YSM Issue 95.4

Yale Scientific 

THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION • ESTABLISHED IN 1894 

DECEMBER 2022 

VOL. 95 NO. 4 • $6.99 

14 

RECODING IN 

THE BRAIN 

STREAMLINING THE 

16 

SEARCH FOR NEW DRUGS 

ON DEMAND 

18 

MEMBRANE DEFORMATION 

THE NEW 

21 

CIRCULAR ECONOMY 

LAB PROFILE: 

24 

CARDS LAB

TABLE OF 

VOL. 95 ISSUE NO. 4 

14 

Recoding in the Brain 

Elisa Howard 

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

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

neurodevelopment and disease. 

16 Streamlining the Search for New Drugs 

Emily Shang 

The research and development process of drug synthesis has always been long and arduous. 

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

receptor using a novel screening technique that can expedite the drug discovery process. 

18 On-Demand Membrane Deformation 

Risha Chakraborty 

Studying complex cellular processes in real-time continues to prove difficult for researchers, 

since manipulating many biological, chemical, and physical factors simultaneously requires nearimpossible 

levels of precision and control. Reimagining the role of common macromolecules in the 

cell might just help. 

21 The New Circular Economy 

Abigail Jolteus 

As climate change worsens, the need for more sustainable methods to produce energy also 

increases. Researchers at the Yale School of Environment have investigated the potential of a new 

technology, bioenergy with carbon capture and storage, which could help create a sustainable 

and low-carbon society. 

24 Lab Profile: CarDS Lab 

Yusuf Rasheed 

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

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

managed through AI and machine learning. 

2 Yale Scientific Magazine December 2022 www.yalescientific.org

CONTENTS 

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

4 

6 

27 

36 

Q&A 

NEWS 

FEATURES 

SPECIALS 

www.yalescientific.org 

Does Parkinson's Smell? • Dinara Bolat 

Would You Trust Working With a Robot? • Jamie Seu 

Hidden Pandemic • Sofia Jacobson 

Big Tech is Always Watching • Alex Dong 

Optimistic Results for RSV Prevention Strategies • Madeleine Popofsky 

Forecasting Extinction • Evelyn Jiang 

It's Not All Bad • Matthew Blair 

The Case Against Intelligent Computer Vision • Samantha Liu 

The Soot Factor • William Archaki 

The Winding Synthetic Road to New Antibiotics • Nathan Mu 

Turtle Transformers • Riya Bhargava 

A New Approach to Cystic Fibrosis • Matthew Zoerb 

The Strength of Weak Ties • Eunsoo Hyun 

An Unexpected Marriage: Robot Drones & Flower Power • Cindy Mei 

Robots vs. Humans: Organic Chemistry Edition • Anya Razmi 

Gamer Neurons • Maya Khurana 

Conan the Bacterium • Kayla Yup 

The Golden Standard • Anavi Uppal 

Undergraduate Profile: Eric Sun (YC '23) • Cindy Kuang 

Alumni Profile: Jonathan Rothberg (GSAS '91) • Sophia Burick 

Science in the Spotlight: Eating to Extinction • Dinesh Bojja 

Science in the Spotlight: Atoms & Ashes • Ximena Leyva Peralta 

Counterpoint: Life on Mars Was Its Own Undoing • Crystal Liu 

Hidden Histories: Nettie Stevens • Anjali Dhanekula 

Synapse Essay Contest: Pulling Teeth • Kate Kim 

December 2022 Yale Scientific Magazine 3

WOULD YOU TRUST 

WORKING WITH A ROBOT? 

& 

DOES PARKINSON'S SMELL? 

By Dinara Bolat 

Currently, no specific diagnostic tests exist for Parkinson’s 

disease, a degenerative brain disorder. Instead, patients 

get diagnosed once they start displaying trademark 

symptoms like tremors, muscle stiffness, and impaired balance. 

However, thanks to Joy Milne, a Scottish nurse with a 

hypersensitive nose, this is changing. 

Milne came to the attention of UK scientists in 2015 when 

she proved her ability to detect people with Parkinson’s by their 

unique smell. With her help, researchers from the Universities 

of Edinburgh and Manchester identified specific molecules that 

cause ‘Parkinson’s smell.’ They identified molecules in the sebum, 

an oily substance on the skin surface, and found that people 

with Parkinson’s have altered lipid signatures compared to non- 

Parkinson’s patients. Using these results, they developed a skinswab 

test to detect this lipid signature which analyzes sebum 

with PS-IM-MS, a type of ion mobility mass spectrometry. This 

new method reveals specific compounds unique to Parkinson’s 

sebum samples and identifies lipid classes that are differentially 

secreted in patients with Parkinson’s. 

Scientists are hopeful that this swab test will be a key tool for earlier 

and faster Parkinson’s diagnosis, leading to more opportunities and 

options for treatment. Although there are still clinical trials and 

accuracy assessments required before the tests can be authorized in 

hospitals, scientists involved claim that the test has a greater than 

ninety percent accuracy. This ground-breaking technology has 

inspired other research teams to study the olfactory signature of 

other diseases, opening a new field of research yet to be explored. ■ 

By Jamie Seu 

It’s a familiar trope: a well-meaning scientist invents a piece 

of revolutionary technology that develops consciousness 

and rises up to destroy the human race. Machine 

consciousness has long been a subject of fear and fascination, 

but for people who regularly interact with robots, such as those 

who work in the manufacturing industry, trust in automation 

is an incredibly pertinent issue. 

To better understand the nuances of trust in human-robot 

collaborations (HRCs), researchers at Texas A&M University 

designed a series of trials that allowed them to study operator 

trust. Participants (operators) were instructed to polish a 

metal surface with a robot along an S-shaped trajectory under 

varying levels of robot reliability and operator cognitive 

fatigue. Working with an unreliable robot reduced task 

efficiency and accuracy (deviation from the defined trajectory) 

but not precision (variance in deviation from the trajectory). 

Participants also perceived the task as more demanding than 

when they worked with a reliable robot. For participants 

experiencing cognitive fatigue, higher fatigue scores and 

reduced task efficiency were reported, with female participants 

more strongly impacted than male participants. 

Analyses of human factors on trust in HRCs can be utilized to 

create more effective worker training programs and adaptations 

to robot design that will maximize efficiency and workplace 

safety, improving and fortifying HRC systems. Robots are here 

to stay, and it’s on us to figure out how to work alongside them 

and trust them as partners. Maybe then they’ll spare us when 

they decide to take over the world. ■ 


The Editor-in-Chief Speaks 

A FUTURE WITH SCIENCE 

In our final issue of the volume, we have focused on what science innovation 

means for the future. Novel technologies come with such great potential 

but almost always with caveats. While science can help lift society towards 

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

prioritize the bigger picture, recognizing the ethical issues that accompany 

innovation. The following stories highlight science at Yale and beyond and 

their implications for the future of our world. 

Our full-length stories spotlight science’s potential in healthcare innovation. 

A study from the Ellman lab uses virtual screening for small molecule synthesis 

targeting antidepressant activity (pg. 16). The CarDS lab at the Yale School 

of Medicine uses data-driven strategies such as machine learning to improve 

cardiovascular healthcare for patients (pg. 24). Another study from the Yale 

School of Environment investigates how to capture energy from biomass in 

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

Beyond academia, the promise of science can be pursued through 

entrepreneurship. Jonathan Rothberg, our alumni profile, describes his prolific 

career, founding numerous companies inspired by the ultimate goal of helping 

someone he loves (pg. 37). 

As technology becomes increasingly advanced, the ethical questions facing 

researchers with each successive discovery have never been more critical. For 

those at the forefront of artificial intelligence, should machines be held to a 

higher standard than humans in the context of, for example, accidents caused 

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

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

out diseases, to engineer in intelligence or physical traits? For those tackling 

aging, what are the implications of increasing human lifespan beyond several 

hundred years—would it broaden the distance between social classes; would it 

stagnate the innovations and perspectives of new generations? 

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

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

masthead, writers, artists, and the Yale science community. Like the amazing 

people behind the stories of the last calendar year, I hope to follow suit and 

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

these stories continue to inspire for years to come. 

About the Art 

Jenny Tan, Editor-in-Chief 

Treating cardiac disease, developing 

pharmaceutical drug candidates, 

quantifying greenhouse gas 

emissions: today’s growing 

medical, environmental, and 

scientific concerns look towards 

novel methods of research such 

as integrated machine learning, 

techno-economic analysis, and 

DNA nanotechnology. This issue’s 

cover reflects the wide array of 

research avenues that scientists take 

in order to solve our world’s most 

poignant problems. 

Anasthasia Shilov, Cover Artist 

MASTHEAD 

December 2022 VOL. 95 NO. 4 

EDITORIAL BOARD 

Editor-in-Chief 

Managing Editors 

News Editor 

Features Editor 

Special Sections Editor 

Articles Editor 

Online Editors 

Copy Editors 

Scope Editors 

Website Editor 

PRODUCTION & DESIGN 

Production Manager 

Layout Editors 

Art Editor 

Cover Artist 

Photography Editor 

BUSINESS 

Publisher 

Operations Manager 

Advertising Manager 

Subscriptions Manager 

OUTREACH 

Synapse Presidents 

Synapse Vice President 

Synapse Outreach Coordinators 

Synapse Events Coordinator 

WEB 

Web Managers 

Head of Social Media Team 

Social Media Coordinators 

STAFF 

William Archaki 

Riya Bhargava 

Matthew Blair 

Dinesh Bojja 

Dinara Bolat 

Wineth De Zoysa 

Mia Gawth 

Daniel Havlat 

Elisa Howard 

Eunsoo Hyun 

Sofia Jacobson 

Evelyn Jiang 

Maya Khurana 

Jenna Kim 

Jessica Le 

Ximena Leyva Peralta 

Cynthia Lin 

Crystal Liu 

Samantha Liu 

Yurou Liu 

Cindy Mei 

Kenna Morgan 

Nathan Mu 

Victor Nguyen 

Avi Patel 

Himani Pattisam 

Emily Poag 

Madeleine Popofsky 

Tony Potchernikov 

Yusuf Rasheed 

Jenny Tan 

Tai Michaels 

Maria Fernanda Pacheco 

Madison Houck 

Alex Dong 

Sophia Li 

Cindy Kuang 

Ethan Olim 

Tori Sodeinde 

Breanna Brownson 

Hannah Han 

Kayla Yup 

Anna Calame 

Hannah Huang 

Meili Gupta 

Catherine Zheng 

Ann-Marie Abunyewa 

Brianna Fernandez 

Malia Kuo 

Anasthasia Shilov 

Jenny Wong 

Jared Gould 

Lauren Chong 

Sophia Burick 

Shudipto Wahed 

Krishna Dasari 

Lucy Zha 

Rayyan Darji 

Hannah Barsouk 

Risha Chakraborty 

Bella Xiong 

Katherine Moon 

Emily Shang 

Anavi Uppal 

Abigail Jolteus 

Elizabeth Watson 

Anya Razmi 

Alex Roseman 

Noora Said 

Jamie Seu 

Rishi Shah 

Ishani Singh 

Kayla Sohn 

Yamato Takabe 

Kara Tao 

Robin Tsai 

Hanwen Zhang 

Lawrence Zhao 

Matthew Zoerb 

The Yale Scientific Magazine (YSM) is published four times a year by Yale 

Scientific Publications, Inc. Third class postage paid in New Haven, CT 

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

NEWS 

Gender Studies & Data Science / Computer Science & Law 

HIDDEN 

PANDEMIC 

BIG TECH IS 

ALWAYS 

WATCHING 

BY SOFIA JACOBSON 

BY ALEX DONG 

IMAGE COURTESY OF PIXABAY 

IMAGE COURTESY OF WIKIMEDIA COMMONS 

The pandemic drastically altered the daily tasks of many 

adults who, in addition to their everyday professions, 

took on new responsibilities in the home, including 

child and elder care. As many of these new duties fell mainly 

to women, associate research scientist Ji-Young Son and 

Professor of Environmental Health Michelle Bell launched a 

series of studies on how women and minority scientists were 

potentially disproportionately impacted by the pandemic. 

One study with the Yale School of Environment, supported 

by the Yale Women Faculty Forum, focused on gender 

disparities in submissions to academic science journals. 

The researchers hypothesized that the percentage of 

women scientists submitting articles would decrease during 

the pandemic. They found that there was actually an increase 

in women’s submissions compared to men. They examined 

99,114 submissions from January 2019 to July 2021. Of 

these, the corresponding authors were 82.1 percent male, 

17.8 percent female, and 0.1 percent nonbinary. Comparing 

the pre-pandemic time to the pandemic time, the percentage 

of women submitting slightly increased to 18.7 percent. 

However, the pandemic did have one notable effect on 

women’s submissions. “The rate of increase in submissions 

[by women] slowed during the pandemic compared to the 

pre-pandemic period,” Son said. 

There is still enormous gender disparity in the sciences. 

Although studies such as this one are bringing the issue to 

light, the problem continues—before, during, and after the 

COVID-19 pandemic. “More resources from universities, 

not [just] individual efforts, and other measures for women 

scientists are needed to promote equality,” Son said. ■ 

Have you ever read Facebook’s Terms of Service after 

downloading the app? Chances are, probably not. While 

we often mindlessly click ‘accept,’ big tech companies 

like Meta have been known to violate user privacy without 

their knowledge or consent. With the rapid rise of big tech, data 

privacy has increasingly become a concern for both individuals 

and regulatory organizations. 

In light of this issue, Adrian Kuenzler (YLS ’15), Assistant 

Professor of Law at Zurich University, presents a new framework 

for how competition between big tech companies can promote 

data privacy. Kuenzler’s research draws on a variety of legal 

investigations, empirical economic analyses, and cognitive 

science studies. He proposes a new way of protecting consumer 

interests by integrating three strategies typically used separately. 

