded<br />

clamp). When they operated such DNA nano-clamps<br />

on the<br />

membrane,<br />

membranes<br />

were able to<br />

be curved, and<br />

many DNA-coated<br />

membrane tubes spontaneously<br />

emerged. However,<br />

fewer tubes were observed<br />

when the closed DNA<br />

clamps were less curved<br />

themselves. Moreover, releasing<br />

the DNA clamps from the<br />

high internal tension state seemed<br />

important for tubulation since preventing<br />

the DNA from changing from its initial state<br />

prevented the phenomenon. Interestingly,<br />

removing the DNA from membrane tubes<br />

led to vesiculation. Thus, Liu and Lin were<br />

able to deduce that the curvature of certain<br />

membrane proteins contributes to membrane<br />

curvature and that the ability of these<br />

proteins to switch conformation can release<br />

energy and act as a biophysical switch to determine<br />

whether the membrane could bud<br />

or not.<br />

Next Steps<br />

ABOUT THE<br />

AUTHOR<br />

Lin and Liu’s study was landmark in several<br />

ways. They were able to provide a proof<br />

of concept that the geometric properties of<br />

DNA nanostructures could act as a reliable<br />

substitute for the geometric properties of<br />

a membrane-bound protein and that tuning<br />

the mechanical properties of the DNA<br />

structures to modulate membrane dynamics<br />

could provide insights into how proteins<br />

impact membrane dynamics. “Membrane<br />

proteins are quite hard to manipulate. With<br />

DNA nanostructures, we can control the<br />

structure, shape, geometry, and modifications,<br />

which means we can do experiments<br />

in a more controlled way,” Liu said. Moreover,<br />

they were able to model membrane<br />

tube formation across multiple designs<br />

and experimental conditions—such as by<br />

varying the curvature and internal tension<br />

of the DNA clamps and changing the starting<br />

curvature of the membrane—and show<br />

that the curvature of the DNA nanostructure<br />

was the instigating factor in tubulation<br />

across these varying conditions. This<br />

highlights the unique advantages of using<br />

DNA nanostructures for such experiments.<br />

These nanostructures enable researchers<br />

to tune previously inaccessible parameters<br />

and ensure experiment reproducibility.<br />

However, both Lin and Liu expressed<br />

some caution about applying such conclusions<br />

definitively to the cells of living organisms.<br />

First, while DNA nanostructures<br />

may be used to structurally approximate<br />

proteins, key differences in the two classes<br />

of molecules’ stability, folding, and activity<br />

need to be accounted for when<br />

making conclusions about how<br />

proteins interact with membranes.<br />

Secondly, since the cellular models<br />

they employed were simplified, their conclusions<br />

from their experiments will probably<br />

need to be verified by studies<br />

in cells extracted from living<br />

organisms since membrane<br />

proteins in cells are engaged in<br />

many more<br />

interactions<br />

than the<br />

minimal set.<br />

Both researchers<br />

are embarking on new projects,<br />

including several in collaboration<br />

with Martin Schwartz, a Yale professor,<br />

to study how membrane proteins and the<br />

DNA structures that mimic them act on<br />

membranes with underlying cytoskeleton<br />

in major cellular processes.<br />

Lin and Liu aim to further investigate<br />

how external signals impact DNA nanostructures<br />

mimicking membrane proteins<br />

and how cellular processes are accordingly<br />

modulated. Eventually, they aim to harness<br />

the similarities between membrane proteins<br />

and DNA nanostructures to create a<br />

reliable cell model from scratch. “It would<br />

be very cool to build synthetic cells that<br />

would work similarly to naturally existing<br />

cells,” Lin said. With these headways in<br />

the field of DNA nanotechnology and cell<br />

biology, the scientific community is on its<br />

way to learning more about<br />

real-time cellular processes<br />

than ever<br />

before. ■<br />

RISHA<br />

CHAKRABORTY<br />

RISHA CHAKRABORTY is a sophomore in Saybrook College majoring in Neuroscience and Chemistry.<br />

In addition to writing for <strong>YSM</strong>, Risha plays trumpet for the Yale Precision Marching Band, Yale Concert<br />

Band and La Orquesta Tertulia, volunteers for HAPPY (Hypertension Awareness and Prevention<br />

Program at Yale) and researches Parkinson’s Disease at Chandra Lab in the School of Medicine. She<br />

enjoys cracking jokes with her friends and taking Choco Pies from the Asian American Cultural Center.<br />

THE AUTHOR WOULD LIKE TO THANK Dr. Liu and Dr. Lin for their time and enthusiasm about their<br />

research.<br />

FURTHER READING<br />

Liu L, Xiong Q, Xie C, Pincet F, Lin C. Actuating tension-loaded DNA clamps drives membrane tubulation.<br />

Science Advances. 2022;8(41). doi:10.1126/sciadv.add1830<br />

20 Yale Scientific Magazine December 2022 www.yalescientific.org


Environment<br />

FOCUS<br />

THE NEW<br />

CIRCULAR<br />

ECONOMY<br />

IMAGE COURTESY OF FLICKR<br />

Bioenergy<br />

for a more<br />

sustainable<br />

and circular<br />

society<br />

BY ABIGAIL<br />

JOLTEUS<br />

ART BY<br />

KARA TAO<br />

Increased wildfires, heat, drought,<br />

and hurricanes are some of the<br />

devastating effects of climate<br />

change that continue to be seen<br />

across the world, and urgent action<br />

must be taken. To ensure that the Earth<br />

remains tolerable for humans to live on,<br />

environmentally friendly technologies<br />

are crucial. Over the past few years,<br />

there has been growing excitement about<br />

hydrogen fueling stations worldwide.<br />

The media portrays hydrogen fuel as a<br />

sustainable alternative to fossil fuels, with<br />

water being the only by-product.<br />

In reality, hydrogen fuels are usually<br />

generated using fossil fuels, emitting<br />

carbon dioxide (CO 2<br />

) as a by-product.<br />

Hydrogen comes from methods such as<br />

steam methane reforming, coal gasification,<br />

and electrolysis from electricity sources<br />

such as grid, solar, etc. Hydrogen fuel<br />

contributes to greenhouse gas emissions<br />

and, consequently, climate change.<br />

But if many methods to generate<br />

hydrogen fuel either directly or indirectly<br />

contribute to greenhouse gas emissions,<br />

what can we do to mitigate its impact on<br />

the climate? The answer lies in a process<br />

called bioenergy with carbon capture and<br />

storage (BECCS), which is the process<br />

of generating energy from biomass or<br />

organic matter while capturing and<br />

storing the CO2 emitted and providing<br />

net negative greenhouse gas emissions.<br />

In previous studies, methods such<br />

as techno-economic analysis (TEA)<br />

and life cycle assessment (LCA) were<br />

used to assess the economic feasibility<br />

and environmental impacts of BECCS.<br />

However, these studies did not consider<br />

the effect of the choice of energy supply.<br />

Moreover, previous studies rarely<br />

explored categories beyond climate<br />

impact, such as a broader range of impact<br />

indicators (e.g., human health impacts) of<br />

hydrogen as a fuel. In order to maximize<br />

the potential of BECCS, a holistic<br />

understanding of the effect of energy<br />

supply strategies and the implementation<br />

of carbon capture is crucial.<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 21