Firstly, users should be able to choose between different 

platforms like Google Chrome and Safari to maintain consumer 

sovereignty. Next, different providers must be interoperable— 

switching platforms and migrating data must be practical. 

Finally, consumer input should be considered and used to 

improve existing services such as feature addition and product 

design. Taken together, these strategies promote consumer voice 

and choice, giving users more authority to prioritize data privacy. 

Authorities typically only use a single approach, often 

overlooking the convergence of the three strategies when 

remedying data privacy issues. “It doesn’t follow that we only 

need one account or that a certain regulatory scheme is always 

appropriate,” Kuenzler said. Ultimately, using the three strategies 

as complements rather than substitutes enables us to better 

navigate data privacy concerns and leads to more effective 

regulatory policy decisions. ■ 


Biology & Health / Environmental Science 

NEWS 

OPTIMISTIC 

RESULTS FOR 

RSV PREVENTION 

STRATEGIES 

FORECASTING 

EXTINCTION 

BY MADELEINE POPOFSKY 

BY EVELYN JIANG 

IMAGE COURTESY OF FLICKR 


Respiratory syncytial virus (RSV), a deadly respiratory virus, 

has swamped hospitals globally. “Most of the [Connecticut] 

hospitals are packed, and they need to build tents outside 

some hospitals to meet [the demand of] the children who are 

infected for RSV,” said Zhe Zheng, a PhD candidate at the Yale 

School of Public Health. Critically, the virus has no vaccine or 

other effective, widely accessible prevention method. 

However, Zheng’s analysis of clinical trial results for three 

prevention strategies in development proves there is hope 

ahead. First, extended half-life monoclonal antibodies, blood 

proteins that counteract pathogens, already have approval 

in the European Union but could take another year or two 

to be approved in the United States. The second, a maternal 

immunization, has promising clinical trial results but hasn’t 

yet been filed for approval. According to Zheng’s findings, each 

could avert more than half of RSV hospitalizations in children 

under six months. Live-attenuated vaccines proved highly 

effective for children between six months and five years, though 

they are still in the early stages of development. 

An important question Zheng shed light on relating to these 

prevention strategies involves the efficacy of seasonal versus 

yearly vaccination plans. While previously reliably seasonal, 

COVID has made RSV’s seasons irregular, in addition to 

differences between seasonality in northern and southern states. 

“A seasonal program may provide minor [cost] advantages 

over a year-round [program], but the year-round would 

cover more children,” Zheng said. Zheng’s research compares 

RSV prevention methods and discusses the best method of 

distribution—information that could relieve overwhelmed 

hospitals and save children’s lives. ■ 

While extinction is a natural phenomenon, human activity 

has accelerated the deterioration of ecosystems worldwide 

and driven an epidemic of species extinctions, leading 

growing numbers of scientists to search for ways to conserve the Earth’s 

existing natural resources for future generations. Geospatial analytical 

tools like range maps, which describe the geographic area a species is 

believed to inhabit, are essential resources for informed conservation 

planning. Researchers can use data from these maps to forecast future 

range dynamics to identify vulnerable “gaps” in protection, informing 

decision-making and conservation resource allocation. 

Traditional gap analyses tend to focus solely on threats 

to species’ range. However, a team of researchers led by 

Nyeema Harris, an associate professor at the Yale School of 

the Environment, has developed an innovative methodology 

that simultaneously analyzes positive conditions and threats to 

generate more comprehensive range maps. 

“We aggregated different layers. Some were threat layers that 

were detrimental to species’ range, and others were resource 

layers that were positive for promoting species conservation,” 

Harris said. “We overlapped these resources and threats to 

identify areas vulnerable to range contractions and that maybe 

aren’t receiving enough conservation and research efforts.” 

The researchers performed a gap analysis across the ranges of 

ninety-one African carnivores to determine whether existing 

and available conservation capacities are sufficient. The team 

assessed factors like hunting pressures, drought vulnerability, 

cultural diversity, and protected area coverage. They found 

that, on average, fifteen percent of a species’ range was at risk of 

contraction. “We hope this analysis can be used to inform future 

conservation and research,” Harris said. ■ 



FOCUS 

Molecular Biology 

IT’S NOT 

ALL BAD 

Examining the role of H-NS 

protein degradation in the 

growth of good bacteria 

BY MATTHEW BLAIR 

IMAGE COURTESY OF ISTOCK 

There is a common misconception that all bacteria are bad 

bacteria. Perhaps this narrative is bolstered by the branding 

of disinfectants claiming to kill 99.9 percent of all viruses 

and bacteria or the cartoonishly frightening drawings on the 

walls of doctor’s offices. This generalization is simply untrue. 

Bacteria play a critical role in helping humans maintain a 

healthy gut. Our gut is an amalgamation of trillions of bacteria 

that form unique interactions and express various genes essential 

to their colonization of the gut. This bacterial colonization helps 

humans to maintain a balanced gut and, consequently, a healthy 

body. Already, questions abound. How do organisms “decide” 

which genes to express? Are there genes whose expression 

is more desirable than others? It is just these questions that 

Jeongjoon Choi, an associate research scientist in the Department 

of Genetics at the Yale School of Medicine, focused on answering. 

Specific genes are expressed when they receive the direction 

to do so from regulatory and signaling proteins. “But what I was 

kind of surprised by is even when you give such an inducing 

signal, some genes are not expressed under certain conditions,” 

Choi said. Interestingly, many unexpressed or silenced genes 

were of a specific variety: horizontally transferred genes 

(HTGs), also called foreign genes. HTGs are important as they 

drive bacterial evolution by introducing foreign DNA, and thus 

new traits, to the recipient organism. 

The silencing of foreign genes is done by the heat-stable 

nucleoid structuring protein (H-NS). Nucleoid structuring 

refers to how this protein upholds the basic structure of DNA. 

Building on this function, H-NS represses foreign genes by 

specifically binding to the corresponding DNA. In some 

instances, gene silencers like H-NS are beneficial. The laissezfaire 

expression of all foreign genes at once would be fatal. 

Unfortunately, however, H-NS can suppress the expression of 

important HTGs. For foreign genes to be expressed, they must 

overcome gene repression by the silencer H-NS. 

Choi’s study provides new insight into how organisms can 

overcome foreign gene repression by silencers such as H-NS. 

It has been a dogma in the field that H-NS amounts remain 

constant regardless of the conditions. Choi made the groundbreaking 

discovery that the abundance of H-NS varies in 

different conditions, such as acidic and neutral conditions. 

Additionally, in some conditions, H-NS is degraded. “Because 

H-NS amounts were believed to stay constant, overcoming 

foreign gene silencing was largely ascribed to anti-silencing 

proteins,” Choi said. Thanks to Choi’s research, there is a new 

understanding that both anti-silencing proteins and H-NS 

degradation work collaboratively to overcome gene silencing by 

H-NS and control foreign gene expression. 

The study focused on Escherichia coli, an example of a “good” 

type of bacteria. Choi found that for the E. coli to grow in the 

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

silencing effect of H-NS can be overcome in two steps. Firstly, 

the DNA binding regulatory protein PhoP—a protein impacting 

the expression of certain parts of DNA displaces H-NS, making 

it susceptible to degradation. Then, the protease Lon—an enzyme 

that breaks down proteins—targets specific regions of H-NS to 

degrade it. With H-NS degraded, E. coli can grow. 

“This is basic molecular biology, and I like basic science, but 

if the basic science wants to change the word, then we need to 

transfer it, making it more applicable for treatment or another 

purpose,” Choi said. The impacts of this finding are far-reaching, 

potentially changing how we address many ailments, from minor 

bacterial infections to tuberculosis. The possibilities of Choi’s 

discovery lie in the manipulation of H-NS. “By manipulating H-NS 

degradability, we can cause our bacteria, not our good bacteria but 

those big, bad bacteria, to be more susceptible to environmental 

changes. This will prevent harmful bacteria from causing much of 

a problem,” Choi said. This approach could work in tandem with 

antibiotics commonly prescribed to remove harmful bacteria. In 

cases of intense antibiotic resistance, H-NS manipulation could be 

the solution: where antibiotics do not work, causing the bacteria to 

be more vulnerable to the natural processes of our body can make 

these harmful bacteria unable to cause disease. 

Choi’s research done in the guts of mice can be extrapolated, with 

some caveats, to human health, making leaps in our understanding 

of how bacteria can be regulated and how we can work to maintain 

a healthy gut through the development of “good” bacteria. ■ 


Computer Science / Biology 

FOCUS 

THE CASE AGAINST 

INTELLIGENT 

COMPUTER VISION 

Neural networks are lagging behind 

human brains in visual perception 

BY SAMANTHA LIU 


Convolutional neural networks, or CNNs, are deep learning 

networks trained with millions of images. Designed to imitate 

primate brains, they proved highly adept at object recognition, 

sparking media excitement over the future of computer vision—the use 

of AI to interpret visual input. Moreover, researchers hoped CNNs could 

offer a shortcut to studying the primate brain. Rather than undertake 

copious MRI scans and patient trials, scientists could run a simulation 

through a CNN to predict how the human brain would respond. 

But the research of Yaoda Xu, a senior research scientist at Yale, 

proves otherwise. Ten years ago, when a perfect visual recognition 

system and its manifold implications—think! driverless cars!—loomed 

on the brink of discovery, those possibilities now seem distant as ever. 

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

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

maybe a primitive, overdeveloped, early visual area of the brain.” 

As her recent paper published in NeuroImage clarifies, where CNNs 

fail is in the realm of identifying transformation tolerant representations. 

The process sounds complex, but it’s something humans carry out every 

day: when a person walks toward a table and sees it enlarge in their field 

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

objects viewed from different perspectives or positions—even as altered 

representations, the brain maps them onto the same visual identity. 

This intuitive procedure proves much more challenging for neural 

networks. In her project, Xu took images of eight real-world objects, 

ranging from a pair of scissors to an elephant, and distorted them in 

various ways. Some she geometrically transformed, moving up and 

down or dilating on the page. Others she subjected to non-Euclidean 

transformations, changing the contrast and resolution. In each case, 

when tested on eight different CNNs, the neural networks showed 

weaker consistency and tolerance for these images. 

The implication is striking: a process trivial for primate brains 

remains elusive for the complex, pre-trained machines meant to 

model them. Xu attributes this discrepancy to the mechanics of 

human cognition versus machine learning. The primate brain 

processes visual information through two streams: dorsal, which 

recognizes the object’s spatial location (the “where”), and ventral, 


which recognizes the object’s identity (the “what”). Though 

seemingly redundant, the ability to identify the same object in 

different contexts arises from these two systems. 

The CNN, in contrast, employs a sub-optimal approach. “In 

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

memorizes each instance of each object it was exposed to, without 

making a connection among these different objects.” Scientists are 

unsure how this algorithm works precisely, thus creating a “black box.” 

But Xu is hopeful about cracking it—if only the scientific community 

reframes its approach. She plans to delve deeper into neuroscience 

research, seeing where and how primate vision diverges from neural 

networks, to shed light on the CNN algorithm and identify stages 

for improvement. Importantly, she believes the key lies in crafting 

a comprehensive biological understanding of vision rather than 

tackling the problem unilaterally through computer engineering. 

She compared this pursuit to trying to replicate flight: someone can 

blindly tweak the wing, fold a new flap, and throw everything against 

the wall until something flies or falls off a cliff. But someone can also 

investigate how flight works, learning the fundamental aerodynamics 

and physics which drive movement to find inspiration for an airplane. 

“What is vision trying to achieve? What is the problem you’re trying 

to solve?” Xu asked. She expressed aversion toward the trial-anderror 

experimentation employed by many computer science labs. “I’m 

showing you that, hey, this is the algorithm and computation that’s 

happening in the brain. If the system you’re building can have the same 

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

Xu looks towards a future where artificial networks could perfectly 

mimic human vision. She recalled how, as a student growing up in 

China, she spent entire weekends hand-washing her clothes. When 

the laundry machine mechanized the process, her free time could be 

put toward more valuable endeavors — like advancing her research 

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

some of our boring tasks can be done by a machine efficiently with 

this kind of visual intelligence, it could lead to another leap in human 

development. We could have the creativity to be who we want or to 

be the best version of ourselves.” ■ 


FOCUS 

Environmental Chemistry 

THE SOOT 

FACTOR 

Picking the sustainable 

jet fuel of the future 

BY WILLIAM ARCHACKI 


Next time you’re cruising at forty thousand feet in the 

air, think about how amazing it is that a few hundred 

tons of metal can whisk you between two distant cities 

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

it almost feels like magic. Behind that magic, though, lie many 

technological innovations—one of the most important being the 

jet fuel that keeps the engines running. 

Most aircraft engines today burn petroleum fuels that emit large 

volumes of carbon dioxide, the primary pollutant behind rising 

global temperatures. To reduce these emissions and make aviation 

more sustainable, biofuels may be a necessary replacement. Biofuels 

consume carbon dioxide from the atmosphere in production, 

balancing the amount they emit when burned. Because they 

have similar physical and chemical properties to petroleum fuels, 

biofuels could easily power existing jet engines. However, with 

thousands of possible biofuels competing for a single spot in 

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

necessary to consider a key piece of data: the soot factor. 

Soot is the black residue left behind by burnt organic matter. 

When dispersed in the atmosphere, it absorbs solar energy and 

contributes to climate change alongside carbon dioxide. Under 

some circumstances, it can even induce the growth of high-altitude 

cirrus clouds that absorb solar radiation more strongly than carbon 

dioxide. When inhaled, soot can lead to the development of heart 

disease and certain cancers, adding to the public health risk of air 

pollution. To minimize the burden of soot emissions on the climate 

and human health, researchers must select biofuels that burn 

without releasing harmful amounts of soot. 

In an effort to improve available data about soot emissions, the 

Pfefferle Lab Group at Yale developed a new method to measure 

a fuel’s “sooting tendency” and then examined two dozen biofuel 

candidates. Earlier techniques for calculating sooting tendency 

required researchers to burn large volumes of fuels to observe the 

complex properties of the flames. The Pfefferle group’s new method 

reduced the amount of fuel necessary to generate data. They opted 

to calculate sooting tendency by measuring the luminosity, or 

brightness, of the fuels’ flames when burning individual drops— 

the brighter the flame, the sootier the fuel. 

The biofuel candidates subjected to this new test all fall under 

the category of terpenes, which are combustible chemicals 

found in organisms ranging from redwood trees to algae. 

Charles McEnally, a chemical engineering research scientist at 

the Pfefferle lab, explained that terpenes are of special interest 

as candidates because of their diversity. 

“What’s interesting about terpenes is that the biochemistry that 

makes them is always the same, and the input molecule is always 

the same: its isoprene,” McEnally said. “Depending on exactly how 

the chemistry works, you can get an enormous number of different 

outputs. There are tens of thousands of terpenes that are known.” 

Out of the twenty-four terpene biofuels that the Pfefferle group tested, 

seven were produced through a process known as hydrogenation, in 

which the chemical structure is modified to include more hydrogen 

atoms and fewer double bonds. These hydrogenated options 

outperformed their unmodified competitors for soot reduction, 

posting lower numbers on the sooting index that the Pfefferle group 

developed. Hydrogenation—as well as other chemical processes that 

are broadly referred to as “upgrading”—have the potential to further 

improve the properties of biofuel candidates. 

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

limited to the molecules that are in petroleum. Almost certainly, out of 

all of organic chemistry, there are other molecules that will make better 

fuels than the ones that happen to be in petroleum,” McEnally said. 

In their paper regarding terpene biofuels, the authors note that 

large-scale production of terpenes could shift toward bioreactors in 

the future. By genetically engineering microorganisms like E. coli 

to synthesize terpenes in bioreactors, the aviation industry could 

find a path to a simple and sustainable fuel source. 

The Pfefferle group’s measurements for terpenes add to an evergrowing 

set of data about biofuel candidates. Their simplified method 

for determining sooting tendency provides a starting point for further 

research. With the group’s work, a biofuel alternative to petroleumbased 

jet fuel may eventually be what takes you to the skies. ■ 


Biochemistry 

FOCUS 

THE WINDING 

SYNTHETIC ROAD 

TO NEW 

ANTIBIOTICS 

BY NATHAN MU 

PHOTOGRAPHY BY MATTHEW ZOERB 

Since the very first use of antibiotics, researchers have known 

about antibiotic resistance in bacteria. However, it takes a 

large investment of time and resources to discover novel 

antibiotics, which must be made cheaply available for patients. 

Therefore, the pharmaceutical industry has turned away from 

antibiotic development due to the immense input required and 

limited opportunity for profit, allowing antibiotic resistance to rise 

and our ability to fight infections to fall. 

Olivia Goethe and Mikaela DiBello, former and current 

graduate student researchers in Professor Seth Herzon’s lab in 

the Yale Department of Chemistry, tackled this issue by seeking 

to create new antibiotics from one core molecule, pleuromutilin. 

Pleuromutilin is naturally produced by fungi, and its derivatives 

have been used clinically as antibiotics for skin infections and 

community-acquired pneumonia. Herzon’s lab has also previously 

worked with pleuromutilins. 

Their recent paper, published in Nature Chemistry, presents a 

new total synthesis pathway to create pleuromutilin derivatives. 

This pathway is an improvement upon Herzon’s previous method 

published in 2017, as well as pre-existing semisynthesis pathways, 

which rely on bacteria to synthesize products rather than commonly 

available chemical reagents. “Our [new] synthetic route can access 

[unique] chemical modifications, like changing functional groups 

and changing ring sizes. But through semisynthesis, you’re kind of 

blocked in. You can only modify the easily accessible functionality,” 

Goethe said. Essentially, this new pathway allows for infinite new 

pleuromutilin derivatives to be produced by changing, removing, and 

rearranging atoms in a way that other synthesis methods could not. 

This total synthesis pathway is a powerful tool for learning about the 

properties of various pleuromutilin derivatives. 

Another key advancement was the ability to produce pleuromutilin 

derivatives in higher yields. Having enough product is vital for testing 

antibiotic activity. Obtaining viable yields of products was not an easy 

process, however. Each step in the synthesis pathway must be executed 

properly to give the correct molecule with the correct orientation or 

stereochemistry. Otherwise, subsequent reactions will result in little 


to no yield of product. This was one of the most challenging parts 

of the research process. It took Goethe months of going through the 

available literature and experimenting with different reactions to 

obtain the desired product in a reaction that initially gave the wrong 

stereochemistry. “I had to have the right stereochemistry in order to 

make a usable amount of [the pleuromutilin derivative], which is why 

I definitely had to fix this, or I was screwed,” Goethe said. 

Out of all the pleuromutilin derivatives tested for antibiotic 

activity, many were surprisingly inactive, including many of the 

core derivatives proposed to improve metabolic stability, which 

would help the overall antibiotic effect. The most successful 

derivative contained a halogen, which was somewhat unexpected. 

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

really any indication that including a halogen there would be 

helpful,” Goethe said. Successful pleuromutilin antibiotics usually 

bind to sites on bacterial ribosomes, but the chloride group had an 

unexpected effect that is worth more exploration. Work can also be 

done to find more compounds and, eventually, test the stability of 

pleuromutilin antibiotics once they enter the body. “It seems like, 

to me, medical chemistry is just a numbers game. You just need to 

make a ton of compounds and study them to get trends. There’s a 

lot of interest in studying pleuromutilins, and we’re contributing to 

the information available about what we can do to this molecule,” 

Goethe said. Ideally, this research will lead to the straightforward 

synthesis of novel, cheap, and accessible antibiotics. 

Goethe found this research for her PhD to be extremely rewarding. 

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

hands from stock materials can be used to kill bacteria,” Goethe 

said. Now, Goethe works at Gilead Sciences, a biopharmaceutical 

company. She works in process chemistry, preparing materials for 

clinical phase trials, which test previously experimental treatments 

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

that I’ll combine the experience that I get here [at Gilead] in drug 

development with the passion I had for antibiotics, and maybe once 

I get a couple of years of experience, I can help antibiotic companies 

actually start to make some more drugs,” Goethe said. ■ 


FOCUS 

Robotic Engineering 

TURTLE 

TRANSFORMERS 

Reshapeable multienvironment 

robots and 

the future of soft robotics 

BY RIYA BHARGAVA 

IMAGE COURTESY OF JOKO DIAZ 

Pictured above is a baby leatherback turtle, a deep-diving 

reptile that lives in the ocean for years but migrates to 

the land to lay eggs. Leatherbacks have sleek, paddlelike 

forelimbs to navigate the seas, claws to walk on sand, 

and a mosaic of breathable cartilage for a shell. Many such 

adaptations have made turtles the masters of their niche 

between the land and the sea for over 200 million years. 

Accordingly, when engineers Robert Baines and Sree Kalyan 

Patiballa sat down to ideate a multi-environment mobile robot, 

they drew inspiration from turtle body plans and kinematics 

and named their robot the Amphibious Turtle Robot, or ART. 

“The importance of the paper is that we are showcasing 

how you can have robots that have adaptive components— 

components that change shape, and how this design paradigm 

can improve their efficiency and effectiveness,” says Baines, a 

PhD student researcher in Rebecca Kramer-Bottiglio’s lab at 

Yale, describing the lab’s recent Nature publication. ART is a 

quadruped with a streamlined shell, weighs nine kilograms, 

and has a body amalgamating soft materials that respond to 

external stimuli and traditional, rigid robotics components. 

The most remarkable feature of the robot is its morphing 

limbs that undergo adaptive morphogenesis—the limbs can 

alter their gait or shape in response to a stimulus, adopting 

morphologic features that best suit aquatic and terrestrial 

locomotion. For example, the limbs can morph into the 

streamlined flippers of a sea turtle when in water and the 

columnar legs of a land-faring tortoise when walking. 

While rigid-bodied robots can be programmed to perform 

a single task efficiently, they do not afford the same body 

compliance needed to design bio-inspired robots with 

muscle-like actions. Soft materials also have move-andhold 

operability–these materials can retain changes in shape 

without the constant application of external force, enhancing 

the overall energy efficiency of the robot. 

The best metric for ART’s performance was the Cost of Transport 

(COT), which measures the effectiveness of robot locomotion in 

terms of energy efficiency. ART had a minimum COT of three and 

ten for aquatic and terrestrial locomotion, respectively–a number 

that equals or outperforms other famous unimodal quadrupeds 

like EPFL’s Cheetah Cub and the Titan V-III. 

However, many improvements must be made before the 

robot is put to commercial use, especially when it comes to 

untethering. “One of the things we’re moving forward with is 

putting additional sensors on the robot to understand how it’s 

moving in the environment,” Baines said. “This way, it would 

know, for example, if it were in choppy water or still water, or 

if it were going down a hill and stumbling versus being stable 

and standing on flat ground.” The lab is also working to find 

better gaits for the robot. 

Even with such challenges, Baines foresees several important 

applications of such robots in the near future. Robots such as 

ART can be used to monitor ecosystems less invasively. “Such 

a platform is unique because it is bio-inspired. It would have 

less disturbance on the environment and the animals living in 

it,” Baines said. Instead of using turbulent propellers, the turtle 

robot swims using streamlined flippers. This design paradigm 

also foreshadows advances in disaster relief distribution, 

security, and the study of animal locomotion physics. ■ 


Biology / Medicine 

FOCUS 

A NEW 

APPROACH TO 

CYSTIC FIBROSIS 

BY MATTHEW ZOERB 


The possibility of rewriting genetic code has given hope to 

the 35,000 Americans suffering from cystic fibrosis (CF). In 

individuals with CF, a mutated gene causes a specific protein 

called the cystic fibrosis transmembrane conductance regulator 

(CFTR) to malfunction, wreaking havoc on the respiratory system. 

In each breath, dust, allergens, and pathogens enter our lungs 

and become trapped in a thin layer of mucus. This mucus must be 

constantly replenished to clean our airways and digest food, but 

without the properly functioning CFTR protein, mucus becomes 

viscous and thick, trapping contaminants in the lungs. The 

symptoms of CF manifest as coughing fits, frequent lung infections, 

and other discomforts. However, with the advent of gene editing, 

there is hope for a treatment for CF and other genetic diseases. 

A recent study by Yale postdoctoral research fellow Alexandra 

Piotrowski-Daspit and Marie Egan, a professor at the Yale 

School of Medicine, investigated a novel gene editing approach 

to restore the function of the mutated CF gene in mice. They 

targeted a specific mutation, the F508del mutation, responsible 

for about ninety percent of CF cases. To edit the mutated gene, 

the researchers encapsulated peptide nucleic acids (PNAs) and 

an unmutated “donor” version of the CFTR gene into polymeric 

nanoparticles. PNAs are synthetic nucleic acids with a similar 

structure to DNA and the same complementary base pairs, which 

allow them to bind to target sites in genomic DNA. Once inside 

the cell, the PNA molecules form complexes around the mutated 

DNA, leveraging the cell’s natural repair mechanisms to insert 

the corrected sequence using the donor DNA as a template. 

There are several key differences between PNA and CRISPR/ 

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

genomic DNA, which reliably enables genetic modification, 

but may accidentally damage DNA in regions other than the 

target site. PNA-based editing reduces the possibility of offtarget 

effects by harnessing the cell’s existing, non-mutagenic 

repair mechanisms to incorporate the correct DNA sequence. 

This makes them an attractive choice since they reduce the 

likelihood of accidentally harming other systems in complex 

living organisms. 

The experiment demonstrated that gene editing has the 

potential to treat CF, which affects multiple organs throughout 

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

to effectively deliver gene editing agents systemically,” lead 

researcher Piotrowski-Daspit said. Even though the percent of 

cells edited in the treatment was less than the estimated five to 

fifteen percent needed to match healthy individuals, a partial 

restoration of function in the affected organs was observed 

without any off-target effects. 

Looking beyond the specific F508del mutation that served as 

the focus of this study, new PNAs will need to be synthesized 

to target other mutations responsible for CF, for which 

no treatments are currently available. Piotrowski-Daspit’s 

personal goal is to improve delivery efficiency and restore 

function to a higher percentage of cells. These advances may 

eventually translate into treatments that can cure CF and other 

genetic diseases in humans. ■ 



FOCUS 

Neuroscience 

RECODING IN 

THE BRAIN 

Applying A-to-I editing in human 

neurodevelopment and disease 

BY ELISA HOWARD 

The human brain is constantly recoding 

itself. Adenosine-to-inosine (A-to-I) 

editing, a form of RNA modification, 

occurs at more than one hundred million 

sites in the human transcriptome, diversifying 

RNA sequences of the human brain. 

In a recent paper published in Cell Reports, 

researchers at Icahn School of Medicine at 

Mount Sinai and the Yale School of Medicine 

investigated the spatiotemporal and genetic 

regulation of A-to-I editing over the course 

of human brain development. Their work 

catalogs A-to-I editing sites throughout 

human brain maturation, enhancing current 

understandings of neurodevelopment and 

underlying mechanisms of neurological 

diseases. “RNA editing is dysregulated in 

neurodevelopmental disorders,” said Winston 

Cuddleston, a PhD candidate at the Icahn 

School of Medicine and lead researcher 

of the study. “We are trying to get a better 

understanding of which RNA editing sites 

PHOTO COURTESY OF HANNAH HAN VIA WINSTON CUDDLESTON 

Postdoctoral fellow Winston Cuddleston, the 

first author of the paper published by the Breen 

Lab, poses for a photograph while running 

biocomputational analyses. 

are dynamically regulated across brain 

development to realize which cellular and 

molecular processes are being affected.” 