FOCUS<br />

Environment<br />

Researchers at the Center for<br />

Industrial Ecology at the Yale School<br />

of Environment wanted to assess the<br />

efficiency and impact of BECCS. “The<br />

basic idea is to evaluate the economic<br />

feasibility and environmental impacts of<br />

emerging biotechnologies,” said Na Wu,<br />

a postdoctoral researcher in the Yao Lab.<br />

To assess its impacts, the researchers<br />

developed the techno-economicenvironmental<br />

assessment (TEES)<br />

framework–a method to evaluate the<br />

environmental and economic impacts of<br />

BECCS and other similar carbon capture<br />

technologies. This framework incorporates<br />

methods used in previous studies, such<br />

as TEA and LCA, but also simulations<br />

of implementing BECCS with different<br />

possible conditions for the biorefinery, the<br />

facility that converts biomass to energy.<br />

How It Works<br />

This study assessed gasification-based<br />

BECCS, using leftover wood scraps and<br />

branches from logging, called forest<br />

residues, as a source of biomass for gas<br />

conversion. Their analysis focused on<br />

forest residues from the Pacific Northwest,<br />

specifically the Douglas fir and ponderosa<br />

pine, because there is a large amount of<br />

biomass present in the region, and due to<br />

wildfires, there is a need to thin the forests.<br />

This assessment was conducted using the<br />

TEES framework and is novel because it<br />

is an integrated model addressing the<br />

knowledge gaps of the biorefinery with<br />

all carbon dioxide emission sources.<br />

These simulation models integrate<br />

energy supply strategies while also<br />

taking into consideration the realworld<br />

application of these models.<br />

“We tried to maximize the carbon<br />

c a p t u r e<br />

a n d<br />

storage process using our simulation<br />

models and integrate that with energy<br />

supply strategies,” Wu said.<br />

In order to simulate real-life scenarios,<br />

the researchers used a system with<br />

various components to measure and<br />

calibrate different options. They modeled<br />

eight biorefinery processes to determine<br />

which scenario is the most economically<br />

and environmentally feasible. These<br />

components include biomass preparation<br />

(such as size reduction and drying),<br />

gasification, cleaning syngas (a mixture of<br />

hydrogen and carbon monoxide), watergas<br />

shifting, carbon capture, pressure swing<br />

adsorption, air separation, and heat power<br />

generation. This was used to simulate the<br />

conditions required to produce syngas<br />

from biomass. Additionally, they modeled<br />

the three main stages of carbon capture:<br />

capturing the CO 2<br />

, transporting it, and<br />

then storing it deep underground. As the<br />

amount of biomass can affect the method’s<br />

perceived efficiency, different scales with<br />

different amounts of biomass were used.<br />

With the appropriate boundaries<br />

established, the researchers analyzed<br />

four different scenarios.<br />

Scenario one<br />

consists of<br />

burning the syngas produced to generate<br />

heat and power simultaneously, leading to<br />

electrical self-sufficiency while trapping<br />

carbon underground (carbon capture).<br />

Scenario two is similar to scenario one but<br />

with no carbon capture, which served as a<br />

baseline to understand the effect of carbon<br />

capture implementation. Scenario three<br />

includes the same components as scenario<br />

one but uses all the syngas products for<br />

hydrogen production, leading to partial<br />

electrical self-sufficiency. Scenario four<br />

includes carbon capture technology but<br />

does not use a combined heat and power<br />

generation plant, which makes it the least<br />

self-sufficient electricity scenario.<br />

The researchers decided which scenario<br />

was most favorable based on considerations<br />

such as the highest capital expenditure and<br />

operating expenditure. The most and least<br />

favorable scenarios varied depending on the<br />

type of expenditure examined. For instance,<br />

scenario one (fully self-sufficient) has the<br />

highest capital expenditure (CAPEX),<br />

whereas scenario two (no carbon capture)<br />

has the lowest CAPEX. This indicates that<br />

carbon capture requires<br />

a large amount<br />

of capital<br />

since scenario<br />

two is the<br />

only scenario<br />

without carbon<br />

capture included.<br />

However, scenario<br />

four (least selfsufficient)<br />

has the highest<br />

yearly operating expenditure<br />

(OPEX), whereas scenario one (fully<br />

22 Yale Scientific Magazine December 2022 www.yalescientific.org


Environment<br />

FOCUS<br />

self-sufficient) has the lowest OPEX due to<br />

the lowest utilities needed as a result of the<br />

full electrical self-sufficiency.<br />

After calculating and analyzing the<br />

minimum selling price for hydrogen and<br />

carbon price for these four scenarios, they<br />

made two main conclusions. First, hydrogen<br />

derived from forest residues has the potential<br />

to achieve similar economic feasibility to<br />

current fossil fuel-based hydrogen with<br />

carbon capture. In fact, when the price of<br />

carbon dioxide is higher than $89 per ton<br />

of CO 2<br />

, all four scenarios become more<br />

economically attractive than the current<br />

fossil fuel-based hydrogen. However, the<br />

opposite—lower economic attractiveness<br />

when the price of CO 2<br />

is lower—also<br />

applies. This leads to the second conclusion,<br />

which is that CO 2<br />

prices help determine<br />

how economically competitive the three<br />

scenarios with carbon capture can be.<br />

To further analyze the effect of renewable<br />

energy, additional cases for scenarios<br />

one (fully electricity self-sufficient) and<br />

four (least electricity self-sufficient) were<br />

examined. Instead of using an electricity<br />

source from the current grid, solar and<br />

wind energy were used. The findings<br />

indicated that renewable energy sources<br />

make scenario four preferable to electricity<br />

self-sufficiency (scenario one). However,<br />

further research needs to be conducted to<br />

determine the optimal renewable energy<br />

design for BECCS.<br />

These findings suggest that using BECCS has<br />

lower environmental impacts than the current<br />

hydrogen production methods and highlight<br />

the need for individuals from various sectors,<br />

including chemistry, analytics, business,<br />

engineering, and more, to successfully<br />

implement this biotechnology approach.<br />

Limitations<br />

There is no denying that BECCS has<br />

an immense amount of potential to be an<br />

excellent environmental solution, but it is<br />

important to acknowledge certain limitations<br />

in this study. The study did not include CO 2<br />

transportation and storage or hydrogen<br />

transportation in its model. Moreover, the<br />

study focused on the Pacific Northwest of<br />

the United States, which is only one small<br />

region in the world. Similar studies must be<br />

conducted in other regions to determine if<br />

this technology is economically feasible and<br />

has reduced environmental impacts.<br />

www.yalescientific.org<br />

A shell gas station that sells premium gasoline fuel.<br />

Implications and Next Steps<br />

Looking towards the future, BECCS could<br />

be used in other waste feedstocks beyond<br />

forest residues to sustainably provide energy,<br />

such as animal wastes, food wastes, etc. This<br />

could be used to reform the agricultural<br />

industry, which is responsible for much of<br />

global greenhouse gas emissions.<br />

The findings from this study can help<br />

inform further research on other types<br />

of carbon capture and storage. Looking<br />

ahead, Wu wants to expand their study<br />

of carbon capture technologies to assess<br />

their economic and environmental impact.<br />

“BECCS is a chemical-based process, but<br />

there are more natural methods for carbon<br />

capture and storage, such as afforestation<br />

and reforestation, enhanced weathering,<br />

and biochar and soil carbon sequestration,”<br />

Wu said. Afforestation and reforestation<br />

rely on trees, enhanced weathering relies<br />

ABOUT THE AUTHOR<br />

IMAGE COURTESY OF FLICKR<br />

on rocks, and biochar and soil carbon<br />

sequestration rely on the soil (after CO 2<br />

is transformed into more stable carbon).<br />

“The next project I am working on is<br />

analyzing enhanced weathering carbon<br />

capture—using rocks to capture CO 2<br />

in the<br />

atmosphere. We are trying to explore the<br />

different possibilities,” Wu said.<br />

“We can help in the decision-making of<br />

various parties, such as researchers working<br />

in the lab, and we can also provide insights<br />

to companies. For instance, we can explain<br />

if it’s a good investment by determining if it<br />

is profitable, and we can also provide insights<br />

to the environmental authorities,” Wu said.<br />

One thing is clear: an interdisciplinary team<br />

is necessary to create a more sustainable,<br />

low-carbon, and circular society. “We<br />

need different kinds of parties: authorities,<br />

companies, chemists, engineers, business<br />

people, etc. In that way, we can make sure we<br />

are heading in the right direction,” Wu said. ■<br />

ABIGAIL JOLTEUS<br />

ABIGAIL JOLTEUS is a sophomore in Berkeley College studying Ecology and Evolutionary Biology. In<br />

addition to writing for <strong>YSM</strong>, she is the web manager. Outside of <strong>YSM</strong>, Jolteus conducts research at<br />

Yale’s School of Medicine.<br />

THE AUTHOR WOULD LIKE TO THANK Dr. Na Wu for her time and enthusiasm about her research.<br />

FURTHER READING<br />

Wu, N., Lan, K., & Yao, Y. (2023). An integrated techno-economic and environmental assessment<br />

for carbon capture in hydrogen production by biomass gasification. Resources, Conservation and<br />

Recycling, 188, 106693. https://doi.org/10.1016/j.resconrec.2022.106693<br />

In-na, P., Sharp, E. B., Caldwell, G. S., Unthank, M. G., Perry, J. J., & Lee, J. G. M. (2022). Engineered living<br />

photosynthetic biocomposites for intensified biological carbon capture. Scientific Reports, 12(1).<br />

https://doi.org/10.1038/s41598-022-21686-3<br />

Nowotny, J., & Veziroglu, T. N. (2011). Impact of hydrogen on the environment. International Journal of<br />

Hydrogen Energy, 36(20), 13218–13224. https://doi.org/10.1016/j.ijhydene.2011.07.071<br />

December 2022 Yale Scientific Magazine 23


FOCUS Lab Profile<br />

AI<br />

COMBINING AI AND<br />

MACHINE<br />

LEARNING<br />

WITH CARDIOVASCULAR<br />

HEALTH<br />

BY YUSUF RASHEED<br />

According to the CDC, one person<br />

dies every thirty-four seconds<br />

from cardiovascular disease in<br />

the United States. It is also the leading<br />

cause of death for men and women<br />

across the country, costing over $200<br />

billion annually. In 2020, around 697,000<br />

people in the United States died from<br />

cardiovascular disease, which accounted<br />

for twenty percent of all deaths that year.<br />

There are strong efforts worldwide in<br />

research and clinical care to improve the<br />

diagnosis and treatment of this disease,<br />

particularly at the Cardiovascular Data<br />

Science (CarDS) Lab at the Yale School<br />

of Medicine, which is tackling this<br />

issue through a creative intersection of<br />

computer science and patient data.<br />

The CarDS Lab aims to improve<br />

cardiovascular health using data-driven<br />

insights into how care is delivered<br />

to patients. This means they use<br />

technology—artificial<br />

intelligence (AI)<br />

with machine<br />

learning, for example—to augment our<br />

ability to diagnose and treat patients. For<br />

example, the lab has built AI models that<br />

can detect cardiac muscle dysfunction<br />

from electrocardiograms (EKG), which<br />

humans are unable to do. “The entire<br />

idea is to democratize the access to<br />

technology so that more people know<br />

they may have [cardiovascular disease]<br />

so that they can be referred to the health<br />

system for more advanced imaging,” said<br />

Yale University Assistant Professor of<br />

Cardiovascular Medicine Rohan Khera,<br />

who is the principal investigator of the<br />

lab. The group also works with national<br />

registries and datasets to define best<br />

methodological practices in conducting<br />

studies, evaluates healthcare policies and<br />

their association with cardiovascular<br />

health outcomes, and interprets clinical<br />

trial results personalized for individual<br />

patients. These goals are reflected in the<br />

structure of the lab, where members are<br />

part of a “core” or a specific aim within<br />

the lab’s overall goal. “Some folks work<br />

on natural language processing, some<br />

work on ECGs, some work on cardiac<br />

imaging, some are focused on EHR<br />

design, some are working on trials.<br />

People present from one theme to the<br />

others, so everybody can learn what<br />

the others are doing, but [they] tend to<br />

focus on their own domain. That’s been<br />

our key, to focus on building micro-labs<br />

within a large lab,” Khera said.<br />

Khera grew up in India, where he<br />

attended the All-India Institute of<br />

Medical Sciences for his medical<br />

training. He then had a variety of<br />

away rotations at several institutions,<br />

including Johns Hopkins University, the<br />

University of California, Los Angeles,<br />

and the University of Pennsylvania,<br />

where he gained broad exposure to basic<br />

translational and clinical research. This<br />

experience continued at the University<br />

of Iowa during his residency and at UT<br />

Southwestern for his fellowship. “When I<br />

graduated fellowship, I knew I was going<br />

to start a research program…It felt like<br />

there was a lot happening at [Yale]. It<br />

was very exciting how [Yale] had been<br />

at the cutting edge of health policy and<br />

outcomes research, so I came here to see<br />

if I could extend that further into more<br />

advanced data science,” Khera said.<br />

“That’s been our key, to<br />

within a large lab.<br />

focus on building micro-labs<br />

”<br />

24 Yale Scientific Magazine December 2022 www.yalescientific.org<br />

IMAGE COURTESY OF PNGNICE


Lab Profile<br />

FOCUS<br />

PHOTO COURTESY OF JENNA KIM VIA DR. KHERA'S TWITTER @ROHAN_KHERA<br />

Members of the CarDS Lab at the 2022 American Heart Association's Scientific Sessions in Chicago, IL<br />