The Science of RNA Editing 

According to the central dogma of molecular 

biology, coined by biophysicist Francis Crick, 

the expression of protein-coding genes 

involves the flow of genetic information from 

DNA to RNA to protein. A gene’s DNA is 

copied into RNA through transcription, and 

that RNA specifies an amino acid sequence for 

protein synthesis in the translation process. 

In eukaryotes, primary RNA transcripts 

undergo diverse post-transcriptional 

modifications, resulting in mature RNA 

molecules prior to protein production. These 

modifications diversify the transcriptome, the 

collection of an organism’s RNA transcripts. 

A-to-I editing is a post-transcriptional 

modification involving adenosine conversion 

to inosine nucleosides. This conversion process 

is catalyzed by a family of enzymes called 

adenosine deaminase acting on RNA (ADAR) 

and occurs most prominently in the central 

nervous system (CNS). These modifications 

affect neuronal genes, including those involved 

in synaptic transmission and signaling. 

In protein-coding regions, A-to-I editing can 

result in amino acid substitutions at locations 

known as recoding sites. These recoding sites 

are necessary for normal neurodevelopment, 

given their involvement in modulating calcium 

permeability, desensitization recovery rates, 

and cytoskeletal organization at excitatory 

synapses, alongside other functions. 

Investigation of A-to-I Sites in the Brain 

Millions of individual A-to-I 

editing modifications have been 

found in humans—many in the brain. 

Nevertheless, according to this study’s senior 

author Michael Breen, assistant professor 

of psychiatry, genetics, and genomic 

sciences at Mount Sinai, only a small 

subset of these modifications appears 

to be functional. “Those sites that 

are functional have precise temporal 

patterns across time: their editing efficiency 

changes throughout age and development in 

the brain,” Breen said. 

Breen and colleagues took a systematic 

look at A-to-I editing sites across 

prenatal and postnatal stages of human 

brain maturation. The researchers 

collected RNA sequencing data from 

brain samples of the dorsolateral 

prefrontal cortex (DLPFC), cerebrum, 

and cerebellum. They also analyzed 

RNA-sequencing data from in vitro 

models of neuronal maturation, postmortem 

cortical samples from late stages of aging, and 

murine and non-human primate models of 

brain development. In doing so, the researchers 

collected brain RNA sequencing data covering 

the human lifespan. 

“RNA editing is dynamically 

regulated in the brain during 

aging, and this is a unique 

property of RNA editing in the 

brain compared to other tissues 

in the body,” Cuddleston said. In 

their paper, Breen, Cuddleston, and 


Neuroscience 

FOCUS 

colleagues provide an atlas of A-to-I 

sites that are spatiotemporally and 

genetically regulated throughout brain 

maturation while uncovering key features of 

RNA editing throughout neurodevelopment. 

In particular, A-to-I editing is enriched in 

repetitive sequences known as Alu elements. 

Using an Alu editing index (AEI) to quantify 

modification levels, Breen and fellow 

researchers observed that global Alu editing 

steadily increases across all stages of brain 

development and neuronal maturation. This 

editing peaks around thirty to fifty-nine years 

of age, while advanced aging stages do not 

exhibit dynamic regulation. 

The researchers identified thousands of 

editing sites that are temporally regulated 

and increase in editing levels throughout 

neurodevelopment. The majority exist in the 

three prime untranslated regions (3' UTRs) 

of genes critical for neurodevelopment. 

The minority of spatiotemporally 

regulated editing sites exist within 

protein-coding regions, and thirtyseven 

RNA-recoding sites appear 

to change in editing levels 

across maturation. 

The researchers 

also describe trends 

in hyper-editing. As 

opposed to A-to-I 

editing at individual 

adenosine nucleosides, 

hyper-editing refers to 

modifying many adjacent adenosines along 

an extended region. The results indicate that 

hyper-editing is enriched in advanced stages 

of aging with the function of stabilizing RNA 

secondary structures. 

A-to-I Editing in Neurodevelopmental 

Disorders 

Editing rates increase globally throughout 

brain development. “Global increase is 

dynamic in different neurological diseases, 

so it could be looked at as a predictor of 

brain health,” Breen said. The researchers 

asked whether sites displaying increased 

editing throughout brain development 

are affected in neurodevelopmental 

disorders. Their results suggest that 

A-to-I sites disrupted in postmortem 

brain tissue from individuals with 

schizophrenia and autism spectrum 

disorder are temporally regulated, 

exhibiting an increase in editing levels 


PHOTO COURTESY OF HANNAH HAN VIA MICHAEL BREEN 

The Breen Lab, headed by principal investigator 

Michael Breen at the Icahn School of Mount Sinai, 

poses for a photograph on a rooftop at sunset. 

across maturation. “Knowing what we think 

these sites do in typical brain development, 

[i.e.,] modulating the ability of micro-RNAs to 

regulate host gene expression, and that these 

sites are disrupted in neurodevelopmental 

diseases gives an immediate avenue towards 

trying to understand what these sites might be 

doing in these disorders,” Breen said. 

Recoding sites where A-to-I editing results 

in amino acid substitutions provide further 

insight into neurodevelopmental diseases. “A 

handful of recoding sites have been described 

as dynamically regulated in Alzheimer’s, 

schizophrenia, and other neurological 

disorders,” Breen said. “We know that these 

sites are important for synaptic transmission, 

and their editing efficiencies are altered in 

these different diseased states.” 

Additionally, hyper-editing data enhances 

the current understanding of the aging brain. 

Only a handful of prior studies investigate 

RNA hyper-editing, and none consider the 

developmental regulation of hyper-editing 

in the brain. Breen and fellow researchers 

discovered that hyper-editing increases in the 

aging brain and appears to affect transcript 

stability rather than directly regulating gene 

ABOUT THE AUTHOR 

expression. Considering all study datasets, 

the normalized hyper-editing signal steadily 

rises across brain development periods and 

peaks into advanced aging stages. “While 

site-selective editing peaks in terms of its 

rate of change in mid-fetal development, 

hyper-editing continues to accumulate all the 

way into advanced aging,” Cuddleston said. 

“This is really important for aging research.” 

RNA hyper-editing may provide insight 

into Alzheimer’s disease, for instance, which 

Cuddleston aims to investigate in the future. 

The Prospects of RNA Biology 

In Cell Reports, Breen and colleagues 

provide an atlas of spatiotemporally and 

genetically regulated A-to-I sites in the brain 

throughout human neurodevelopment while 

unearthing key features of RNA editing 

throughout the lifespan. These findings not 

only improve current understandings of 

human brain development at the RNA level 

but also provide an avenue for learning more 

about the foundations of neurodevelopmental 

disorders. “We know very little about RNA 

modifications and what those might mean 

for disease pathology,” Breen said. “We 

are just starting to paint that picture.” It is 

through understanding such diseases at 

the neurobiological level that progress can 

be made toward treatment development. 

“Understanding which RNA editing events 

are functionally relevant for disease is how we 

are going to get closer to therapeutics that we 

can use in the clinic,” Cuddleston said. 

With thousands of temporally regulated 

RNA editing sites, the brain is a fascinating 

organ of continual change. How is your 

brain recoding itself? ■ 

A R T B Y E V E L Y N J I A N G 

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

YSM, she researches axon regeneration using stimulated emission depletion (STED) microscopy in 

the Strittmatter Lab at the Yale School of Medicine. She is the Donor Outreach Coordinator for the 

American Red Cross at Yale, the Mentorship Chair for the Yale Neuroscience Education Undergraduate 

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

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

Connecticut Hospice. 

THE AUTHOR WOULD LIKE TO THANK Michael Breen and Winston Cuddleston for their time and 

enthusiasm about their research. 

FURTHER READING 

ELISA HOWARD 

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

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


FOCUS 

Chemistry / Pharmacology 

STREAMLINING 

THE SEARCH 

FOR NEW 

DRUGS 

Discovering promising molecules 

with antidepressant activity 

BY EMILY SHANG 

Have you ever wondered how scientists 

synthesize drugs? Everything, from 

the Advil you take to alleviate a 

headache to the Vitamin C gummies you eat 

to strengthen your immune system, needs 

to undergo rigorous scientific testing and 

scrutiny to ensure that it is safe for human 

consumption. The process of efficiently finding 

and synthesizing drugs is especially challenging 

for those treating specific medical maladies 

since the drug’s functional mechanism must 

be investigated. Drugs often function by 

targeting specific receptors in our bodies and 

either block the effects of the receptor’s typical 

function (antagonism) or activate the receptor 

to create a response (agonism). 

The Challenge of Synthesizing Drugs 

that designing a drug that is specific, effective, 

and safe is no easy task: it’s why the research 

and development process, not to mention the 

process of clinical trials and safety testing, is so 

long and arduous. 

But recently, in a collaboration between 

the Ellman Lab at Yale University, the Irwin 

and Shoichet Labs at the University of 

California San Francisco, the Wetsel Lab at 

Duke University, the Skiniotis Lab at Stanford 

University, and the Roth Lab at the University 

of North Carolina, researchers have been able 

to use a novel virtual screening technique 

to streamline the beginning stages of drug 

discovery by finding promising molecules that 

bind potently and selectively to the 5-HT 2A 

receptor. This receptor is a serotonin receptor 

involved in producing both the negative 

(hallucinations, delusions) and positive effects 

(alleviation of anxiety, depression) of the 

psychedelic drug lysergic acid diethylamide 

(LSD) and its affiliates in the brain. 

When synthesizing new drugs, researchers 

have a lot of metrics to satisfy and a lot of 

factors to consider. First, the specificity and 

favorability of the drug to the drug target: are 

the pieces of the receptor and drug compatible, 

and is there a possibility for off-target binding? 

Second, the size of the drug: will its molecular 

weight hinder its ability to get where it needs to 

be in the body? Third, the molecular kinetics of 

the drug: how many of the bonds are rotatable, 

and how stable and likely is the conformation 

it takes on to bind the receptor? It’s no secret 

PHOTOGRAPHY BY EMILY POAG 

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


Chemistry / Pharmacology 

FOCUS 

The virtual screening process started with a 

broad analysis of the commonalities between 

the chemical structures of a variety of FDAapproved 

drugs. Researchers found that the 

most often-observed structures included 

the six-membered nitrogen heterocycles 

piperidine and pyridine. Thus, they began 

looking into using a virtual library technique 

to create a tetrahydropyridine (THP) drug, a 

much less investigated subclass of the kinds 

of structural molecules described above. 

This structure also produces some obstacles 

for synthesis, which made it an interesting 

candidate for virtual screening and analysis of 

molecular docking and binding. 

Creating a Database of THP Molecules 

Using the THP structure as a foundation, 

the researchers created a database of 75 

million THP molecules. The contents of this 

database were limited to synthetic chemistry 

techniques available to the Ellman Lab using 

three different types of starting materials: 

an amine, enal/enone, and alkyne. The 

researchers also implemented a molecular 

weight limit of 350 grams per mole to 

increase the likelihood that the compounds 

would have effective delivery in animals. 

They also considered a cationic property of 

the molecule that would help the molecule 

competitively bind to G-coupled protein 

receptors such as the 5-HT 2A 

receptor, as well 

as eliminate chiral starting materials that 

would have resulted in mixtures of THPs with 

different three-dimensional structures, for a 

simplified single-conformation output. 

Narrowing Down the Search 

These 75 million THP molecules were then 

pared down using computational molecular 

binding techniques. Since the structure 

of the 5-HT 2A 

receptor was unknown, the 

researchers composed one thousand models 

of the receptor bound to LSD in the hopes of 

analyzing the dynamics of the binding and 

finding a competitive molecule. Using this 

refined structure of the 5-HT 2A 

receptor, the 

binding of the 75 million THP molecules was 

evaluated, and thirty molecules were selected 

as most likely to bind to the receptor. From the 

thirty molecules, seventeen molecules were 

able to be synthesized using commercially 

available materials. Four of these molecules 

were identified to bind to 5HT 2A 

receptors, 

and two of these molecules exceeded preset 

binding thresholds in testing. Based upon 


the initial THPs that bound to the receptor, 

the team then designed, synthesized, and 

tested numerous additional analogs to obtain 

compounds that were potent and selective 

5-HT 2A 

receptor agonists. 

“While you can dock to predict binding, at 

this stage, you cannot predict if a compound 

is going to be an agonist or an antagonist. 

Virtual screening is just a foot in the door; 

afterwards, you really need chemistry for 

synthesizing a lot of compounds, testing a 

lot of compounds, critical analysis of data, 

and many iterations,” said Jonathan Ellman, 

principal investigator of the Ellman Lab. 

The 5-HT 2A 

receptor can undergo two 

different pathways once activated. The first 

is the beta arrestin pathway, which has been 

linked to undesired psychedelic effects, 

and the second is the G-protein mediated 

pathway. “Our molecules are more biased 

towards the G-protein mediated pathway, 

and we didn’t see the psychedelic effects,” 

James Kweon, one of the lead researchers 

from the Ellman group, explained. While 

it’s very hard to predict just by looking 

at a chemical structure which signaling 

pathway will be favored, the molecules 

synthesized by the Ellman Lab are able to 

bias the receptor towards the G-protein 

mediated pathway rather than the beta 

arrestin pathway, which can then separate 

the psychedelic function of the receptor 

from the antidepressant function. 

Looking Into the Future 

The next steps for the Ellman Lab and 

their collaborators include using the same 

virtual screening approach to find more 

complex molecules to selectively target 

a new receptor: this time, a pain receptor 

that is targeted by opioid drugs such as 

morphine. They hope to separate the harsh 

respiratory distress associated with opioid 

use by synthesizing a molecule with great 

IMAGE COURTESY OF CREATIVE COMMONS 

A schematic depicts the virtual screening process 

to look for promising molecules. 

functional selectivity that can separate 

these negative effects from the painrelieving 

positive effects. “We’re basically 

trying to demonstrate that virtual screening 

really can be used as a tool for even more 

complex molecules,” Kweon said. 

The kinds of molecules they’re synthesizing 

have a three-dimensional component which 

opens up more complex levels of docking 

analysis and will show that the technique 

of virtual screening is capable of taking on 

complex problems and solutions. Given its 

efficacy in successfully finding possible drug 

molecules fast, it’s likely this virtual screening 

technique will become increasingly important 

for the discovery of new drugs. ■ 

ABOUT THE AUTHOR EMILY SHANG 

EMILY SHANG is a sophomore in Timothy Dwight College studying Molecular Biophysics and 

Biochemistry. In addition to managing the website at YSM, she loves to play chess and perform research 

at the Yale School of Medicine. 

THE AUTHOR WOULD LIKE TO THANK Dr. Jonathan Ellman and James Kweon of the Ellman lab for 

their cooperation and contributions to this article. 


ART BY 

MALIA KUO 

Kaplan, A.L., Confair, D.N., Kim, K. et al. Bespoke library docking for 5-HT2A receptor agonists with 

antidepressant activity. Nature 610, 582–591 (2022). https://doi.org/10.1038/s41586-022-05258-z 


FOCUS 

Nanotechnology 

ON DEMAND 

MEMBRANE 

Using DNA nanostructures to understand and control the cell membrane 

BY RISHA CHAKRABORTY 

ART BY MALIA KUO 

Scientists learn more about the cell 

every day. From taking microscopic 

pictures to performing biochemical 

tests on pellets of harvested cells, biologists 

are able to determine the organization and 

interactions of major cellular components, 

including organelles, proteins, and nucleic 

acids. But understanding what these interactions 

look like in real-time is much more 

difficult than capturing fluorescent images, 

which offer a freeze-frame snapshot 

of the cell, and biochemical assays, which 

offer only a general understanding of molecular 

interactions but are often limited 

by the experimenter’s ability to manipulate 

the reacting biomolecules in space 

and time. In a recent article in Science Advances, 

Yale Professor of Cell Biology and 

Biomedical Engineering Chenxiang Lin 

and postdoctoral fellow Longfei Liu pioneer 

a unique way to study cell biology by 

harnessing the power of DNA as a molecule 

with a highly controllable structure to 

study the interactions of proteins and the 

cell membrane in real-time. 

Students typically learn that DNA is the 

genetic code of the cell, responsible for encoding 

the information eventually converted 

to the proteins responsible for cellular functions. 

But Lin offers an alternate perspective 

on DNA: that DNA itself has unique structural 

and chemical properties that can guide the 

assembly of other biomolecules and modulate 

how they interact. The DNA contained within 

our cells’ nuclei is in the traditional double-stranded 

helix because this conformation 

keeps DNA stable and relatively easy to 

transcribe. But scientists can now control the 

sequence of short single-stranded DNA molecules, 

called oligonucleotides, such that they 

spontaneously form nanoscale assemblages 

of precisely defined shapes. And because 

DNA oligonucleotides are easier to synthesize 

and chemically modify than molecules not 

found in nature or even proteins, they form 

nanostructures desirable for biochemical and 

biophysical experiments, where scientists 

want to study the finest details of molecular 

organization, dynamics, and function. The 

programmability and self-assembling nature 

of the DNA structures allow scientists to repeat 

such experiments many times and with 

all kinds of permutations. “This bottom-up 

approach is very powerful since all you need 

to do is design the DNA molecules correctly. 

The DNA strands can find each other and 

self-assemble into larger structures, with precise 

experimenter control.” Lin explained. 

History of DNA Nanotechnology 

According to Lin, the idea to use DNA as 

a structural macromolecule for more than 

IMAGES COURTESY OF FLICKR 



FOCUS 

just encoding genetic material harkens 

back forty years to New York University 

Professor Ned Seeman. Seeman imagined 

DNA nanostructures completely conceptually 

before creating them was even possible. 

DNA nanotechnology began to materialize 

upon creating a stable four-way 

DNA junction in a test tube resembling the 

Holliday junction, a somewhat complicated 

three-dimensional arrangement of single-stranded 

DNA pieces that forms during 

a type of DNA repair called homologous recombination. 

Scientists then began experimenting 

with combining multiple small, 

single-stranded DNA oligonucleotides into 

“tiles” and harnessing the symmetry of 

these tiles to build two-dimensional lattices 

or three-dimensional crystalline structures. 

In 2006, Paul Rothemund at the California 

Institute of Technology invented a new 

technology called DNA origami. He folded 

a single-stranded DNA extracted from 

viruses into shapes like smiley faces with 

the help of tens to hundreds of oligonucleotides. 

Importantly, these helper strands 

could each carry additional modifications 

to attach other molecules to the DNA origami 

structure at precise locations. 

Scientists sought to create domains in the 

DNA nanostructure that would change 

in conformation in response 

to some physiologically 

relevant signal, such as changes in 

pH, visible light, or UV radiation. These 

DNA nanostructures can mimic proteins 

to study how changes in these proteins’ 

structures would impact their biochemical 

activities. DNA structures containing 

regions of non-conventional motifs, such 

as four stacked cytidine bases (one of four 

nitrogen-containing cyclic molecules that 

comprise the inside of the DNA helix), 

change in conformation in acidic environments, 

which are characteristic of cancerous 

cells. Similarly, chemically joining an 

azo-benzene group (two hexagonal carbon 

rings connected by two nitrogen atoms) to 

the DNA backbone allows DNA to change 

conformation in response to a visible or UV 

light source. Such trigger-responsive DNA 

structures allow engineers to build nanorobots 

under users’ command by adding a 

drop of a chemical or simply by shining a 

light. This is also very useful for mimicking 

the dynamic activity of some proteins that 

act as enzymatic molecular switches. 

Studying Membrane Dynamics 

Unfortunately, while DNA nanotechnology 

has seen some traction in studying soluble, 

cytoplasmic proteins, proteins embedded 

in the cell’s 

membranes 

are harder to manipulate. Membrane 

proteins are crucial for many of the cell’s most 

basic functions, such as motion, regulating 

molecular traffic through the membrane, 

and interacting with pathogens, all of which 

require the membrane proteins to respond 

to changes in the membrane landscape and 

sometimes actively remodel the membrane. 

However, the membrane proteins are often 

involved in very complex interactions with 

lipids, other membrane proteins, and the cytoskeleton, 

scaffolding proteins that give cells 

their shape. Because this system is so complicated, 

Lin and Liu aimed to build a highly reductionist 

cell membrane model to contain 

only some features or proteins of interest. In 

their article, the proteins were foregone and 

replaced with mimics made of DNA. “These 

DNA structures were designed to look like 

a membrane-remodeling protein and work 

like one,” Lin said. “By tweaking them and 

observing how they behave on membrane, 

we may learn a thing or two about how the 

protein works in cells.” This system enabled 

them to study cell membranes as a platform 

and create artificial environments relevant to 

biological problems. 

One of the most important membrane 

dynamics researchers have attempted to 



FOCUS 


model is membrane 

tubulation, whereby 

one part of a membrane 

pokes out from an existing 

piece of a membrane but 

remains in close contact, essentially 

creating an extended “tube” of the membrane. 

This process is ubiquitous across 

the cell, involved in organelle and cell division, 

as well as packaging molecules for 

transport in membrane-enclosed vesicles. 

The interaction requires exquisite molecular 

machinery to change the membrane 

curvature and actually pinch the membrane 

destined to be separated from the 

old membrane (budding). 

Liu and Lin were able to understand the 

key factors required for membrane vesicle 

formation to occur using DNA nanostructures. 

The DNA nanostructures in their 

study mimicked the proteins that integrate 

into the membrane, contributing to membrane 

curvature. This allowed them to study 

the proteins’ properties and their effect 

on tubulation and vesiculation. The DNA 

nanostructures they integrated into their 

cell membrane model were initially set in an 

open state with high internal tension. Releasing 

such tension caused the DNA structures 

to buckle and adopt a closed, highly curved 

conformation (imagine a spring-loaded 

clamp). When they operated such DNA nano-clamps 

on the 

membrane, 

membranes 

were able to 

be curved, and 

many DNA-coated 

membrane tubes spontaneously 

emerged. However, 

fewer tubes were observed 

when the closed DNA 

clamps were less curved 

themselves. Moreover, releasing 

the DNA clamps from the 

high internal tension state seemed 

important for tubulation since preventing 

the DNA from changing from its initial state 

prevented the phenomenon. Interestingly, 

removing the DNA from membrane tubes 

led to vesiculation. Thus, Liu and Lin were 

able to deduce that the curvature of certain 

membrane proteins contributes to membrane 

curvature and that the ability of these 

proteins to switch conformation can release 

energy and act as a biophysical switch to determine 

whether the membrane could bud 

or not. 

Next Steps 

ABOUT THE 

AUTHOR 

Lin and Liu’s study was landmark in several 

ways. They were able to provide a proof 

of concept that the geometric properties of 

DNA nanostructures could act as a reliable 

substitute for the geometric properties of 

a membrane-bound protein and that tuning 

the mechanical properties of the DNA 

structures to modulate membrane dynamics 

could provide insights into how proteins 

impact membrane dynamics. “Membrane 

proteins are quite hard to manipulate. With 

DNA nanostructures, we can control the 

structure, shape, geometry, and modifications, 

which means we can do experiments 

in a more controlled way,” Liu said. Moreover, 

they were able to model membrane 

tube formation across multiple designs 

and experimental conditions—such as by 

varying the curvature and internal tension 

of the DNA clamps and changing the starting 

curvature of the membrane—and show 

that the curvature of the DNA nanostructure 

was the instigating factor in tubulation 

across these varying conditions. This 

highlights the unique advantages of using 

DNA nanostructures for such experiments. 

These nanostructures enable researchers 

to tune previously inaccessible parameters 

and ensure experiment reproducibility. 

However, both Lin and Liu expressed 

some caution about applying such conclusions 

definitively to the cells of living organisms. 

First, while DNA nanostructures 

may be used to structurally approximate 

proteins, key differences in the two classes 

of molecules’ stability, folding, and activity 

need to be accounted for when 

making conclusions about how 

proteins interact with membranes. 

Secondly, since the cellular models 

they employed were simplified, their conclusions 

from their experiments will probably 

need to be verified by studies 

in cells extracted from living 

organisms since membrane 

proteins in cells are engaged in 

many more 

interactions 

than the 

minimal set. 

Both researchers 

are embarking on new projects, 

including several in collaboration 

with Martin Schwartz, a Yale professor, 

to study how membrane proteins and the 

DNA structures that mimic them act on 

membranes with underlying cytoskeleton 

in major cellular processes. 

Lin and Liu aim to further investigate 

how external signals impact DNA nanostructures 

mimicking membrane proteins 

and how cellular processes are accordingly 

modulated. Eventually, they aim to harness 

the similarities between membrane proteins 

and DNA nanostructures to create a 

reliable cell model from scratch. “It would 

be very cool to build synthetic cells that 

would work similarly to naturally existing 

cells,” Lin said. With these headways in 

the field of DNA nanotechnology and cell 

biology, the scientific community is on its 

way to learning more about 

real-time cellular processes 

than ever 

before. ■ 

RISHA 

CHAKRABORTY 

RISHA CHAKRABORTY is a sophomore in Saybrook College majoring in Neuroscience and Chemistry. 

In addition to writing for YSM, Risha plays trumpet for the Yale Precision Marching Band, Yale Concert 

Band and La Orquesta Tertulia, volunteers for HAPPY (Hypertension Awareness and Prevention 

Program at Yale) and researches Parkinson’s Disease at Chandra Lab in the School of Medicine. She 

enjoys cracking jokes with her friends and taking Choco Pies from the Asian American Cultural Center. 

THE AUTHOR WOULD LIKE TO THANK Dr. Liu and Dr. Lin for their time and enthusiasm about their 

research. 


Liu L, Xiong Q, Xie C, Pincet F, Lin C. Actuating tension-loaded DNA clamps drives membrane tubulation. 

Science Advances. 2022;8(41). doi:10.1126/sciadv.add1830 


Environment 

FOCUS 

THE NEW 

CIRCULAR 

ECONOMY 


Bioenergy 

for a more 

sustainable 

and circular 

society 

BY ABIGAIL 

JOLTEUS 

ART BY 

KARA TAO 

Increased wildfires, heat, drought, 

and hurricanes are some of the 

devastating effects of climate 

change that continue to be seen 

across the world, and urgent action 

must be taken. To ensure that the Earth 

remains tolerable for humans to live on, 

environmentally friendly technologies 

are crucial. Over the past few years, 

there has been growing excitement about 

hydrogen fueling stations worldwide. 

The media portrays hydrogen fuel as a 

sustainable alternative to fossil fuels, with 

water being the only by-product. 

In reality, hydrogen fuels are usually 

generated using fossil fuels, emitting 

carbon dioxide (CO 2 

) as a by-product. 

Hydrogen comes from methods such as 

steam methane reforming, coal gasification, 

and electrolysis from electricity sources 

such as grid, solar, etc. Hydrogen fuel 

contributes to greenhouse gas emissions 

and, consequently, climate change. 

But if many methods to generate 

hydrogen fuel either directly or indirectly 

contribute to greenhouse gas emissions, 

what can we do to mitigate its impact on 

the climate? The answer lies in a process 

called bioenergy with carbon capture and 

storage (BECCS), which is the process 

of generating energy from biomass or 

organic matter while capturing and 

storing the CO2 emitted and providing 

net negative greenhouse gas emissions. 

In previous studies, methods such 

as techno-economic analysis (TEA) 

and life cycle assessment (LCA) were 

used to assess the economic feasibility 

and environmental impacts of BECCS. 