these findings independently in the<br />

ACCORD BP trial. “The traditional<br />

interpretation of clinical trials does not<br />

necessarily inform us about whether a<br />

given treatment works for each patient…<br />

We’re interested in better understanding<br />

how the results of a study can be<br />

individualized for each unique patient<br />

in front of us at the clinic…We think<br />

that’s pretty interesting because not<br />

every patient should be treated in<br />

the same way.<br />

And that’s one<br />

step closer to<br />

more personalized<br />

cardiovascular<br />

care,” said<br />

Evangelos<br />

Oikonomou,<br />

a clinical fellow<br />

in cardiovascular<br />

medicine at Yale.<br />

Khera started his faculty position at<br />

Yale in July 2020, during the peak of the<br />

COVID-19 pandemic. “Everything was<br />

shut down, and there was a lot of time<br />

spent thinking how one would structure<br />

the lab when nobody’s around,” Khera<br />

said. He noted that there were fewer<br />

opportunities to meet new people who<br />

would be interested in the lab, so he<br />

spent the first several months of the lab’s<br />

inception exploring the Yale community.<br />

He credits the decision to run the lab<br />

virtually as one of the key reasons for its<br />

success, as people do not need to be in the<br />

same room all the timeNow, the CarDS<br />

lab has grown to over twenty people.<br />

Along this mission to integrate<br />

machine learning with cardiovascular<br />

health, the lab recently published a<br />

paper titled “Individualising intensive<br />

systolic blood pressure reduction in<br />

hypertension using computational trial<br />

phenomaps and machine learning: a<br />

post-hoc analysis of randomised clinical<br />

trials.” This study looked at two clinical<br />

trials, SPRINT and ACCORD BP, which<br />

each compared intensive versus standard<br />

blood pressure control treatment. Using<br />

a machine learning algorithm and a<br />

“phenomapping strategy,” which creates<br />

a network of all patients recruited in<br />

the trial to compare their phenotypes,<br />

they found that not every patient in the<br />

www.yalescientific.org<br />

SPRINT trial benefitted to the same<br />

extent from the intensive blood pressure<br />

control treatment. In other words, the<br />

effect of the treatment seemed to vary<br />

across different types of patients. From<br />

these results, the lab was able to analyze<br />

a given patient’s key characteristics and<br />

can tell how likely that patient is to<br />

benefit from intensive blood pressure<br />

control treatment. They then validated<br />

PHOTO COURTESY OF JENNA KIM VIA<br />

DR. KHERA'S TWITTER @ROHAN_KHERA<br />

Veer Sangha, recipient of the Elizabeth Barrett-<br />

Connor Research Award, with PI Dr. Rohan Khera<br />

“We’re<br />

interested<br />

in better<br />

understanding<br />

how the results of a<br />

study can be individualized<br />

for each unique patient in<br />

front of us at the clinic…<br />

We think that’s pretty<br />

interesting because not<br />

every patient should be<br />

treated in the same way.<br />

”<br />

A second project that the lab has been<br />

working on is developing AI models to<br />

diagnose structural heart diseases from<br />

printed ECG scans. The focus on ECG<br />

comes from the fact that they are the<br />

most widely accessible and ubiquitous<br />

tool in the world to better understand a<br />

patient’s heart. However, physicians are<br />

only able to diagnose certain conditions<br />

and heart rhythm disorders from ECGs,<br />

creating the need for more expensive<br />

and harder-to-obtain screening tools for<br />

other heart conditions.<br />

December 2022 Yale Scientific Magazine 25


FOCUS<br />

Lab Profile<br />

The goal of the project is to<br />

be able to diagnose these conditions from<br />

ECGs—leading this effort is Yale College<br />

senior Veer Sangha YC '23, who has<br />

recently received the Rhodes Scholarship<br />

for his work with the lab. “We have a large<br />

repository of patients at the hospital, so<br />

we have their ECGs, and we know which<br />

patient has which disease," Sangha said.<br />

"So we can train our deep learning models<br />

to be able to learn features in the ECG that<br />

are relevant to a certain class of disorders<br />

or a certain disorder that a patient may<br />

have. And it can learn these features that<br />

humans themselves cannot learn.”<br />

To make this further accessible for<br />

patients, Sangha developed the model<br />

so that it didn’t need to use the signal<br />

data from the ECGs, which is not always<br />

available at the point of care. Instead, the<br />

model can make these inferences from<br />

printed scans of an ECG, which are widely<br />

available to patients and their clinicians.<br />

For undergraduate students interested in<br />

joining the CarDS lab, Khera recommends<br />

using the lab’s website Contact page or<br />

reaching out to him directly. He also<br />

suggests that students who want to join<br />

should ideally be interested in health<br />

technology and its applications and have<br />

some coding experience. Finally, he enjoys<br />

having students who want to be part of<br />

the lab for a long period of time. “Those<br />

who engage for a longer time are always<br />

there in a community learning, adapting,<br />

and growing. The folks that have really<br />

developed their careers in the lab have<br />

been associated with us for a couple of<br />

years already now,” Khera said.<br />

You can learn more about the CarDS Lab<br />

at https://www.cards-lab.org/. ■<br />

IMAGES COURTESY OF CARDS LAB WEBSITE<br />

Principal Investigator Dr. Rohan Khera (top) and members of the CarDS Lab<br />

ABOUT THE AUTHOR<br />

YUSUF RASHEED<br />

YUSUF RASHEED hails from the Bay Area and is a sophomore in Trumbull College majoring in<br />

Biomedical Engineering. He has a deep interest in physician-patient relationships and how budding<br />

medical professionals can develop their soft skills during and after their education. He hopes to apply<br />

his experience in engineering to a clinial setting in the future by improving and personalizing patient<br />

care. Yusuf also believes in the power of writing to effect change at all levels, whether that's personally<br />

through a journal or publicly through the Yale Scientific Magazine. He encourages all interested<br />

students to get involved with the magazine and try their hand at writing an article.<br />

THE AUTHOR WOULD LIKE TO THANK Dr. Rohan Khera, Dr. Evangelos Oikonomou, and Veer<br />