However, these studies did not consider 

the effect of the choice of energy supply. 

Moreover, previous studies rarely 

explored categories beyond climate 

impact, such as a broader range of impact 

indicators (e.g., human health impacts) of 

hydrogen as a fuel. In order to maximize 

the potential of BECCS, a holistic 

understanding of the effect of energy 

supply strategies and the implementation 

of carbon capture is crucial. 



FOCUS 

Environment 

Researchers at the Center for 

Industrial Ecology at the Yale School 

of Environment wanted to assess the 

efficiency and impact of BECCS. “The 

basic idea is to evaluate the economic 

feasibility and environmental impacts of 

emerging biotechnologies,” said Na Wu, 

a postdoctoral researcher in the Yao Lab. 

To assess its impacts, the researchers 

developed the techno-economicenvironmental 

assessment (TEES) 

framework–a method to evaluate the 

environmental and economic impacts of 

BECCS and other similar carbon capture 

technologies. This framework incorporates 

methods used in previous studies, such 

as TEA and LCA, but also simulations 

of implementing BECCS with different 

possible conditions for the biorefinery, the 

facility that converts biomass to energy. 

How It Works 

This study assessed gasification-based 

BECCS, using leftover wood scraps and 

branches from logging, called forest 

residues, as a source of biomass for gas 

conversion. Their analysis focused on 

forest residues from the Pacific Northwest, 

specifically the Douglas fir and ponderosa 

pine, because there is a large amount of 

biomass present in the region, and due to 

wildfires, there is a need to thin the forests. 

This assessment was conducted using the 

TEES framework and is novel because it 

is an integrated model addressing the 

knowledge gaps of the biorefinery with 

all carbon dioxide emission sources. 

These simulation models integrate 

energy supply strategies while also 

taking into consideration the realworld 

application of these models. 

“We tried to maximize the carbon 

c a p t u r e 

a n d 

storage process using our simulation 

models and integrate that with energy 

supply strategies,” Wu said. 

In order to simulate real-life scenarios, 

the researchers used a system with 

various components to measure and 

calibrate different options. They modeled 

eight biorefinery processes to determine 

which scenario is the most economically 

and environmentally feasible. These 

components include biomass preparation 

(such as size reduction and drying), 

gasification, cleaning syngas (a mixture of 

hydrogen and carbon monoxide), watergas 

shifting, carbon capture, pressure swing 

adsorption, air separation, and heat power 

generation. This was used to simulate the 

conditions required to produce syngas 

from biomass. Additionally, they modeled 

the three main stages of carbon capture: 

capturing the CO 2 

, transporting it, and 

then storing it deep underground. As the 

amount of biomass can affect the method’s 

perceived efficiency, different scales with 

different amounts of biomass were used. 

With the appropriate boundaries 

established, the researchers analyzed 

four different scenarios. 

Scenario one 

consists of 

burning the syngas produced to generate 

heat and power simultaneously, leading to 

electrical self-sufficiency while trapping 

carbon underground (carbon capture). 

Scenario two is similar to scenario one but 

with no carbon capture, which served as a 

baseline to understand the effect of carbon 

capture implementation. Scenario three 

includes the same components as scenario 

one but uses all the syngas products for 

hydrogen production, leading to partial 

electrical self-sufficiency. Scenario four 

includes carbon capture technology but 

does not use a combined heat and power 

generation plant, which makes it the least 

self-sufficient electricity scenario. 

The researchers decided which scenario 

was most favorable based on considerations 

such as the highest capital expenditure and 

operating expenditure. The most and least 

favorable scenarios varied depending on the 

type of expenditure examined. For instance, 

scenario one (fully self-sufficient) has the 

highest capital expenditure (CAPEX), 

whereas scenario two (no carbon capture) 

has the lowest CAPEX. This indicates that 

carbon capture requires 

a large amount 

of capital 

since scenario 

two is the 

only scenario 

without carbon 

capture included. 

However, scenario 

four (least selfsufficient) 

has the highest 

yearly operating expenditure 

(OPEX), whereas scenario one (fully 


Environment 

FOCUS 

self-sufficient) has the lowest OPEX due to 

the lowest utilities needed as a result of the 

full electrical self-sufficiency. 

After calculating and analyzing the 

minimum selling price for hydrogen and 

carbon price for these four scenarios, they 

made two main conclusions. First, hydrogen 

derived from forest residues has the potential 

to achieve similar economic feasibility to 

current fossil fuel-based hydrogen with 

carbon capture. In fact, when the price of 

carbon dioxide is higher than $89 per ton 

of CO 2 

, all four scenarios become more 

economically attractive than the current 

fossil fuel-based hydrogen. However, the 

opposite—lower economic attractiveness 

when the price of CO 2 

is lower—also 

applies. This leads to the second conclusion, 

which is that CO 2 

prices help determine 

how economically competitive the three 

scenarios with carbon capture can be. 

To further analyze the effect of renewable 

energy, additional cases for scenarios 

one (fully electricity self-sufficient) and 

four (least electricity self-sufficient) were 

examined. Instead of using an electricity 

source from the current grid, solar and 

wind energy were used. The findings 

indicated that renewable energy sources 

make scenario four preferable to electricity 

self-sufficiency (scenario one). However, 

further research needs to be conducted to 

determine the optimal renewable energy 

design for BECCS. 

These findings suggest that using BECCS has 

lower environmental impacts than the current 

hydrogen production methods and highlight 

the need for individuals from various sectors, 

including chemistry, analytics, business, 

engineering, and more, to successfully 

implement this biotechnology approach. 

Limitations 

There is no denying that BECCS has 

an immense amount of potential to be an 

excellent environmental solution, but it is 

important to acknowledge certain limitations 

in this study. The study did not include CO 2 

transportation and storage or hydrogen 

transportation in its model. Moreover, the 

study focused on the Pacific Northwest of 

the United States, which is only one small 

region in the world. Similar studies must be 

conducted in other regions to determine if 

this technology is economically feasible and 

has reduced environmental impacts. 


A shell gas station that sells premium gasoline fuel. 

Implications and Next Steps 

Looking towards the future, BECCS could 

be used in other waste feedstocks beyond 

forest residues to sustainably provide energy, 

such as animal wastes, food wastes, etc. This 

could be used to reform the agricultural 

industry, which is responsible for much of 

global greenhouse gas emissions. 

The findings from this study can help 

inform further research on other types 

of carbon capture and storage. Looking 

ahead, Wu wants to expand their study 

of carbon capture technologies to assess 

their economic and environmental impact. 

“BECCS is a chemical-based process, but 

there are more natural methods for carbon 

capture and storage, such as afforestation 

and reforestation, enhanced weathering, 

and biochar and soil carbon sequestration,” 

Wu said. Afforestation and reforestation 

rely on trees, enhanced weathering relies 



on rocks, and biochar and soil carbon 

sequestration rely on the soil (after CO 2 

is transformed into more stable carbon). 

“The next project I am working on is 

analyzing enhanced weathering carbon 

capture—using rocks to capture CO 2 

in the 

atmosphere. We are trying to explore the 

different possibilities,” Wu said. 

“We can help in the decision-making of 

various parties, such as researchers working 

in the lab, and we can also provide insights 

to companies. For instance, we can explain 

if it’s a good investment by determining if it 

is profitable, and we can also provide insights 

to the environmental authorities,” Wu said. 

One thing is clear: an interdisciplinary team 

is necessary to create a more sustainable, 

low-carbon, and circular society. “We 

need different kinds of parties: authorities, 

companies, chemists, engineers, business 

people, etc. In that way, we can make sure we 

are heading in the right direction,” Wu said. ■ 

ABIGAIL JOLTEUS 

ABIGAIL JOLTEUS is a sophomore in Berkeley College studying Ecology and Evolutionary Biology. In 

addition to writing for YSM, she is the web manager. Outside of YSM, Jolteus conducts research at 

Yale’s School of Medicine. 

THE AUTHOR WOULD LIKE TO THANK Dr. Na Wu for her time and enthusiasm about her research. 


Wu, N., Lan, K., & Yao, Y. (2023). An integrated techno-economic and environmental assessment 

for carbon capture in hydrogen production by biomass gasification. Resources, Conservation and 

Recycling, 188, 106693. https://doi.org/10.1016/j.resconrec.2022.106693 

In-na, P., Sharp, E. B., Caldwell, G. S., Unthank, M. G., Perry, J. J., & Lee, J. G. M. (2022). Engineered living 

photosynthetic biocomposites for intensified biological carbon capture. Scientific Reports, 12(1). 

https://doi.org/10.1038/s41598-022-21686-3 

Nowotny, J., & Veziroglu, T. N. (2011). Impact of hydrogen on the environment. International Journal of 

Hydrogen Energy, 36(20), 13218–13224. https://doi.org/10.1016/j.ijhydene.2011.07.071 


FOCUS Lab Profile 

AI 

COMBINING AI AND 

MACHINE 

LEARNING 

WITH CARDIOVASCULAR 

HEALTH 

BY YUSUF RASHEED 

According to the CDC, one person 

dies every thirty-four seconds 

from cardiovascular disease in 

the United States. It is also the leading 

cause of death for men and women 

across the country, costing over $200 

billion annually. In 2020, around 697,000 

people in the United States died from 

cardiovascular disease, which accounted 

for twenty percent of all deaths that year. 

There are strong efforts worldwide in 

research and clinical care to improve the 

diagnosis and treatment of this disease, 

particularly at the Cardiovascular Data 

Science (CarDS) Lab at the Yale School 

of Medicine, which is tackling this 

issue through a creative intersection of 

computer science and patient data. 

The CarDS Lab aims to improve 

cardiovascular health using data-driven 

insights into how care is delivered 

to patients. This means they use 

technology—artificial 

intelligence (AI) 

with machine 

learning, for example—to augment our 

ability to diagnose and treat patients. For 

example, the lab has built AI models that 

can detect cardiac muscle dysfunction 

from electrocardiograms (EKG), which 

humans are unable to do. “The entire 

idea is to democratize the access to 

technology so that more people know 

they may have [cardiovascular disease] 

so that they can be referred to the health 

system for more advanced imaging,” said 

Yale University Assistant Professor of 

Cardiovascular Medicine Rohan Khera, 

who is the principal investigator of the 

lab. The group also works with national 

registries and datasets to define best 

methodological practices in conducting 

studies, evaluates healthcare policies and 

their association with cardiovascular 

health outcomes, and interprets clinical 

trial results personalized for individual 

patients. These goals are reflected in the 

structure of the lab, where members are 

part of a “core” or a specific aim within 

the lab’s overall goal. “Some folks work 

on natural language processing, some 

work on ECGs, some work on cardiac 

imaging, some are focused on EHR 

design, some are working on trials. 

People present from one theme to the 

others, so everybody can learn what 

the others are doing, but [they] tend to 

focus on their own domain. That’s been 

our key, to focus on building micro-labs 

within a large lab,” Khera said. 

Khera grew up in India, where he 

attended the All-India Institute of 

Medical Sciences for his medical 

training. He then had a variety of 

away rotations at several institutions, 

including Johns Hopkins University, the 

University of California, Los Angeles, 

and the University of Pennsylvania, 

where he gained broad exposure to basic 

translational and clinical research. This 

experience continued at the University 

of Iowa during his residency and at UT 

Southwestern for his fellowship. “When I 

graduated fellowship, I knew I was going 

to start a research program…It felt like 

there was a lot happening at [Yale]. It 

was very exciting how [Yale] had been 

at the cutting edge of health policy and 

outcomes research, so I came here to see 

if I could extend that further into more 

advanced data science,” Khera said. 

“That’s been our key, to 

within a large lab. 

focus on building micro-labs 

” 

24 Yale Scientific Magazine December 2022 www.yalescientific.org 

IMAGE COURTESY OF PNGNICE

Lab Profile 

FOCUS 

PHOTO COURTESY OF JENNA KIM VIA DR. KHERA'S TWITTER @ROHAN_KHERA 

Members of the CarDS Lab at the 2022 American Heart Association's Scientific Sessions in Chicago, IL 

these findings independently in the 

ACCORD BP trial. “The traditional 

interpretation of clinical trials does not 

necessarily inform us about whether a 

given treatment works for each patient… 

We’re interested in better understanding 

how the results of a study can be 

individualized for each unique patient 

in front of us at the clinic…We think 

that’s pretty interesting because not 

every patient should be treated in 

the same way. 

And that’s one 

step closer to 

more personalized 

cardiovascular 

care,” said 

Evangelos 

Oikonomou, 

a clinical fellow 

in cardiovascular 

medicine at Yale. 

Khera started his faculty position at 

Yale in July 2020, during the peak of the 

COVID-19 pandemic. “Everything was 

shut down, and there was a lot of time 

spent thinking how one would structure 

the lab when nobody’s around,” Khera 

said. He noted that there were fewer 

opportunities to meet new people who 

would be interested in the lab, so he 

spent the first several months of the lab’s 

inception exploring the Yale community. 

He credits the decision to run the lab 

virtually as one of the key reasons for its 

success, as people do not need to be in the 

same room all the timeNow, the CarDS 

lab has grown to over twenty people. 