Sangha for their valuable time and support for this article.<br />

26 Yale Scientific Magazine December 2022 www.yalescientific.org


THE STRENGTH<br />

OF WEAK TIES<br />

Sociology<br />

FEATURE<br />

IMAGE COURTESY OF PIXABAY<br />

BY EUNSOO HYUN<br />

ART BY KARA TAO<br />

CAN LINKEDIN ACQUAINTANCES HELP YOU FIND A NEW JOB?<br />

In 1973, American sociologist Mark Granovetter published a<br />

paper that fundamentally changed the field of sociology. The<br />

paper, titled “The Strength of Weak Ties,” theorized that weak<br />

ties (think casual acquaintances, friends-of-friends, and other<br />

arm’s-length relationships) help disseminate new information and<br />

provide more job opportunities than strong ties (such as close<br />

friends, family, or immediate coworkers).<br />

This phenomenon, which may seem counterintuitive at first<br />

glance, happens because weak ties—interpersonal relationships with<br />

fewer mutual connections—help expose people to new information<br />

and opportunities outside their immediate social bubble. “Weak ties<br />

tend to span a broader width of the overall social network of the<br />

labor market. Strong ties tend to be redundant because you have<br />

access to the same sort of resources, information, and so on,” said<br />

Karthik Rajkumar, an applied research scientist at LinkedIn.<br />

For Rajkumar, it was fascinating to see this correlation in action.<br />

As a graduate student applying to internships in 2019, he found<br />

himself sending out resume after resume, just hoping to hear back at<br />

all. (A familiar story to many readers, especially those now looking<br />

for jobs and summer opportunities!) “It really made me think:<br />

there’s so much more to the job market and the interview process<br />

than your resume and your credentials and your interviewing skills.<br />

There’s that personal touch—that connection, and that’s something<br />

I learned the hard way,” Rajkumar said. This prompted him to ask:<br />

what is the effect of social networks on job mobility?<br />

The term “job mobility” means that people in the labor market are<br />

able to move to new jobs when they want. “Job transmission” refers<br />

to job mobility as a result of connections made. “‘Job transmission’<br />

is this idea that if I connected with you now, am I going to join your<br />

company a year down the line?” Rajkumar said.<br />

Rajkumar and his co-authors designed a study to test for a causal<br />

relationship between interpersonal ties and job mobility<br />

using five years of data from LinkedIn. Their new<br />

paper in Science, titled “A causal test of<br />

the strength<br />

of weak ties”, is the first to conduct a<br />

large-scale,<br />

experimental study of a causal—<br />

not just correlational—<br />

relationship between weak<br />

ties and employment. More<br />

specifically, the researchers<br />

used LinkedIn’s People<br />

You May Know (PYMK)<br />

algorithm, which recommends new<br />

www.yalescientific.org<br />

connections for LinkedIn users to add to their networks. By adjusting<br />

the algorithm, the team randomly varied whether users got weak or<br />

strong tie recommendations in the PYMK section. The tie strength<br />

between two users was determined by the number of messages sent<br />

back and forth and the number of mutual connections they had.<br />

The results empirically validated the theory that weak ties cause<br />

increased job mobility. This discovery disproved the “paradox<br />

of weak ties,” identified by previous correlational studies that<br />

proposed strong ties as the agents behind job mobility. The overall<br />

relationship between tie strength, measured by the number of<br />

mutual friends, and job mobility was nonlinear, following an<br />

“inverted U-shape.” In other words, the weakest ties weren’t the best<br />

at increasing job mobility. Rather, moderately weak ties increased<br />

job mobility and job transmissions the most. The strongest ties<br />

affected job mobility the least.<br />

However, when they looked at the results according to<br />

interaction intensity (the number of messages exchanged) as the<br />

metric of tie strength, weak ties with low interaction were the most<br />

helpful. Interestingly, these results varied by job industry. Weak<br />

ties mattered most when applying to jobs in industries that rely on<br />

software, but strong ties still held sway in less digital industries. This<br />

difference may be due to the importance of up-to-date information<br />

in rapidly evolving industries like tech. “Weak ties are conduits for<br />

information. They’re very efficient in bridging these information<br />

gaps across vast corners of the social network,” Rajkumar said.<br />

So how has this discovery been applied to sites like LinkedIn? One<br />

example is the updated “People You May Know” section. Before, the<br />

PYMK page simply showed a list of connections. Now, LinkedIn<br />

separates these connections into categories—connections from the<br />

same school, company, industry, and so on. “A lot of times, I hear<br />

people say, oh, I would like to have weak ties,<br />

but you know—how would I approach a<br />

total stranger? It’s all about finding that<br />

commonality, whether it’s your professional<br />

interest or mutual connections,”<br />

Rajkumar said.<br />

The discovery of a causal<br />

relationship between<br />

weak ties and job mobility<br />

provides important insights<br />

for networks like LinkedIn<br />

as the labor market becomes<br />

increasingly digitized. ■<br />

December 2022 Yale Scientific Magazine 27


FEATURE<br />

Robotics<br />

AN UNEXPECTED MARRIAGE:<br />

ROBOT DRONES & FLOWER POWER<br />

SAVING KAUAI’S ENDANGERED PLANTS<br />

WITH A CLIFF SAMPLING DRONE<br />

BY CINDY MEI<br />

ART BY SOPHIA ZHAO<br />

Flying over the cliffs of Kauai, a drone known as the Mamba<br />

sweeps the area on a rescue mission, searching for valuable<br />

buds of life beyond normal reach. On these cliffs lie extremely<br />

rare plants, many only found in Kauai, and some the last of their<br />

kind. The Hawaiian island is home to 250 endemic flora species<br />

found exclusively on the island, ninety-seven percent of which are<br />

classified as endangered or extinct. Environmental hazards are<br />

increasing the extinction rate to five hundred times the expected<br />

rate without human interference. For years, botanists have braved<br />

Kauai’s cliffs and other hard-to-access locations in search of these<br />

critically endangered plants. However, the areas are extremely<br />

hazardous and are time-consuming and expensive to access.<br />

For years, drones have been a prominent tool in environmental<br />

conservation and monitoring in harsh environments, imaging across<br />

different wavelengths of light and identifying plant habitats and<br />

distributions. However, the development of drones to navigate and<br />

interact with dangerous and inaccessible environments is an entirely<br />

new innovation in this field. “What differentiates what we’re doing<br />

with drones is that we’re interacting directly with the environment,”<br />

said Hughes La Vigne, a PhD student of robotics engineering at the<br />

University of Sherbrooke and co-founder of Outreach Robotics.<br />

The company first took root following the creation of the DeLeaves<br />

sampling system, a device designed to collect branches from treetops<br />

and canopies. “The purpose of Outreach Robotics is to develop<br />

robotic tools that could help scientists working in conservation,<br />

reforestation, and other environmental purposes,” La Vigne said.<br />

Enter the Mamba, the first aerial system that can sample plants<br />

on cliffs and transport them to a safer place. With a grant from<br />

National Geographic, Outreach Robotics teamed up with Ben<br />

Nyberg, a PhD student at the University of Copenhagen and the<br />

drone coordinator of the National Tropical Botanical Garden<br />

(NTBG), a nonprofit organization dedicated to the conservation<br />

and restoration of tropical plants. The project, which was published<br />

in Scientific Reports this fall, spanned two years of prototyping,<br />

iterating, and testing amid disruptions from COVID-19.<br />

Throughout the design process, the team considered many factors<br />

to optimize and stabilize flight collections. The drone had to be able<br />

to endure windy conditions, collect samples quickly and gently, and<br />

navigate around unwelcoming terrain. The final system prototype<br />

utilized a suspended platform equipped with propellers that swung<br />

in a pendulum, reducing rigidity and allowing an extended reach<br />

from cliffsides, minimizing the potential for collisions. In addition,<br />

the Mamba had to be easy to use with minimal roboticist training.<br />

“When you’re developing tools that might have an impact on<br />

conservation or the environment, you want it to be used by people<br />

who are working in that field,” La Vigne said.<br />

The final design was tested in two field trials in late 2021 and<br />

early 2022, with La Vigne and fellow University of Sherbrooke<br />

researcher and Outreach Robotics co-founder Guillaume Charron<br />

teleoperating the Mamba from the ground. Following imaging<br />

and identification of plant species targets, the Mamba navigated<br />

to the sites with built-in global navigation systems. Using an active<br />

robotic arm wrist suspended by long, snaking cables beneath the<br />

drone, the Mamba was able to cut and recover eleven otherwise<br />

inaccessible samples of seeds and cuttings with minimal impact<br />

from five critically endangered plants on Kauai’s cliffs. These<br />

plants were then deposited at the NTBG, which used methods<br />

such as seed banking and ex situ cultivation to maintain growth.<br />

The final prototype of the Mamba was also time-efficient and<br />

could reach several sampling sites from one base station.<br />

Since then, some plants like the Lysimachia iniki have flourished<br />

in the NTBG nurseries, becoming the first recovered plants of<br />

their kind to do so in captivity, while others, like the Euphorbia<br />

eleanoriae, did not survive in the long run. L. iniki grew roots for<br />

the first time in captivity, bolstering the hope that the surviving<br />

single-population plants of Kauai will be able to regrow with the<br />

combined effort of the drones and conservation. In future projects,<br />

the Mamba will be taken to other islands of Hawaii, where ninety<br />

percent of flora is not found anywhere else on Earth, in its pursuit<br />

to save these rare plants. “This is what we dreamed about for the<br />

last two years or so when we saw that drones were being used to<br />

interact with the environment,” La Vigne said. “[NTBG] is doing an<br />

amazing job to preserve these endemic species, and our goal is to<br />

help them and continue to work with environmental scientists.” ■<br />

28 Yale Scientific Magazine December 2022 www.yalescientific.org


ROBOTS<br />

Using AI and robots to optimize<br />

organic chemistry reactions<br />

vs<br />

Chemistry / Machine Learning<br />

HUMANS<br />

ORGANIC CHEMISTRY EDITION<br />

FEATURE<br />

BY ANYA RAZMI<br />

ART BY MALIA KUO<br />

For thousands of years, human innovation has been defined<br />

by the creation of big tools: the wheel, the watch, the scythe.<br />

Only in the last two centuries have we begun to investigate the<br />

power of small tools: molecules. From synthetic dyes to life-saving<br />

medications, molecular toolmaking has the potential to solve some<br />

of society’s greatest technological challenges.<br />

But making molecules isn’t easy. The synthesis of small organic<br />

molecules usually requires very specific reaction conditions—a<br />

tailored combination of solvents, temperature, pressure, and<br />

catalysts—to maximize product yield. Knowing which conditions<br />

suit which reactions takes expertise, the kind of expertise that only<br />

organic chemists, after years of highly specialized study, possess.<br />

“Right now, molecule making is this very exclusive club that only<br />

a few of us can get into,” said Martin Burke, professor of chemistry<br />

at the University of Illinois at Urbana-Champaign. “We want to<br />

shatter those barriers and invite everyone into the molecule-making<br />

space.” A recent collaboration between Burke and his colleague<br />

Bartosz Grzybowski, Professor at the Polish Academy of Sciences,<br />

is working to achieve just that. The paper, titled “Closed-loop<br />

optimization of general reaction conditions for heteroaryl Suzuki-<br />

Miyaura coupling,” was published in Science in October. Together,<br />

the two teams of researchers searched for a way to optimize general<br />

conditions—conditions that, regardless of the building blocks<br />

used, maximize the final product of a reaction. In particular,<br />

they investigated Suzuki-Miyaura cross-coupling (SMC), the<br />

quintessential reaction for carbon-carbon bond formation.<br />

With so many factors affecting a reaction, finding the best<br />

combination to optimize yield is enormously challenging. “The<br />

haystack is astronomical,” Burke said. “It’s literally beyond the capacity<br />

of collective capability of our planet.” The researchers needed a way<br />

to shrink this haystack—to find a list of possibilities for general<br />

conditions, then test them as quickly and accurately as possible.<br />

The solution? Artificial intelligence and robots.<br />

At the Beckman Institute in Illinois, robots performed 530<br />

chemical reactions. Syringes, purification columns, and pipettes<br />

were connected by masses of tubing, all of which worked in sync<br />

to carry out experiments independent of human hands. It wasn’t<br />

humans typing in which conditions the robots should use, either—<br />

it was AI. Grzybowski and his colleagues developed a machine<br />

learning algorithm to instruct the robots on which conditions to test.<br />

The process was a closed loop: Once a reaction had been<br />

performed, the data was transferred to the AI. The algorithm then<br />

developed altered procedures and transferred them back to the<br />

robot, which performed the reaction again under this new set of<br />

conditions. Then the cycle repeated.<br />

www.yalescientific.org<br />

“The AI was in Poland. The robots are in Illinois. The loop was<br />

happening across the world,” Burke said.<br />

Burke and his colleagues had tried defining general conditions<br />

before. In 2009, they published a paper in the Journal of the American<br />

Chemical Society which used human-guided experimentation to<br />

identify general reaction conditions for the SMC reaction. It was<br />

the best that humans could do, and it took six years.<br />

Within four months, artificial intelligence doubled their yield.<br />

The implications of this result are far-reaching. The scientists’<br />

ultimate goal is a “plug-and-play” platform in which researchers<br />

can enter the desired function for a molecule and have robots<br />

create it for them. With this type of technology, the synthesis of<br />

organic molecules could be democratized, no longer limited to a<br />

small group of experts. Ideally, this platform would use a limited<br />

number of reactions—maybe even just one.<br />

“Right now, in chemistry, there are about fifty to one hundred<br />

thousand reaction types. And it all might be unnecessary, in some<br />

sense,” Grzybowski said. “Nature uses very few operations, but<br />

repeatedly, in an iterative fashion. The robots are trying to do<br />

exactly the same.”<br />

Part of the algorithm’s success hinged upon its ability to probe<br />

both negative and positive results. “The AI was learning not<br />

only what works, but also what doesn’t work,” Grzybowski said.<br />

“With failure, the robot learns. And then it finds the right path.”<br />

For this algorithm to succeed,<br />

negative results were<br />

just as important<br />

as positive ones.<br />

This is a notable<br />

departure<br />

from how the<br />

scientific field<br />

currently works: people<br />

don’t publish negative<br />

results. For Burke, this<br />

was an important lesson.<br />

“We don’t spend a lot of time<br />

trying to figure out why things<br />

fail,” Burke said. “We’re always trying<br />

to teach AI about how to do the things<br />

that we do. I think things just flipped.<br />

AI is teaching us something very<br />

important about how to do science.<br />

I feel like I learned something from<br />

AI, and that’s exciting.” ■<br />

December 2022 Yale Scientific Magazine 29


FEATURE<br />

Cell Biology<br />

GAMER NEURONS<br />

IN VITRO NEURONS PLAY A<br />

SIMULATED GAME OF PONG<br />

Our brains are a collection of<br />

billions of neurons, firing in<br />

synchrony to make up the<br />

complex organ that is our brain. But<br />

zooming in, what if we consider a small,<br />

isolated subset of cells? What might<br />

they be capable of?<br />

Neurons are unique cells in the body.<br />

Unlike other cells, which can simply<br />

maintain their functions isolated in a<br />

petri dish, neurons process information,<br />

meaning they need a stimulus that<br />

prompts them to act. This makes them<br />

both fascinating and difficult to study.<br />

Computational models have been used<br />

to study neural networks, but they are<br />

limited by the constraints of technology,<br />

which is no substitute for a biological<br />

system. To alleviate this concern, what<br />

if neural networks could be made from<br />

biological neurons in a petri dish? In<br />

their recent paper, Brett Kagan, his<br />

colleagues at Cortical Labs, and several<br />

university collaborators have set out<br />

to study the interface of biology and<br />

intelligence by exploring how biological<br />

neurons respond to electrophysiological<br />

input and feedback in vitro.<br />

The team’s research process started<br />

in 2019. However, the pandemic threw<br />

a wrench in their plans, especially<br />

with Australia’s strict lockdown<br />

procedures. “Fortunately, we were able<br />

to get exemptions to go to work because<br />

we were considered critical workers,<br />

being in a hospital setting. But it was<br />

incredibly different circumstances<br />

nonetheless, getting supplies in and all<br />

the basic little things that we used to<br />

take for granted,” Kagan said. Once the<br />

lab could work around the restrictions,<br />

the group hit the ground running,<br />

resuming their research skillfully and<br />

deliberately. Kagan and his colleagues<br />

adopted an approach called “agile<br />

science,” where they set up a series of<br />

small pilot experiments in tandem to<br />

see which conditions would be best for<br />

their cells. This allowed them to adjust<br />

their research environment as they went<br />

along and optimize their experiments<br />

throughout the process. By growing<br />

long-term cortical neurons that formed<br />

dense connections with supporting glial<br />

cells, Kagan and his colleagues were able<br />

to study the behavior and capabilities of<br />

these biological neurons in a petri dish.<br />

A silicon chip inside the dish<br />

stimulated the neurons to create a<br />

simulated Pong game-world, where<br />

a paddle is moved up and down the<br />

screen to block a ball from hitting the<br />

side. “We chose Pong because we wanted<br />

something [in] real time, simple to<br />

code for with a clear ‘win and/or lose’<br />

condition—in this case, there was a really<br />

clear lose condition—and [something]<br />

recognizable to people. It’s actually the<br />

fiftieth anniversary of Pong [this year],”<br />

30 Yale Scientific Magazine December 2022 www.yalescientific.org


Cell Biology<br />

FEATURE<br />

Kagan said. Inputs from the silicon chip<br />

were delivered to a predefined sensory<br />

area of eight electrodes. These electrodes<br />

stimulated sensory neurons that then<br />

communicated with motor neurons also<br />

cultured in the dish. The researchers<br />

wanted to see if the motor neurons<br />

would learn to move the paddle and<br />

intercept the ball. Any time the neurons<br />

missed an interception, they would be<br />

stimulated randomly, while successfully<br />

intercepting the ball meant they would<br />

receive predictable stimulation.<br />

Why might random stimulation in<br />

response to error cause the neurons<br />

to learn to play the game? Kagan and<br />

his team used the idea behind the free<br />

energy principle, developed by Karl<br />

Friston, a collaborator on their paper,<br />

to inform their hypothesis. As Kagan<br />

explained, the free energy principle says<br />

that a system will minimize the surprise<br />

or uncertainty in its environment.<br />

“What we did was give the neuron<br />

feedback randomly if it got [the game]<br />

wrong. If the free energy principle is<br />

true, then the system should reorganize<br />

itself to minimize randomness,” Kagan<br />

said. This means that to minimize the<br />

amount of random stimulation they<br />

received, the in vitro neurons would<br />

need to learn to play the game.<br />

This learning could be done in one<br />

of two ways: either the neurons could<br />

create a model or a “belief system” so that<br />

the network can respond and match the<br />

model with the real world, or they could<br />

physically act upon their environment<br />

to change their surroundings. Kagan<br />

and his colleagues showed that in vitro<br />

neurons learned to move the paddle to<br />

play Pong, and biological neurons can<br />

thus be adaptive. “We found that these<br />

neurons want to act in a way that can<br />

minimize unpredictability, [and] we<br />

can see this by them learning to play<br />

Pong,” Kagan said.<br />

They also uncovered some interesting<br />

and unexpected findings. Kagan<br />

explained that one of the intriguing<br />

results of the paper was their data<br />

on information entropy, which is the<br />

amount of information conveyed in an<br />

event. “It was really exciting because<br />

it showed that the cultures were able<br />

to distinguish between internal and<br />

external noise,” Kagan said. Essentially,<br />

they showed that the neurons could<br />

determine the difference between<br />

information generated on their own and<br />

information from an outside source,<br />

highlighting the specificity with which<br />

the neurons can source the signals they<br />

receive. “[It] makes sense because I can<br />

distinguish between my thoughts and<br />

your words, so there must be a way to<br />

break that up. But to see that you’re<br />

getting one response for external noise<br />

and one response for internal noise was<br />

pretty exciting,” Kagan said.<br />

This system, which Kagan and<br />

colleagues aptly termed “DishBrain,”<br />

sits at the interface of neurobiology and<br />

computational technology. Short-term<br />

benefits of the system are numerous:<br />

drug discovery, disease modeling, and<br />

building a basic understanding of how<br />

neurons create intelligence. “All general<br />

intelligence that we have ever seen is<br />

biological—from flies to cats to humans,”<br />

Kagan said. Still, there are limits to<br />

biological neural networks. “This does<br />

not mean that you end up with a human<br />

in a dish. What it means is that neurons<br />

are this biomimetic material that can<br />

adapt to new information, so can you<br />

use it as an information processor,”<br />

Kagan said. “It offers us an ethically<br />

responsible way to move forward.”<br />

Though many questions remain,<br />

Kagan and his colleagues at Cortical<br />

Labs are looking forward to digging<br />

deeper into their work and making<br />

new, exciting findings. Now, they’re<br />

working on perfecting their research<br />

infrastructure, from creating new<br />

biological environments to advancing<br />

their technology. “We’re trying to improve<br />

what we call the wetware (the cells), the<br />

hardware, [and] the software. We’re<br />

starting to do some disease modeling and<br />

drug testing, and all of these options are<br />

super exciting,” Kagan said. While many<br />

questions remain, neurons are certainly<br />

firing at Cortical Labs to help uncover<br />

more answers. This exciting research is<br />

sure to produce more interesting data that<br />

will guide the field of neuroscience and<br />

biological intelligence in the future. ■<br />

BY MAYA<br />

KHURANA<br />

ART BY<br />

MALIA KUO<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 31


FEATURE<br />

Planetary Sciences<br />

CONAN THE BACTERIUM<br />

COULD THE WORLD’S TOUGHEST<br />

ORGANISM SURVIVE ON MARS?<br />

BY KAYLA YUP<br />

ART BY BREANNA<br />

BROWNSON<br />

Conan the Bacterium may be<br />

Earth’s most promising astronaut.<br />

Named the world’s “toughest<br />

organism,” Deinococcus radiodurans—<br />

nicknamed Conan—could survive for<br />

a whopping 280 million years if buried<br />

ten meters beneath the Martian surface.<br />

This resilience suggests that if life ever<br />

existed on Mars, it could still exist today.<br />

The surface of Mars is deeply frozen<br />

and extremely dry. The atmosphere<br />

contains almost no oxygen and is over<br />

one hundred times thinner than Earth’s.<br />

Any life form released on Mars would<br />

essentially be freeze-dried and exposed<br />

to intense radiation from the sun. But<br />

Conan regularly challenges known limits<br />

of survival. The microbe can be frozen,<br />

desiccated, and face intense radiation, yet<br />

still live to see another day. In a recent<br />

study led by Michael Daly, a professor<br />

of pathology at Uniformed Services<br />

University of the Health Sciences and<br />

a member of the National Academies<br />

Committee on Planetary Protection,<br />

Conan and five other organisms were<br />

tested for potential survivability on Mars.<br />

As missions to and from Mars reach<br />

fruition, worry over cross-contamination<br />

between planets is putting the spotlight on<br />

Conan and other hitchhiking microbes.<br />

Future manned missions would expose<br />

Mars to astronauts and their microbiomes,<br />

raising the concern that Earthen microbes<br />

could be released and contaminate<br />

Mars’ surface. Daly’s study examined<br />

six microbes found in the human gut:<br />

Conan the Bacterium, E. coli, three sporeforming<br />

Bacillus bacteria, and a strain<br />

of baker’s yeast called Saccharomyces<br />

cerevisiae. In this study, Conan and the<br />

baker’s yeast broke all previous radiation<br />

survival records, even when compared to<br />

Bacillus spores, which are renowned for<br />

their resistance.<br />

To simulate the conditions on<br />

Mars, all six organisms were first<br />

dried in a desiccation chamber<br />

for five days and then stored on<br />

dry ice. The frozen organisms<br />

were later placed in an irradiator<br />

and exposed to very large doses of<br />

ionizing radiation in the form of<br />

gamma rays and protons—imitating<br />

forms of radiation from the sun.<br />

When charged particles, including<br />

protons from the sun, approach Earth,<br />

our magnetic field deflects them, and our<br />

atmosphere blocks them. But Mars has no<br />

magnetosphere and virtually<br />

no atmosphere to protect<br />

itself: protons are free<br />

to crash into the<br />

Martian surface<br />

and generate<br />

additional<br />

gamma rays.<br />

This is why<br />

the most<br />

dangerous<br />

part of Mars<br />

is the top ten<br />

centimeters of the<br />

Martian surface—<br />

Conan could only<br />

survive that amount of<br />

ionizing radiation for about<br />

1.5 million years. Further below the<br />

surface, shielding can protect against main<br />

forms of ionizing radiation, leaving only<br />

t h e<br />

p l a n e t ’ s<br />

low natural<br />

background<br />

radiation, as<br />

it is on Earth.<br />

“The deeper you<br />

go [into Mars’<br />

surface], the<br />

more likely it is<br />

that you will find<br />

the remnants of<br />

life,” Daly said. “The<br />

survivability of life is<br />

now greater than we had ever<br />

thought possible.”<br />

Conan’s mechanisms for survival<br />

have previously been characterized, but<br />

32 Yale Scientific Magazine December 2022 www.yalescientific.org


Planetary Sciences<br />

FEATURE<br />

not in the context of Mars. Past studies<br />

looked at radiation under Earthen<br />

conditions, representing a planet where<br />

life revolves around liquid water. The<br />

limits of ionizing radiation survival<br />

have traditionally been established by<br />

increasing doses of gamma radiation<br />

until the last viable microbe is dead. In<br />

decades past, Conan’s ‘survival limit’<br />

was approximately 25,000 kGy of gamma<br />

radiation under aqueous conditions. The<br />

present study found that if first dried and<br />

then frozen into a dormant state, Conan<br />

could withstand a whopping 140,000<br />

kGy of gamma radiation.<br />

“In the past, folks and scientists<br />

considered the survivability of life on<br />

Mars to be on the order of perhaps<br />

millions of years,” Daly said. “But<br />

we now have the evidence to<br />

support that life, when dormant,<br />

could likely survive hundreds of<br />

millions of years.”<br />

There are two essential<br />

reasons for Conan’s extreme<br />

resistance to radiation: the<br />

hyperaccumulation of manganese<br />

antioxidants (Mn-antioxidants)<br />

coupled with polyploidy and<br />

the presence of multiple identical<br />

genomes. Mn-antioxidants protect<br />

proteins needed to rebuild DNA, and<br />

polyploidy provides the cell with backup<br />

genomes used in repair.<br />

Extremophiles like Conan accumulate<br />

Mn-antioxidants, which are small<br />

complexes that consist of manganous<br />

ions bound to a variety of common<br />

metabolites. Generally, the more Mnantioxidants<br />

accumulated in a cell, the<br />

greater the organism’s resistance to<br />

ionizing radiation. Ionizing radiation<br />

is a high-energy form of radiation that<br />

can strip electrons from water, forming<br />

unstable molecules called ‘reactive<br />

oxygen species’ (ROS). The most toxic<br />

ROS in irradiated cells is superoxide,<br />

which “fries” the proteome, Daly<br />

explained. The proteome is the organism’s<br />

set of proteins—including the molecular<br />

machinery required to reassemble DNA<br />

broken by radiation. Mn-antioxidants<br />

in Conan defend the proteome against<br />

ROS and thereby preserve the enzymes<br />

needed to rebuild its broken genomes<br />

after radiation. In contrast, cells like E.<br />

coli that lack this Mn-antioxidant defense<br />

lose the ability to reassemble DNA<br />

damaged by radiation.<br />

Manganese antioxidants do not prevent<br />

DNA damage caused by radiation—<br />

luckily, the second molecular trick in<br />

Conan’s tool kit is polyploidy. Polyploidy<br />

means that when one genome is damaged,<br />

other undamaged copies can be used to<br />

repair the broken one. Conan contains<br />

eight identical copies of its genome per<br />

cell. The team showed that the organisms<br />

with the greatest resistance to radiation<br />

are polyploid. E. coli and Bacillus spores<br />

typically have only one or two genome<br />

copies, while baker’s yeast has four copies.<br />

In Conan, the eight genome copies are<br />

linked together by interstrand crosslinks<br />

called Holliday junctions, further<br />

accelerating DNA repair. “When you get<br />

a double-strand break caused by radiation<br />

in the genome, then the repair templates<br />

for homologous recombination are never<br />

far away,” Daly said.<br />

The baker’s yeast strain studied is also<br />

a polyploid, but this fungus accumulates<br />

fewer Mn-antioxidants than Conan. By<br />

comparison, E. coli does not accumulate<br />

Mn-antioxidants and typically has only<br />

one or two copies of its genomes. While<br />

the Bacillus spores accumulate Mnantioxidants,<br />

they are merely haploids,<br />

containing only a single copy of the<br />

genome. In the end, the data showed<br />

that dried and frozen Conan would<br />

possibly survive 280 million years when<br />

buried ten meters below the Martian<br />

subsurface, the yeast would survive<br />

48 million years, E. coli would survive<br />

sixteen million years, and Bacillus<br />

spores would survive relatively less.<br />

The forthcoming ExoMars mission’s<br />

Rosalind Franklin rover plans to drill<br />

two meters below the surface of Mars and<br />

collect samples in search of life. While<br />

the surface of Mars has been frozen and<br />

desiccated for billions of years, Daly<br />

theorized that life could still exist not<br />

far beneath the surface. He explained<br />

that Mars’ lack of an atmosphere means<br />

IMAGE COURTESY OF DALY<br />

These Deinococcus bacteria were used in a new<br />

study that suggests that if there is or ever was life<br />

on Mars, it would still exist today.<br />

that meteorites regularly bombard<br />

the planet. Upon impact, frozen water<br />

beneath a crater will melt, and simple<br />

organic compounds delivered by some<br />

meteorites could fertilize and fuel<br />

cellular recovery. If this theory holds<br />

true, Conan could have a Martian<br />

doppelganger out there to challenge its<br />

title as the world’s toughest organism.<br />

Article IX of the Outer Space Treaty (OST)<br />

of 1967 is an international agreement aimed<br />

at preventing harmful cross-contamination<br />

in the exploration of life across celestial<br />

bodies. While Conan’s survivability<br />

suggests that forward-contamination of<br />

Mars would be essentially permanent over<br />

mission time-frames of thousands of years,<br />

this would not be considered harmful under<br />

the OST because the organisms cannot<br />

proliferate when frozen and desiccated.<br />

Harmful backward contamination from<br />

Mars to Earth is also unlikely because if<br />

life ever evolved on Mars, it would now<br />

be anaerobic—able to survive without<br />

oxygen—and susceptible to the toxic effects<br />

of Earth’s oxygen-rich atmosphere.<br />

“It is not considered harmful<br />

contamination unless these organisms<br />

were dispersed across the planet and<br />

somehow found some warmth and water,”<br />

Daly explained. “There are good reasons<br />

to think that we can explore the surfaces<br />

of Mars without harming the science that<br />

is dedicated to looking for the possibility<br />

of extraterrestrial life. One can speculate<br />

that Martian life, if it ever existed there,<br />

still exists below the surface.” ■<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 33