Along this mission to integrate 

machine learning with cardiovascular 

health, the lab recently published a 

paper titled “Individualising intensive 

systolic blood pressure reduction in 

hypertension using computational trial 

phenomaps and machine learning: a 

post-hoc analysis of randomised clinical 

trials.” This study looked at two clinical 

trials, SPRINT and ACCORD BP, which 

each compared intensive versus standard 

blood pressure control treatment. Using 

a machine learning algorithm and a 

“phenomapping strategy,” which creates 

a network of all patients recruited in 

the trial to compare their phenotypes, 

they found that not every patient in the 


SPRINT trial benefitted to the same 

extent from the intensive blood pressure 

control treatment. In other words, the 

effect of the treatment seemed to vary 

across different types of patients. From 

these results, the lab was able to analyze 

a given patient’s key characteristics and 

can tell how likely that patient is to 

benefit from intensive blood pressure 

control treatment. They then validated 

PHOTO COURTESY OF JENNA KIM VIA 

DR. KHERA'S TWITTER @ROHAN_KHERA 

Veer Sangha, recipient of the Elizabeth Barrett- 

Connor Research Award, with PI Dr. Rohan Khera 

“We’re 

interested 

in better 

understanding 

how the results of a 

study can be individualized 

for each unique patient in 

front of us at the clinic… 

We think that’s pretty 

interesting because not 

every patient should be 

treated in the same way. 

” 

A second project that the lab has been 

working on is developing AI models to 

diagnose structural heart diseases from 

printed ECG scans. The focus on ECG 

comes from the fact that they are the 

most widely accessible and ubiquitous 

tool in the world to better understand a 

patient’s heart. However, physicians are 

only able to diagnose certain conditions 

and heart rhythm disorders from ECGs, 

creating the need for more expensive 

and harder-to-obtain screening tools for 

other heart conditions. 


FOCUS 

Lab Profile 

The goal of the project is to 

be able to diagnose these conditions from 

ECGs—leading this effort is Yale College 

senior Veer Sangha YC '23, who has 

recently received the Rhodes Scholarship 

for his work with the lab. “We have a large 

repository of patients at the hospital, so 

we have their ECGs, and we know which 

patient has which disease," Sangha said. 

"So we can train our deep learning models 

to be able to learn features in the ECG that 

are relevant to a certain class of disorders 

or a certain disorder that a patient may 

have. And it can learn these features that 

humans themselves cannot learn.” 

To make this further accessible for 

patients, Sangha developed the model 

so that it didn’t need to use the signal 

data from the ECGs, which is not always 

available at the point of care. Instead, the 

model can make these inferences from 

printed scans of an ECG, which are widely 

available to patients and their clinicians. 

For undergraduate students interested in 

joining the CarDS lab, Khera recommends 

using the lab’s website Contact page or 

reaching out to him directly. He also 

suggests that students who want to join 

should ideally be interested in health 

technology and its applications and have 

some coding experience. Finally, he enjoys 

having students who want to be part of 

the lab for a long period of time. “Those 

who engage for a longer time are always 

there in a community learning, adapting, 

and growing. The folks that have really 

developed their careers in the lab have 

been associated with us for a couple of 

years already now,” Khera said. 

You can learn more about the CarDS Lab 

at https://www.cards-lab.org/. ■ 

IMAGES COURTESY OF CARDS LAB WEBSITE 

Principal Investigator Dr. Rohan Khera (top) and members of the CarDS Lab 


YUSUF RASHEED 

YUSUF RASHEED hails from the Bay Area and is a sophomore in Trumbull College majoring in 

Biomedical Engineering. He has a deep interest in physician-patient relationships and how budding 

medical professionals can develop their soft skills during and after their education. He hopes to apply 

his experience in engineering to a clinial setting in the future by improving and personalizing patient 

care. Yusuf also believes in the power of writing to effect change at all levels, whether that's personally 

through a journal or publicly through the Yale Scientific Magazine. He encourages all interested 

students to get involved with the magazine and try their hand at writing an article. 

THE AUTHOR WOULD LIKE TO THANK Dr. Rohan Khera, Dr. Evangelos Oikonomou, and Veer 

Sangha for their valuable time and support for this article. 


THE STRENGTH 

OF WEAK TIES 

Sociology 

FEATURE 

IMAGE COURTESY OF PIXABAY 

BY EUNSOO HYUN 

ART BY KARA TAO 

CAN LINKEDIN ACQUAINTANCES HELP YOU FIND A NEW JOB? 

In 1973, American sociologist Mark Granovetter published a 

paper that fundamentally changed the field of sociology. The 

paper, titled “The Strength of Weak Ties,” theorized that weak 

ties (think casual acquaintances, friends-of-friends, and other 

arm’s-length relationships) help disseminate new information and 

provide more job opportunities than strong ties (such as close 

friends, family, or immediate coworkers). 

This phenomenon, which may seem counterintuitive at first 

glance, happens because weak ties—interpersonal relationships with 

fewer mutual connections—help expose people to new information 

and opportunities outside their immediate social bubble. “Weak ties 

tend to span a broader width of the overall social network of the 

labor market. Strong ties tend to be redundant because you have 

access to the same sort of resources, information, and so on,” said 

Karthik Rajkumar, an applied research scientist at LinkedIn. 

For Rajkumar, it was fascinating to see this correlation in action. 

As a graduate student applying to internships in 2019, he found 

himself sending out resume after resume, just hoping to hear back at 

all. (A familiar story to many readers, especially those now looking 

for jobs and summer opportunities!) “It really made me think: 

there’s so much more to the job market and the interview process 

than your resume and your credentials and your interviewing skills. 

There’s that personal touch—that connection, and that’s something 

I learned the hard way,” Rajkumar said. This prompted him to ask: 

what is the effect of social networks on job mobility? 

The term “job mobility” means that people in the labor market are 

able to move to new jobs when they want. “Job transmission” refers 

to job mobility as a result of connections made. “‘Job transmission’ 

is this idea that if I connected with you now, am I going to join your 

company a year down the line?” Rajkumar said. 

Rajkumar and his co-authors designed a study to test for a causal 

relationship between interpersonal ties and job mobility 

using five years of data from LinkedIn. Their new 

paper in Science, titled “A causal test of 

the strength 

of weak ties”, is the first to conduct a 

large-scale, 

experimental study of a causal— 

not just correlational— 

relationship between weak 

ties and employment. More 

specifically, the researchers 

used LinkedIn’s People 

You May Know (PYMK) 

algorithm, which recommends new 


connections for LinkedIn users to add to their networks. By adjusting 

the algorithm, the team randomly varied whether users got weak or 

strong tie recommendations in the PYMK section. The tie strength 

between two users was determined by the number of messages sent 

back and forth and the number of mutual connections they had. 

The results empirically validated the theory that weak ties cause 

increased job mobility. This discovery disproved the “paradox 

of weak ties,” identified by previous correlational studies that 

proposed strong ties as the agents behind job mobility. The overall 

relationship between tie strength, measured by the number of 

mutual friends, and job mobility was nonlinear, following an 

“inverted U-shape.” In other words, the weakest ties weren’t the best 

at increasing job mobility. Rather, moderately weak ties increased 

job mobility and job transmissions the most. The strongest ties 

affected job mobility the least. 

However, when they looked at the results according to 

interaction intensity (the number of messages exchanged) as the 

metric of tie strength, weak ties with low interaction were the most 

helpful. Interestingly, these results varied by job industry. Weak 

ties mattered most when applying to jobs in industries that rely on 

software, but strong ties still held sway in less digital industries. This 

difference may be due to the importance of up-to-date information 

in rapidly evolving industries like tech. “Weak ties are conduits for 

information. They’re very efficient in bridging these information 

gaps across vast corners of the social network,” Rajkumar said. 

So how has this discovery been applied to sites like LinkedIn? One 

example is the updated “People You May Know” section. Before, the 

PYMK page simply showed a list of connections. Now, LinkedIn 

separates these connections into categories—connections from the 

same school, company, industry, and so on. “A lot of times, I hear 

people say, oh, I would like to have weak ties, 

but you know—how would I approach a 

total stranger? It’s all about finding that 

commonality, whether it’s your professional 

interest or mutual connections,” 

Rajkumar said. 

The discovery of a causal 

relationship between 

weak ties and job mobility 

provides important insights 

for networks like LinkedIn 

as the labor market becomes 

increasingly digitized. ■ 


FEATURE 

Robotics 

AN UNEXPECTED MARRIAGE: 

ROBOT DRONES & FLOWER POWER 

SAVING KAUAI’S ENDANGERED PLANTS 

WITH A CLIFF SAMPLING DRONE 

BY CINDY MEI 

ART BY SOPHIA ZHAO 

Flying over the cliffs of Kauai, a drone known as the Mamba 

sweeps the area on a rescue mission, searching for valuable 

buds of life beyond normal reach. On these cliffs lie extremely 

rare plants, many only found in Kauai, and some the last of their 

kind. The Hawaiian island is home to 250 endemic flora species 

found exclusively on the island, ninety-seven percent of which are 

classified as endangered or extinct. Environmental hazards are 

increasing the extinction rate to five hundred times the expected 

rate without human interference. For years, botanists have braved 

Kauai’s cliffs and other hard-to-access locations in search of these 

critically endangered plants. However, the areas are extremely 

hazardous and are time-consuming and expensive to access. 

For years, drones have been a prominent tool in environmental 

conservation and monitoring in harsh environments, imaging across 

different wavelengths of light and identifying plant habitats and 

distributions. However, the development of drones to navigate and 

interact with dangerous and inaccessible environments is an entirely 

new innovation in this field. “What differentiates what we’re doing 

with drones is that we’re interacting directly with the environment,” 

said Hughes La Vigne, a PhD student of robotics engineering at the 

University of Sherbrooke and co-founder of Outreach Robotics. 

The company first took root following the creation of the DeLeaves 

sampling system, a device designed to collect branches from treetops 

and canopies. “The purpose of Outreach Robotics is to develop 

robotic tools that could help scientists working in conservation, 

reforestation, and other environmental purposes,” La Vigne said. 

Enter the Mamba, the first aerial system that can sample plants 

on cliffs and transport them to a safer place. With a grant from 

National Geographic, Outreach Robotics teamed up with Ben 

Nyberg, a PhD student at the University of Copenhagen and the 

drone coordinator of the National Tropical Botanical Garden 

(NTBG), a nonprofit organization dedicated to the conservation 

and restoration of tropical plants. The project, which was published 

in Scientific Reports this fall, spanned two years of prototyping, 

iterating, and testing amid disruptions from COVID-19. 

Throughout the design process, the team considered many factors 

to optimize and stabilize flight collections. The drone had to be able 

to endure windy conditions, collect samples quickly and gently, and 

navigate around unwelcoming terrain. The final system prototype 

utilized a suspended platform equipped with propellers that swung 

in a pendulum, reducing rigidity and allowing an extended reach 

from cliffsides, minimizing the potential for collisions. In addition, 

the Mamba had to be easy to use with minimal roboticist training. 

“When you’re developing tools that might have an impact on 

conservation or the environment, you want it to be used by people 

who are working in that field,” La Vigne said. 

The final design was tested in two field trials in late 2021 and 

early 2022, with La Vigne and fellow University of Sherbrooke 

researcher and Outreach Robotics co-founder Guillaume Charron 

teleoperating the Mamba from the ground. Following imaging 

and identification of plant species targets, the Mamba navigated 

to the sites with built-in global navigation systems. Using an active 

robotic arm wrist suspended by long, snaking cables beneath the 

drone, the Mamba was able to cut and recover eleven otherwise 

inaccessible samples of seeds and cuttings with minimal impact 

from five critically endangered plants on Kauai’s cliffs. These 

plants were then deposited at the NTBG, which used methods 

such as seed banking and ex situ cultivation to maintain growth. 

The final prototype of the Mamba was also time-efficient and 

could reach several sampling sites from one base station. 

Since then, some plants like the Lysimachia iniki have flourished 

in the NTBG nurseries, becoming the first recovered plants of 

their kind to do so in captivity, while others, like the Euphorbia 

eleanoriae, did not survive in the long run. L. iniki grew roots for 

the first time in captivity, bolstering the hope that the surviving 

single-population plants of Kauai will be able to regrow with the 

combined effort of the drones and conservation. In future projects, 

the Mamba will be taken to other islands of Hawaii, where ninety 

percent of flora is not found anywhere else on Earth, in its pursuit 

to save these rare plants. “This is what we dreamed about for the 

last two years or so when we saw that drones were being used to 

interact with the environment,” La Vigne said. “[NTBG] is doing an 

amazing job to preserve these endemic species, and our goal is to 

help them and continue to work with environmental scientists.” ■ 


ROBOTS 

Using AI and robots to optimize 

organic chemistry reactions 

vs 

Chemistry / Machine Learning 

HUMANS 

ORGANIC CHEMISTRY EDITION 

FEATURE 

BY ANYA RAZMI 


For thousands of years, human innovation has been defined 

by the creation of big tools: the wheel, the watch, the scythe. 

Only in the last two centuries have we begun to investigate the 

power of small tools: molecules. From synthetic dyes to life-saving 

medications, molecular toolmaking has the potential to solve some 

of society’s greatest technological challenges. 

But making molecules isn’t easy. The synthesis of small organic 

molecules usually requires very specific reaction conditions—a 

tailored combination of solvents, temperature, pressure, and 

catalysts—to maximize product yield. Knowing which conditions 

suit which reactions takes expertise, the kind of expertise that only 

organic chemists, after years of highly specialized study, possess. 

“Right now, molecule making is this very exclusive club that only 

a few of us can get into,” said Martin Burke, professor of chemistry 

at the University of Illinois at Urbana-Champaign. “We want to 

shatter those barriers and invite everyone into the molecule-making 

space.” A recent collaboration between Burke and his colleague 

Bartosz Grzybowski, Professor at the Polish Academy of Sciences, 

is working to achieve just that. The paper, titled “Closed-loop 

optimization of general reaction conditions for heteroaryl Suzuki- 

Miyaura coupling,” was published in Science in October. Together, 

the two teams of researchers searched for a way to optimize general 

conditions—conditions that, regardless of the building blocks 

used, maximize the final product of a reaction. In particular, 

they investigated Suzuki-Miyaura cross-coupling (SMC), the 

quintessential reaction for carbon-carbon bond formation. 