FEATURE<br />

Chemistry<br />

THE GOLDEN<br />

Whether you're cooking a meal<br />

or mixing a drink, chances are<br />

that you taste your creation<br />

to figure out if it's right or not. Maybe<br />

there's too much sugar in the lemonade,<br />

or your tomato sauce isn't cooked enough,<br />

or your stir-fry needs more salt. Our<br />

senses have always helped us decode the<br />

mysteries of what we eat and drink. But<br />

now, we can also use chemistry to figure<br />

out when our favorite refreshments are<br />

perfect to consume. Researchers from<br />

the University of Glasgow and the Scotch<br />

Whisky Research Institute have recently<br />

designed a way to determine the flavor<br />

maturity of whiskey by using gold.<br />

After whiskey is distilled, it is stored for<br />

years in charred wooden casks to gain its<br />

characteristic flavor and amber color. The<br />

type of cask used for whiskey storage and<br />

the duration of aging can dramatically<br />

change its flavor profile. This flavor comes<br />

from chemicals called congeners that the<br />

whiskey absorbs from its wooden cask.<br />

Traditionally, casks of whiskey must be<br />

constantly sampled by a master blender,<br />

who determines if the flavor is just<br />

right. Since there are often hundreds or<br />

thousands of casks to sample, each taking<br />

so long to age, whiskey distillers are very<br />

interested in developing a quicker way to<br />

assess the maturity of their products.<br />

William Peveler, a chemist at the<br />

University of Glasgow in Scotland, first<br />

came across the science of whiskey when<br />

he saw a related infographic in Chemical<br />

& Engineering News magazine. He noticed<br />

that some of whiskey's chemical structures<br />

looked similar to the chemicals he worked<br />

with during his doctoral studies, which<br />

focused on creating gold nanoparticles.<br />

He wondered if whiskey could also be<br />

used to make these nanoparticles, and<br />

his team tested the hypothesis by using<br />

a cheap supermarket-brand whiskey in<br />

their lab. "And it did work, which was<br />

surprising since things don't always do<br />

that!" Peveler joked.<br />

The researchers found that the qualities<br />

of gold nanoparticles that form in<br />

different types of whiskey can<br />

reveal how long it has been<br />

aged. Their analysis involves<br />

taking just fifty microliters<br />

of whiskey—the equivalent of<br />

one droplet—and mixing in the<br />

same amount of gold salt. The<br />

flavor congeners in the whiskey<br />

reduce the gold salt into gold<br />

nanoparticles and stabilize<br />

them against growing any<br />

larger than a few hundred<br />

nanometers. These<br />

particles are so tiny that<br />

they can’t be seen by the<br />

naked eye. However, they<br />

do give the whiskey a visibly<br />

different color because<br />

gold nanoparticles absorb<br />

light very strongly compared<br />

to many other materials. Gold<br />

nanoparticles typically absorb<br />

green wavelengths of light the<br />

strongest. This means that we<br />

don’t usually see green light from<br />

gold nanoparticles—rather, we perceive<br />

the gold nanoparticles as different tones<br />

of pink, red, or purple. After just fifteen<br />

minutes, the final color of the sample<br />

reveals how aged or flavorful the whiskey<br />

is. Whiskeys with more flavor congeners<br />

generally produce more nanoparticles,<br />

giving the sample a more intense color.<br />

The researchers' use of gold might<br />

strike some as strange. "Of course, you<br />

use gold, and everyone goes, 'Well, gold's<br />

really expensive. Why are you using<br />

gold?'" Peveler said. Peveler's group also<br />

explored using silver for their study since<br />

silver is cheaper and its nanoparticles<br />

absorb light even more strongly than gold<br />

nanoparticles. However, the composition<br />

of silver is<br />

different, and the<br />

researchers found that<br />

the chemistry of whiskey<br />

wasn't powerful enough to<br />

reduce silver into satisfactory<br />

amounts of nanoparticles. The<br />

color of the whiskey and silver mixture<br />

did change, but it took hours or days for<br />

the reaction to become visible, so Peveler's<br />

team stuck with gold. And surprisingly,<br />

34 Yale Scientific Magazine December 2022 www.yalescientific.org


Chemistry<br />

FEATURE<br />

BY ANAVI UPPAL<br />

ART BY NOORA SAID<br />

STANDARD<br />

t h e gold they used wasn't that<br />

expensive: the amount<br />

of gold needed for each<br />

whiskey test is much less<br />

than one cent.<br />

In their research lab,<br />

Peveler and his team used<br />

a spectral photometer<br />

worth thousands of<br />

dollars to analyze the<br />

exact colors of these<br />

whiskey mixtures.<br />

This instrument<br />

looks at light on<br />

a wavelengthby-wavelength<br />

basis to see<br />

how much of<br />

each color<br />

the whiskey<br />

absorbs.<br />

H o w e v e r,<br />

i t ' s<br />

possible<br />

to create a much cheaper version of this<br />

device that whiskey distillers could use to<br />

quickly and inexpensively test their own<br />

samples in-house. This device would use a<br />

diffraction grating, a clear piece of plastic<br />

or glass that spreads out white light into<br />

the rainbow of colors that it is composed<br />

of. By shining a light through the whiskey<br />

mixture and looking at it through a<br />

diffraction grating, you can tell which<br />

specific colors of light are being absorbed<br />

or reflected by the whiskey, revealing its<br />

age. Such a setup could be strapped to a<br />

smartphone camera and would only cost<br />

tens of dollars to make.<br />

In future studies, the researchers hope<br />

to use gold nanoparticles to measure more<br />

than just the age of whiskey. "What we<br />

saw tantalizing hints of in the paper but<br />

couldn't necessarily pin down in the time<br />

frame that we were working with was that<br />

sometimes we measured a whiskey, and<br />

it gave a really different colored particle,<br />

or it was a much bigger particle, or a<br />

different shape," Peveler said. "Sometimes<br />

we saw spheres. Sometimes we saw a sort<br />

of triangle plate-like thing. Sometimes<br />

we saw rods or a star-type shape. My<br />

hypothesis is that that is linked to the<br />

different chemistry that is coming out of<br />

the wood." Ideally, the gold nanoparticles<br />

would not only allow whiskey distillers to<br />

determine how much flavor has infused<br />

the whiskey but also identify the specific<br />

flavors. For example, they might be able<br />

to correlate certain particle shapes or<br />

colors with buttery flavors or with smoky<br />

undertones. "That's going to be a key<br />

challenge going forward," Peveler said.<br />

Through chemistry, it's becoming<br />

possible to dissect the flavors we encounter<br />

in our daily lives. "I'm fascinated by this<br />

kind of stuff: how we taste, how we smell,<br />

how we perceive flavor, and things like<br />

that," Peveler said. Peveler has previously<br />

done similar sensing research that goes<br />

even beyond food and beverages, such as<br />

detecting explosives in wastewater and<br />

sensing liver disease in blood. But as a big<br />

whiskey fan—and a researcher based in<br />

Scotland, which is famous worldwide for<br />

its whiskey—he has particularly enjoyed<br />

working with it for this project. "It's<br />

whiskey! It's fun, right?" ■<br />

USING GOLD<br />

NANOPARTICLES<br />

TO REVEAL THE<br />

AGE OF WHISKEY<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 35


UNDERGRADUATE PROFILE<br />

ERIC SUN<br />

YC ’23<br />

BY CINDY KUANG<br />

Eric Sun (MY ’23) is a lot of things: aspiring physician-scientist,<br />

cancer biology researcher, competitive yo-yo player, longdistance<br />

runner, and most recently—a 2022 Barry Goldwater<br />

Scholar. Double majoring in Molecular Biophysics and Biochemistry<br />

(MB&B) and Statistics & Data Science (S&DS), Eric dedicates his time<br />

outside the classroom to researching and understanding cancer drug<br />

resistance, with previous work in epigenetics and DNA damage.<br />

Growing up in northern Virginia, Eric was always excited by<br />

the proximity of the National Institute of Health in Maryland:<br />

“You see experiments in the textbook, and you’re like – how do<br />

you actually do that?” Eric said.<br />

At sixteen years old, Eric cold-emailed NIH principal investigators<br />

hoping for a summer laboratory experience and ultimately joined<br />

Philipp Oberdoerffer and Mirit Aladjem’s labs, where he spent the<br />

next two years. There, he studied the<br />

epigenetics<br />

behind the DNA damage response,<br />

primarily<br />

how different types and<br />

modifications of histones<br />

(which are what DNA<br />

wraps around in the cell’s<br />

nucleus) could dictate or<br />

inform the environment<br />

in which DNA repair<br />

processes occur.<br />

He continued<br />

pursuing this<br />

interest in<br />

epigenetics at Yale,<br />

where he joined<br />

Andrew Xiao’s lab<br />

in the fall of 2019<br />

as a first-year. “I felt<br />

that the projects that<br />

were ongoing were really<br />

fascinating,<br />

PHOTO COURTESY OF SOPHIA LI VIA ERIC SUN<br />

and there was great mentorship<br />

from the MD/<br />

PhD students in the lab that have helped me tremendously<br />

through the last couple years, especially navigating the pathway<br />

of applying for an MD/PhD,” Eric said.<br />

Despite initial setbacks due to COVID-19, Eric’s work on<br />

cancer drug resistance—specifically targeted therapies in the<br />

context of lung adenocarcinoma—has made great progress. He<br />

focuses on epidermal growth factor receptor (EGFR) mutant lung<br />

adenocarcinoma, a subclass of non-small cell lung cancers, and<br />

how these cancers ultimately develop resistance against therapies<br />

that are initially greatly effective.<br />

Currently, in the clinic, patients with EGFR mutant lung<br />

adenocarcinoma are treated with specific targeted therapies called<br />

tyrosine kinase inhibitors, one of which—Osimertinib—is used as a<br />

first-line treatment for EGFR mutant lung adenocarcinoma patients,<br />

and is the focus of Eric’s research. These patients are sensitive to<br />

these targeted therapies because these inhibitors bind to mutated<br />

EGFR but not wild-type EGFR, effectively only targeting and killing<br />

the cancer cells and not wild-type healthy cells.<br />

“The problem is, patients often develop resistance in just a<br />

matter of months,” Eric said. “In the clinical setting, we see<br />

tumors initially regress but then expand again and metastasize<br />

further, so understanding why tumors become resistant has been<br />

a major question in the field.”<br />

Eric’s project particularly questions how oncogene amplification<br />

is involved in resistance, notably how two copies of an oncogene<br />

can amplify to fifty copies or even one-hundred copies and how<br />

the cell can then exploit that upregulation to develop therapeutic<br />

resistance. Through mining sequencing data, including rich clinical<br />

trial data from the National Cancer Institute, as well as hands-on<br />

imaging, genomics, and assay work at the bench in different cell<br />

line models, Eric has studied the acquisition of resistance through<br />

various approaches. “We have a lot of data from<br />

various aspects, from patient data to cell line<br />

models, suggesting a common mechanism<br />

of oncogene amplification that drives<br />

Osimertinib resistance,” Eric said.<br />

Eric reflected on the Barry Goldwater<br />

Scholarship and how the award has<br />

influenced him as a researcher. “I take<br />

pride in that it’s an affirmation that<br />

I’m doing the right things,” Eric said.<br />

“Really, I’ve been mentored really<br />

well, and it’s a testament to the faculty<br />

and the professors that I’ve been able<br />

to get to know at Yale who really<br />

supported me both in the classroom<br />

and in my research.”<br />

After graduation, Eric plans to pursue an<br />

MD/PhD, stating that though he really enjoys<br />

research, he also really loves spending time in the<br />

clinic to see how his research interfaces with clinical issues.<br />

“I don’t think science lives in a vacuum; you don’t do science just<br />

for science. You see patients, you see what their challenges are,<br />

you see patients fail treatment with a drug or develop resistance,<br />

and then you go back to the bench and ask: now how do you<br />

understand this?” Eric said.<br />

Regarding advice for aspiring researchers, Eric stressed a confident<br />

mentality. “Just don’t be afraid in general. Reach out to people, screw<br />

up an experiment, those are small things in the grand scheme of<br />

everything. If you’re afraid, you aren’t even going to try,” Eric said.<br />

Without a doubt, Eric’s passion and enthusiasm for science and<br />

medicine will not just better the research community but will also<br />

continue to inspire everyone around him for years to come. ■<br />

36 Yale Scientific Magazine December 2022 www.yalescientific.org


ALUMNI PROFILE<br />

JONATHAN ROTHBERG<br />

GSAS ’91<br />

BY SOPHIA BURICK<br />

J<br />

onathan Rothberg GSAS’ 91, the pioneer of nextgeneration<br />

DNA sequencing, has always had a scientific<br />

bent and entrepreneurial spirit. His father, a chemical<br />

engineer, built his own company and turned the basement of<br />

their family home into a laboratory. Conversations around the<br />

dinner table often revolved around business.<br />

After earning his bachelor’s in Chemical Engineering from Carnegie<br />

Mellon University in 1985, Rothberg arrived at Yale to complete a PhD<br />

in Biology. In the lab of Yale professor emeritus Spyros Artavanis-<br />

Tsakonas, he investigated the molecular basis of nervous system wiring.<br />

While still a student at Yale, Rothberg founded his first company,<br />

Curagen. Curagen was one of the first movers in the genomics industry<br />

in the 1990s. They invented a new field dubbed global proteomics,<br />

which entails identifying and analyzing all the proteins in a sample.<br />

“We were the first ones to map out all the protein interactions in a yeast<br />

cell, which got featured on the cover of Nature,” Rothberg said.<br />

When his son had difficulties breathing after birth, Rothberg was<br />

frustrated that genome sequencing technology was not fast enough to<br />

provide him with genetic answers regarding his son’s condition.<br />

While in the hospital, Rothberg saw<br />

an InfoWeek magazine cover<br />

featuring the new Pentium<br />

semiconductor chip. In<br />

that moment, inspiration<br />

struck. He could<br />

apply the concept of<br />

transistors—which are<br />

used in circuits in large<br />

quantities to switch<br />

or amplify electrical<br />

signals in a massively<br />

parallel way—to DNA<br />

sequencing. “I could<br />

interrogate a sequence of<br />

bases, but this time, instead<br />

of doing it in one test tube, I<br />

could do it thousands of times or<br />

millions of times in parallel,” Rothberg<br />

said. While still working at Curagen, Rothberg<br />

founded his second company, 454 Life Sciences, to develop this<br />

revolutionary technology. Rothberg’s method became known as<br />

next-generation sequencing and is still used today.<br />

Shockingly, Rothberg was fired by the boards of Curagen and 454<br />

for this idea. The company’s board believed the completion of the<br />

Human Genome Project had rendered the technology obsolete and<br />

sold 454 Life Sciences for 140 million dollars.<br />

Still convinced that next-generation DNA sequencing was the<br />

future, Rothberg founded Ion Torrent. This time, he would have to<br />

do something different. Instead of just using the general concept<br />

www.yalescientific.org<br />

PHOTO COURTESY OF ALEX DONG VIA JONATHAN ROTHBERG<br />

of massively parallel analysis derived from transistors on a chip—<br />

sequencing the DNA at many different spots simultaneously—<br />

Rothberg approached the issue more directly, creating a<br />

semiconductor chip that could<br />

directly sequence DNA in<br />

a massively parallel way.<br />

Out of this idea came<br />

the Ion Torrent chip: a<br />

semiconductor chip<br />

capable of sensing the<br />

chemistry of DNA<br />

PHOTO COURTESY OF ALEX DONG VIA JONATHAN ROTHBERG<br />

synthesis through<br />

pH changes, allowing<br />

the user to rapidly<br />

sequence DNA. “We<br />

were really on a great<br />

path to a thousand dollars<br />

genome by just going to newer<br />

factories or foundries and making<br />

denser chips,” Rothberg said.<br />

Rothberg sold Ion Torrent to Life Technologies for 725 million<br />

dollars—five times the amount 454 Life Sciences was sold for.<br />

Ironically, almost exactly ten years after he was fired for the<br />

idea, President Barack Obama awarded Rothberg a National<br />

Medal of Technology and Innovation for his work on nextgeneration<br />

sequencing.<br />

After Ion Torrent, Rothberg wanted to transition to<br />

parallel entrepreneurship—helping several different<br />

startups develop at once. To do this, he launched a startup<br />

accelerator called 4Catalyzer. Rothberg has three key<br />

criteria that startups under 4Catalyzer must meet: each<br />

startup must solve a problem that affects the life of someone<br />

they love, use artificial intelligence, and take advantage of<br />

semiconductors or the concept of large-scale integration<br />

behind semiconductors. One of 4Catalyzer’s startups, Detect,<br />

played a major role in the COVID-19 pandemic. Detect’s mission<br />

was to develop an at-home COVID test with sensitivity comparable to a<br />

PCR test. The test they developed was sometimes demonstrated to be ten<br />

thousand times more sensitive than the at-home alternative of antigen<br />

tests. Now, Detect is applying their technology to other ailments. “It will<br />

be for universal testing, and they’ll do STIs, COVID, and flu. They’ve<br />

raised about 160 million dollars for the company,” Rothberg said.<br />

Many of the companies under 4Catalyzer, like Detect, are headed by<br />

Yale graduates, and Rothberg is always eager to work with the latest<br />

talent coming out of Yale. For Yalies looking to try their hand at scientific<br />

entrepreneurship, Rothberg’s advice is simple. “Find somebody that<br />

compliments you. If you’re good at business, find someone good at<br />

science. I think that raises your probability of success the greatest—just<br />

finding a complement that you can work with,” Rothberg said.■<br />

December 2022 Yale Scientific Magazine 37


EATING TO EXTINCTION<br />

BY DINESH BOJJA<br />

SCIENCE<br />

IN<br />

IMAGE COURTESY OF FLICKR<br />

THE WORLD'S RAREST FOODS AND<br />

WHY WE NEED TO SAVE THEM<br />

Every day, our dining halls are filled with countless choices: dozens of<br />

types of pizza, chicken tikka masala and aloo gobi, Cajun fish tacos,<br />

and cheese quesadillas. But if we take these foods back to their base<br />

ingredients, that variety vanishes. In fact, only three plants—rice, wheat, and<br />

maize—account for half of all calories consumed globally. This expanse of<br />

diverse food options masks a dramatic loss in true food biodiversity and the<br />

increased homogenization of agriculture and food production.<br />

In his book Eating to Extinction: The World’s Rarest Foods and Why We<br />

Need to Save Them, Dan Saladino discusses the uniformity of modern food<br />

production, driven by a steep demand for low-cost, high-quantity food<br />

species. For example, half of the world’s cheese is made from bacteria and<br />

enzymes produced by the same company. The same breed of pig controls the<br />

international pork trade. And only one of the 1500 types of bananas dominates<br />

the global market. Saladino attributes this trend—sacrificing variety for<br />

surfeit—to a few concurrent factors: shifts in land usage, the introduction of<br />

chemical fertilizers and pesticides, and a rise in genetic modifications for crops<br />

and livestock alike. Dubbed the “Green Revolution,” this shift in the 1960s<br />

and 1970s was marked by unparalleled crop prosperity and food production,<br />

enough to sustain the world’s growing population. Overall yields of staple<br />

crops skyrocketed, but other wild crops were driven to near extinction.<br />

While there may be more food produced overall, this marks a dangerous<br />

trend. A decline in food biodiversity increases the risk of pests and diseases<br />

disrupting global food security. For example, one fungus, Fusarium<br />

graminearum, has led to billions of dollars of damage by infecting wheat<br />

crops in Europe, Asia, and the Americas. Saladino runs through countless<br />

examples of mass-produced foods overshadowing traditional species, from<br />

Cosmic Crisp and Red Delicious apples overpowering the apple market<br />

to slaughterhouse chickens, eliminating the need for traditional breeds or<br />

historically used but now obsolete species. A loss of diversity comes with a<br />

loss of culture, identity, and history.<br />

It is not too late to reverse the trend, however. From scientific seed repositories<br />

in Norway to government-run food conservation efforts, thousands of different<br />

crops, animals, and fruits have been painstakingly preserved in hopes of future<br />

reintroduction and production. Thankfully, corporations also have recognized<br />

the need for increased food biodiversity, and twenty of the world’s biggest food<br />

businesses have pledged to preserve traditional foods.<br />

But the real hope is in the hands of farmers daring to continue their<br />

tradition, even in the face of agricultural giants. A “chocolate lab” in<br />

Venezuela specializes in producing traditional chocolate made from Criollo<br />

cacao. A village of resilient fishermen holds steadfast to their roots of selling<br />

wild Atlantic salmon. A group of millers on the Orkney Islands work with<br />

agronomists to bring back nutritious Bere barley. Even on the individual<br />

level, every effort is the chance to bring another species back from the brink<br />

of extinction. With a stroke of encouragement and support, the opportunity<br />

to restore food biodiversity is within reach. ■<br />

38 Yale Scientific Magazine December 2022 www.yalescientific.org


ATOMS AND ASHES<br />

A GLOBAL HISTORY OF<br />

NUCLEAR DISASTERS<br />

Ever since scientists first split the atom in 1938, nuclear power has both<br />

fascinated and terrified millions. Today, ten percent of world energy<br />

is supplied by almost 440 nuclear reactors. In the US, closer to twenty<br />

percent of electricity comes from nuclear power. Regarded as a highly efficient,<br />

low-emission energy source, nuclear energy is an attractive option for many<br />

countries seeking to reduce their carbon footprint while meeting population<br />

needs. Yet, nuclear disasters like Chernobyl have shown the risks of working<br />

with radioactive material. Considering the industry’s troubled history raises<br />

the question: Just how safe is nuclear energy?<br />

In his new book Atoms and Ashes: A Global History of Nuclear Disasters, Serhii<br />

Plokhy, Harvard University professor of Ukrainian History, explores the dangers<br />

of nuclear power through six of the worst nuclear disasters: the 1954 Castle<br />

Bravo hydrogen bomb test, the 1957 Kyshtym nuclear waste tank explosion, the<br />

1957 English Windscale reactor fire, the 1979 Three Mile Island partial reactor<br />

meltdown, the 1986 Chernobyl reactor meltdown, and the 2011 Fukushima<br />

disaster.<br />

Plokhy expertly creates a picture of the international nuclear industry. “The<br />

story told here is a global one,” he writes, examining “not only the actions<br />

and omissions of those directly involved but also the ideologies, politics,<br />

and cultures that contributed to the disasters.” For example, the Castle Bravo<br />

accident sets the stage for later chapters by introducing the pressures of the<br />

Cold War, government efforts to cover up disasters, and the inevitability of<br />

human error when dealing with emerging science and technology.<br />

Plokhy complements his well-researched piece with a skillful narration.<br />

Meticulously selected testimonies bring every accident to life, making the<br />

historical events all the more palpable and impactful. Discussing the Fukushima<br />

meltdown, Plokhy anchors his narration around plant superintendent Yoshida.<br />

“Yoshida was sitting behind his desk, [...] when things around him started<br />

shaking. [..] ‘My mind should have been panicking. But strangely, [it] was<br />

telling me to keep calm and start planning,’ recalled Yoshida,” Plokhy writes. In<br />

this manner, Plokhy builds an entertaining, well-informed historical thriller.<br />

Atoms and Ashes shows that science and technology alone cannot cause or<br />

BY XIMENA LEYVA PERALTA<br />

T H E<br />

SPOTLIGHT<br />

prevent nuclear disasters. Many political, social, and cultural factors are involved<br />

in regulating nuclear energy. New international legislation was established through<br />

international cooperation to prevent future nuclear accidents, making it easier to<br />

exchange technology and enforce rigorous standard safety measurements.<br />

Though the impacts of nuclear disasters should not be disregarded, their<br />

rate and severity are lower than accidents in the coal, gas, and hydropower<br />

industries. While not perfect, nuclear fission reactors are the most efficient<br />

zero-emission energy source. As Plokhy recognizes, “the major accidents<br />

involved [...] technologies developed in the 1950s and 1960s, [offering] some<br />

hope that the [industry’s] major errors [are] behind us.” Better policy-making<br />

and increased funding for research and development promise a safer future<br />

for nuclear energy. Moreover, they open the door to a promising, carbonfree,<br />

potentially safer option to power the second half of this century: nuclear<br />

fusion, fusing atoms instead of splitting them apart. ■<br />

IMAGE COURTESY OF WIKIMEDIA COMMONS<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 39


COUNTERPOINT<br />

Life on Mars Was<br />

Its Own Undoing<br />

Has life existed on Mars? If so, how would<br />

it have affected Mars’s climate? There has<br />

been ample research on Earth’s early life<br />

forms and their effect on the planet. Scientists<br />

have been particularly interested in methanogens,<br />

microorganisms that consume hydrogen (H2) and<br />

carbon dioxide (CO2) and generate methane (CH4)<br />

as waste. Both CO2 and CH4 are greenhouse gases,<br />

which trap heat in the atmosphere and lead to<br />

temperature increases, but CH4 retains twenty-five<br />

times more heat than CO2. Therefore, methanogen<br />

metabolism increased global temperature and, as a<br />

result, made Earth habitable to other organisms.<br />

However, a recent study in Nature Astronomy<br />

found that if methanogens ever existed on early<br />

Mars during the Noachian period (about four<br />

billion years ago), they would have had an opposite<br />

cooling effect. This is because early Mars had a<br />

CO2-dominated atmosphere, as opposed to early<br />

Earth’s nitrogen-dominated atmosphere. Collisions<br />

between CO2 and H2 molecules absorb more heat<br />

energy than CO2-CH4 collisions or CH4 alone.<br />

Since the existence of methanogens would have<br />

drastically changed the climate, it is important to<br />

evaluate whether the early Mars environment could<br />

support methanogenic life. The researchers concluded<br />

that Mars’ subsurface environment was probably<br />

favorable to microbial life. Mars’ crust is covered by<br />

regolith, a loose, heterogeneous layer made of dust,<br />

sand, and broken rocks. At that time, regolith may<br />

have sheltered microorganisms from ultraviolet and<br />

cosmic radiation. Simultaneously, brine, highlyconcentrated<br />

salt water, would have filled the porous<br />

layer and provided an aqueous environment.<br />

In addition to an aqueous solution and shelter<br />

from radiation, the land must also have been free<br />

of surface ice to sustain life. Ice-free regions allow<br />

gases to exchange from the atmosphere, which<br />

microorganisms need to survive. Ice coverage<br />

depends on surface temperature and the brine<br />

freezing point. Researchers estimated the surface<br />

temperature on early Mars by modeling H2 and<br />

CH4 concentrations combined with the latitude<br />

By Crystal Liu<br />

ARTIST’S IMPRESSION OF MARS FOUR BILLION YEARS AGO.<br />

IMAGE COURTESY OF ESO/M. KORNMESSER.<br />

and elevation of any given geographical area. They<br />

found that before any life forms existed, the average<br />

surface temperature ranged from 216 to 294 K (-57<br />

to 21°C). Brine’s freezing point, however, is largely<br />

unknown. As salt concentration increases, the<br />

solution’s freezing point decreases, which is why<br />

we salt the road before a snowfall to prevent snow<br />

from settling. Brine likely consisted of other ions<br />

besides sodium and chloride, which would also<br />

have altered the freezing point. Estimates of early<br />

Mars brine freezing points from existing literature<br />

range from 203 to 273 K (-70 to 0°C).<br />

Researchers ran three models, estimating the<br />

probability of methanogenic life with brine freezing<br />

points of 203, 252, or 273 K. If brine had a lower freezing<br />

point, more area would be ice-free and habitable. With<br />

a freezing point of 203 K, one hundred percent of Mars’<br />

surface would have been ice-free, whereas simulations at<br />

273 K generated a median of only 0.15 percent ice-free<br />

area. In all three cases, some parts of Mars would have<br />

been habitable to methanogens, typically in lowlands at<br />

low-to-medium latitudes. It is important to note that<br />

this study only shows that early Mars satisfied every<br />

condition for methanogenic life rather than confirming<br />

the existence of life. However, the studies’ findings will<br />

inform the search for traces of life in fossil records.<br />

If methanogens had really existed, their metabolic<br />

activity would have significantly changed Mars’<br />

climate, leading to new equilibrium temperature<br />

and atmospheric composition. The study estimates<br />

a reduction of 33 to 45 K. As a result, the fraction<br />

of ice-free regions would have dropped, and<br />

habitability would have been compromised. Even<br />

in places with no ice coverage, methanogens would<br />

have been forced deeper into the crust, which was<br />

warmer but scarcer in essential gases. Somewhat<br />

counterintuitively, if Mars had a lower brine freezing<br />

point, more methanogens could have existed in the<br />

first place, but they would have induced a larger drop<br />

in temperature and lower habitability at the steady<br />

state. Unlike on Earth, where the first life forms<br />

facilitated the emergence of later organisms, life on<br />

Mars may have been its own undoing. ■<br />

40 Yale Scientific Magazine December 2022 www.yalescientific.org


HIDDEN<br />

HISTORIES<br />

NETTIE STEVENS<br />

BY ANJALI<br />

DHANEKULA<br />

ART BY<br />

MALIA KUO<br />

Nettie Maria Stevens was born on July 7, 1861, in<br />

Cavendish, Vermont, where her family had lived for<br />

several generations. Still feeling the aftereffects of the<br />

Civil War, women in the US generally had few educational and<br />

professional opportunities. However, in part because of her<br />

father’s accumulated wealth, Stevens attended public schools,<br />

eventually graduating from Westford Academy at the age of<br />

nineteen. Stevens was a dedicated student, earning praise from<br />

teachers and peers alike.<br />

After graduation, Stevens became a high school teacher to<br />

save money to continue her education. Later, she attended Bryn<br />

Mawr College and pursued a graduate scholarship in biology.<br />

After just six months at Bryn Mawr, Stevens performed such<br />

brilliant work that she was awarded a fellowship to conduct<br />

research abroad. She studied at the Zoological Station in Naples,<br />

Italy and the Zoological Institute of the University of Würzburg<br />

in Germany. After earning her doctorate at Bryn Mawr, she<br />

continued to teach and research at the college until her death<br />

due to breast cancer in 1912.<br />

Stevens studied morphology, the study of the forms of<br />

living organisms, and cytology, the study of the structure and<br />

function of plant and animal cells. Her research focused on sex<br />

determination, how biological sex and sex characteristics are<br />

determined in organisms. At the time of Stevens’ research, there<br />

were two major schools of thought on sex determination. Some<br />

believed sex was determined by external factors and others<br />

believed that sex was determined at the point of fertilization,<br />

not by the surrounding environment. Over the course of her<br />

research, Stevens noticed that male mealworms produced<br />

sperm with either a large chromosome (now known as the<br />

X chromosome) and sperm with a small chromosome (now<br />

known as the Y chromosome), but female mealworms only<br />

produced eggs with large chromosomes. She concluded that<br />

chromosomes, specifically on the paternal side, are responsible<br />

for sex determination.<br />

Despite Stevens publishing her groundbreaking discoveries, many<br />

credit Edmund Wilson, a geneticist who worked in the same fields<br />

as Stevens, for the finding. While Stevens and Wilson worked on<br />

chromosomal sex determination simultaneously, they arrived at<br />

the conclusion independently. In fact, Thomas Hunt Morgan, a<br />

mentor to Stevens who did not accept the theory of chromosomal<br />

inheritance at the time, is often credited with discovering the genetic<br />

basis for sex discrimination. Morgan even went on to win a Nobel<br />

Prize in 1933 “for his discoveries concerning the role played by the<br />

chromosome in heredity.”<br />

Stevens is not the only female scientist whose contributions to<br />

science were not recognized as her own until long after her death.<br />

Others include Rosalind Franklin, who co-discovered the helical<br />

structure of DNA, and Esther Lederberg, who discovered a virus<br />

that infects E. coli bacteria, a widely used tool in the current study<br />

of genetics. This pattern indicates the Matilda effect: the repeated<br />

dismissal of scientific discoveries made by women in science.<br />

Stevens’ discoveries about sex determination are the basis for many<br />

advancements in research on Turner syndrome and Down syndrome,<br />

as well as developments in the chromosomal basis of heredity.<br />

Although Stevens dedicated much of her life to her education and<br />

research, making crucial contributions to the field of genetics, the<br />

highest position she ever reached was as an associate in experimental<br />

morphology at Bryn Mawr College. Thomas Hunt Morgan described<br />

her as more of a lab technician than a true scientist. Reporters at the<br />

time stressed Wilson’s discovery over Stevens’, even though Stevens<br />

stated her conclusions more explicitly.<br />

Without Stevens’ discoveries, it is impossible to know where<br />

the field of genetics would be today. Yet, like many other female<br />

researchers, her work has been consistently undervalued. There is<br />

limited research available on how to diminish gender bias in scientific<br />

fields. However, by continuing to acknowledge the contributions of<br />

female scientists, we can work to create a world where the Matilda<br />

effect does not exist—a world in which we celebrate Nettie Maria<br />

Stevens for her achievements. ■<br />

www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 41


SYNAPSE<br />

Essay Contest Winner<br />

P<br />

LLING TEETH<br />

I<br />

turned sixteen last May, meaning, I<br />

have officially entered the “wisdom<br />

teeth removal” era of my life.<br />

According to my last dentist visit, I have<br />

3 lovely molars waiting for me in a couple<br />

of years' time. That got me thinking, why<br />

do we even have wisdom teeth?<br />

Retired now, wisdom teeth’s original<br />

function was to grind down hearty, rough<br />

food. According to Herman Pontzer,<br />

an evolutionary anthropologist at Duke<br />

University, the myth of the prehistoric<br />

diet consisting mostly of meat isn’t true.<br />

Instead, early humans ate what they could<br />

forage from their environment, which<br />

heavily varied depending on location,<br />

season, and climate. In an article for<br />

National Geographic, Leslie Aiello,<br />

president of the Wenner-Gren Foundation<br />

for Anthropological Research in New<br />

York City says this, “What bothers a lot of<br />

paleoanthropologists is that we actually<br />

didn’t have just one caveman diet, The<br />

human diet goes back at least two million<br />

years. We had a lot of cavemen out there.”<br />

Even so, all paleoanthropologists seem<br />

to agree on one thing; The diet of early<br />

human beings was coarse and rough.<br />

Enter, the adaptation to have a third<br />

set of molars. Wisdom teeth grew in with<br />

the function to provide more chewing<br />

power. Now, with softer foods and the<br />

inventions of cutlery, wisdom teeth are<br />

obsolete. If anything, they are quite a<br />

literal source of irritation. This is due to<br />

human jaws becoming much smaller over<br />

time. Without the extra space, wisdom<br />

teeth become blocked by surrounding<br />

teeth. This can result in bone and<br />

jaw disruption, as well as damage to<br />

neighboring teeth. To avoid these side<br />

effects, many young adults undergo a<br />

42 Yale Scientific Magazine December 2022 www.yalescientific.org


Essay Contest Winner<br />

SYNAPSE<br />

ART BY MALIA KUO<br />

procedure to have<br />

them removed. Annually, Americans<br />

remove around 10 million wisdom teeth.<br />

This adaptation, while useful at the time,<br />

has been outgrown for thousands of years.<br />

It goes to show that some solutions work<br />

better in the past and are best left there.<br />

Although optimization isn’t contained to<br />

biological changes, it is in human nature<br />

to find the “better” solution. According<br />

to Applied Psychology: Health and Wellbeing,<br />

“Optimal functioning, which may<br />

be in physical, cognitive, emotional, and/or<br />

social terms, emphasizes the importance of<br />

a person’s inner strength, state of resilience,<br />

virtue, and the maximization in capability”<br />

People most often self-optimize to achieve<br />

self-fulfillment and inner satisfaction.<br />

I share this human need to optimize; I<br />

myself have terrible handwriting.<br />

It started in third grade<br />

when my mom told me<br />

"teachers will take off points<br />

KATE KIM is a junior at James Hillhouse<br />

High School in New Haven,<br />

CT, where she enjoys swimming<br />

for the East Haven/New Haven<br />

girls' swim team and participating<br />

in the student council as class president.<br />

She loves painting, writing,<br />

and opening SAT books (but not<br />

studying in them). Through her<br />

writing, she aims to capture her life<br />

experiences as a recording for her<br />

future self.<br />

Kate Kim is the winner of the 2022<br />

Yale Synapse Essay Contest for<br />

high school students<br />

for messy writing". From then on, I was<br />

living a double life. Picture chicken scratch for<br />

personal notes transcribed into calligraphy<br />

for official assignments. Even now, I have<br />

separate notebooks for in-class notes and<br />

for homework. But like wisdom teeth,<br />

the solution my eight-year-old self came<br />

up with seems to have run its course.<br />

The strategy slows me down. I<br />

have piles of notes waiting for me to<br />

transcribe them, I get lost in lesson material<br />

after rewriting notes from weeks prior and<br />

I'm pretty certain I have acute Tendinitis.<br />

One could argue that my strategy was<br />

never an optimized solution to my issue.<br />

“Why didn’t I just learn to write neater from<br />

the start?” I asked myself while rewriting my<br />

notes. It was then that I realized understand<br />

that optimization comes in stages.<br />

My handwriting solution may have not<br />

been the best solution, but it was one that was<br />

a quick fix to my needs when I was eight. My<br />

issue lay within the fact that I never sought a<br />

better solution, becoming comfortable with<br />

a fix that I outgrew years ago.<br />

Now, I grapple with the consequences:<br />

Deciphering the scrawl of my handwriting,<br />

late nights revising pages upon pages of<br />

work, and practicing neat handwriting in<br />

the limited free time a high school junior<br />

has. Maybe it's time I do my own operation<br />

and remove the problem at its root. ■<br />

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www.yalescientific.org<br />

December 2022 Yale Scientific Magazine 43


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