With so many factors affecting a reaction, finding the best 

combination to optimize yield is enormously challenging. “The 

haystack is astronomical,” Burke said. “It’s literally beyond the capacity 

of collective capability of our planet.” The researchers needed a way 

to shrink this haystack—to find a list of possibilities for general 

conditions, then test them as quickly and accurately as possible. 

The solution? Artificial intelligence and robots. 

At the Beckman Institute in Illinois, robots performed 530 

chemical reactions. Syringes, purification columns, and pipettes 

were connected by masses of tubing, all of which worked in sync 

to carry out experiments independent of human hands. It wasn’t 

humans typing in which conditions the robots should use, either— 

it was AI. Grzybowski and his colleagues developed a machine 

learning algorithm to instruct the robots on which conditions to test. 

The process was a closed loop: Once a reaction had been 

performed, the data was transferred to the AI. The algorithm then 

developed altered procedures and transferred them back to the 

robot, which performed the reaction again under this new set of 

conditions. Then the cycle repeated. 


“The AI was in Poland. The robots are in Illinois. The loop was 

happening across the world,” Burke said. 

Burke and his colleagues had tried defining general conditions 

before. In 2009, they published a paper in the Journal of the American 

Chemical Society which used human-guided experimentation to 

identify general reaction conditions for the SMC reaction. It was 

the best that humans could do, and it took six years. 

Within four months, artificial intelligence doubled their yield. 

The implications of this result are far-reaching. The scientists’ 

ultimate goal is a “plug-and-play” platform in which researchers 

can enter the desired function for a molecule and have robots 

create it for them. With this type of technology, the synthesis of 

organic molecules could be democratized, no longer limited to a 

small group of experts. Ideally, this platform would use a limited 

number of reactions—maybe even just one. 

“Right now, in chemistry, there are about fifty to one hundred 

thousand reaction types. And it all might be unnecessary, in some 

sense,” Grzybowski said. “Nature uses very few operations, but 

repeatedly, in an iterative fashion. The robots are trying to do 

exactly the same.” 

Part of the algorithm’s success hinged upon its ability to probe 

both negative and positive results. “The AI was learning not 

only what works, but also what doesn’t work,” Grzybowski said. 

“With failure, the robot learns. And then it finds the right path.” 

For this algorithm to succeed, 

negative results were 

just as important 

as positive ones. 

This is a notable 

departure 

from how the 

scientific field 

currently works: people 

don’t publish negative 

results. For Burke, this 

was an important lesson. 

“We don’t spend a lot of time 

trying to figure out why things 

fail,” Burke said. “We’re always trying 

to teach AI about how to do the things 

that we do. I think things just flipped. 

AI is teaching us something very 

important about how to do science. 

I feel like I learned something from 

AI, and that’s exciting.” ■ 


FEATURE 

Cell Biology 

GAMER NEURONS 

IN VITRO NEURONS PLAY A 

SIMULATED GAME OF PONG 

Our brains are a collection of 

billions of neurons, firing in 

synchrony to make up the 

complex organ that is our brain. But 

zooming in, what if we consider a small, 

isolated subset of cells? What might 

they be capable of? 

Neurons are unique cells in the body. 

Unlike other cells, which can simply 

maintain their functions isolated in a 

petri dish, neurons process information, 

meaning they need a stimulus that 

prompts them to act. This makes them 

both fascinating and difficult to study. 

Computational models have been used 

to study neural networks, but they are 

limited by the constraints of technology, 

which is no substitute for a biological 

system. To alleviate this concern, what 

if neural networks could be made from 

biological neurons in a petri dish? In 

their recent paper, Brett Kagan, his 

colleagues at Cortical Labs, and several 

university collaborators have set out 

to study the interface of biology and 

intelligence by exploring how biological 

neurons respond to electrophysiological 

input and feedback in vitro. 

The team’s research process started 

in 2019. However, the pandemic threw 

a wrench in their plans, especially 

with Australia’s strict lockdown 

procedures. “Fortunately, we were able 

to get exemptions to go to work because 

we were considered critical workers, 

being in a hospital setting. But it was 

incredibly different circumstances 

nonetheless, getting supplies in and all 

the basic little things that we used to 

take for granted,” Kagan said. Once the 

lab could work around the restrictions, 

the group hit the ground running, 

resuming their research skillfully and 

deliberately. Kagan and his colleagues 

adopted an approach called “agile 

science,” where they set up a series of 

small pilot experiments in tandem to 

see which conditions would be best for 

their cells. This allowed them to adjust 

their research environment as they went 

along and optimize their experiments 

throughout the process. By growing 

long-term cortical neurons that formed 

dense connections with supporting glial 

cells, Kagan and his colleagues were able 

to study the behavior and capabilities of 

these biological neurons in a petri dish. 

A silicon chip inside the dish 

stimulated the neurons to create a 

simulated Pong game-world, where 

a paddle is moved up and down the 

screen to block a ball from hitting the 

side. “We chose Pong because we wanted 

something [in] real time, simple to 

code for with a clear ‘win and/or lose’ 

condition—in this case, there was a really 

clear lose condition—and [something] 

recognizable to people. It’s actually the 

fiftieth anniversary of Pong [this year],” 


Cell Biology 

FEATURE 

Kagan said. Inputs from the silicon chip 

were delivered to a predefined sensory 

area of eight electrodes. These electrodes 

stimulated sensory neurons that then 

communicated with motor neurons also 

cultured in the dish. The researchers 

wanted to see if the motor neurons 

would learn to move the paddle and 

intercept the ball. Any time the neurons 

missed an interception, they would be 

stimulated randomly, while successfully 

intercepting the ball meant they would 

receive predictable stimulation. 

Why might random stimulation in 

response to error cause the neurons 

to learn to play the game? Kagan and 

his team used the idea behind the free 

energy principle, developed by Karl 

Friston, a collaborator on their paper, 

to inform their hypothesis. As Kagan 

explained, the free energy principle says 

that a system will minimize the surprise 

or uncertainty in its environment. 

“What we did was give the neuron 

feedback randomly if it got [the game] 

wrong. If the free energy principle is 

true, then the system should reorganize 

itself to minimize randomness,” Kagan 

said. This means that to minimize the 

amount of random stimulation they 

received, the in vitro neurons would 

need to learn to play the game. 

This learning could be done in one 

of two ways: either the neurons could 

create a model or a “belief system” so that 

the network can respond and match the 

model with the real world, or they could 

physically act upon their environment 

to change their surroundings. Kagan 

and his colleagues showed that in vitro 

neurons learned to move the paddle to 

play Pong, and biological neurons can 

thus be adaptive. “We found that these 

neurons want to act in a way that can 

minimize unpredictability, [and] we 

can see this by them learning to play 

Pong,” Kagan said. 

They also uncovered some interesting 

and unexpected findings. Kagan 

explained that one of the intriguing 

results of the paper was their data 

on information entropy, which is the 

amount of information conveyed in an 

event. “It was really exciting because 

it showed that the cultures were able 

to distinguish between internal and 

external noise,” Kagan said. Essentially, 

they showed that the neurons could 

determine the difference between 

information generated on their own and 

information from an outside source, 

highlighting the specificity with which 

the neurons can source the signals they 

receive. “[It] makes sense because I can 

distinguish between my thoughts and 

your words, so there must be a way to 

break that up. But to see that you’re 

getting one response for external noise 

and one response for internal noise was 

pretty exciting,” Kagan said. 

This system, which Kagan and 

colleagues aptly termed “DishBrain,” 

sits at the interface of neurobiology and 

computational technology. Short-term 

benefits of the system are numerous: 

drug discovery, disease modeling, and 

building a basic understanding of how 

neurons create intelligence. “All general 

intelligence that we have ever seen is 

biological—from flies to cats to humans,” 

Kagan said. Still, there are limits to 

biological neural networks. “This does 

not mean that you end up with a human 

in a dish. What it means is that neurons 

are this biomimetic material that can 

adapt to new information, so can you 

use it as an information processor,” 

Kagan said. “It offers us an ethically 

responsible way to move forward.” 

Though many questions remain, 

Kagan and his colleagues at Cortical 

Labs are looking forward to digging 

deeper into their work and making 

new, exciting findings. Now, they’re 

working on perfecting their research 

infrastructure, from creating new 

biological environments to advancing 

their technology. “We’re trying to improve 

what we call the wetware (the cells), the 

hardware, [and] the software. We’re 

starting to do some disease modeling and 

drug testing, and all of these options are 

super exciting,” Kagan said. While many 

questions remain, neurons are certainly 

firing at Cortical Labs to help uncover 

more answers. This exciting research is 

sure to produce more interesting data that 

will guide the field of neuroscience and 

biological intelligence in the future. ■ 

BY MAYA 

KHURANA 

ART BY 

MALIA KUO 



FEATURE 

Planetary Sciences 

CONAN THE BACTERIUM 

COULD THE WORLD’S TOUGHEST 

ORGANISM SURVIVE ON MARS? 

BY KAYLA YUP 

ART BY BREANNA 

BROWNSON 

Conan the Bacterium may be 

Earth’s most promising astronaut. 

Named the world’s “toughest 

organism,” Deinococcus radiodurans— 

nicknamed Conan—could survive for 

a whopping 280 million years if buried 

ten meters beneath the Martian surface. 

This resilience suggests that if life ever 

existed on Mars, it could still exist today. 

The surface of Mars is deeply frozen 

and extremely dry. The atmosphere 

contains almost no oxygen and is over 

one hundred times thinner than Earth’s. 

Any life form released on Mars would 

essentially be freeze-dried and exposed 

to intense radiation from the sun. But 

Conan regularly challenges known limits 

of survival. The microbe can be frozen, 

desiccated, and face intense radiation, yet 

still live to see another day. In a recent 

study led by Michael Daly, a professor 

of pathology at Uniformed Services 

University of the Health Sciences and 

a member of the National Academies 

Committee on Planetary Protection, 

Conan and five other organisms were 

tested for potential survivability on Mars. 

As missions to and from Mars reach 

fruition, worry over cross-contamination 

between planets is putting the spotlight on 

Conan and other hitchhiking microbes. 

Future manned missions would expose 

Mars to astronauts and their microbiomes, 

raising the concern that Earthen microbes 

could be released and contaminate 

Mars’ surface. Daly’s study examined 

six microbes found in the human gut: 

Conan the Bacterium, E. coli, three sporeforming 

Bacillus bacteria, and a strain 

of baker’s yeast called Saccharomyces 

cerevisiae. In this study, Conan and the 

baker’s yeast broke all previous radiation 

survival records, even when compared to 

Bacillus spores, which are renowned for 

their resistance. 

To simulate the conditions on 

Mars, all six organisms were first 

dried in a desiccation chamber 

for five days and then stored on 

dry ice. The frozen organisms 

were later placed in an irradiator 

and exposed to very large doses of 

ionizing radiation in the form of 

gamma rays and protons—imitating 

forms of radiation from the sun. 

When charged particles, including 

protons from the sun, approach Earth, 

our magnetic field deflects them, and our 

atmosphere blocks them. But Mars has no 

magnetosphere and virtually 

no atmosphere to protect 

itself: protons are free 

to crash into the 

Martian surface 

and generate 

additional 

gamma rays. 

This is why 

the most 

dangerous 

part of Mars 

is the top ten 

centimeters of the 

Martian surface— 

Conan could only 

survive that amount of 

ionizing radiation for about 

1.5 million years. Further below the 

surface, shielding can protect against main 

forms of ionizing radiation, leaving only 

t h e 

p l a n e t ’ s 

low natural 

background 

radiation, as 

it is on Earth. 

“The deeper you 

go [into Mars’ 

surface], the 

more likely it is 

that you will find 

the remnants of 

life,” Daly said. “The 

survivability of life is 

now greater than we had ever 

thought possible.” 

Conan’s mechanisms for survival 

have previously been characterized, but 


Planetary Sciences 

FEATURE 

not in the context of Mars. Past studies 

looked at radiation under Earthen 

conditions, representing a planet where 

life revolves around liquid water. The 

limits of ionizing radiation survival 

have traditionally been established by 

increasing doses of gamma radiation 

until the last viable microbe is dead. In 

decades past, Conan’s ‘survival limit’ 

was approximately 25,000 kGy of gamma 

radiation under aqueous conditions. The 

present study found that if first dried and 

then frozen into a dormant state, Conan 

could withstand a whopping 140,000 

kGy of gamma radiation. 

“In the past, folks and scientists 

considered the survivability of life on 

Mars to be on the order of perhaps 

millions of years,” Daly said. “But 

we now have the evidence to 

support that life, when dormant, 

could likely survive hundreds of 

millions of years.” 

There are two essential 

reasons for Conan’s extreme 

resistance to radiation: the 

hyperaccumulation of manganese 

antioxidants (Mn-antioxidants) 

coupled with polyploidy and 

the presence of multiple identical 

genomes. Mn-antioxidants protect 

proteins needed to rebuild DNA, and 

polyploidy provides the cell with backup 

genomes used in repair. 

Extremophiles like Conan accumulate 

Mn-antioxidants, which are small 

complexes that consist of manganous 

ions bound to a variety of common 

metabolites. Generally, the more Mnantioxidants 

accumulated in a cell, the 

greater the organism’s resistance to 

ionizing radiation. Ionizing radiation 

is a high-energy form of radiation that 

can strip electrons from water, forming 

unstable molecules called ‘reactive 

oxygen species’ (ROS). The most toxic 

ROS in irradiated cells is superoxide, 

which “fries” the proteome, Daly 

explained. The proteome is the organism’s 

set of proteins—including the molecular 

machinery required to reassemble DNA 

broken by radiation. Mn-antioxidants 

in Conan defend the proteome against 

ROS and thereby preserve the enzymes 

needed to rebuild its broken genomes 

after radiation. In contrast, cells like E. 

coli that lack this Mn-antioxidant defense 

lose the ability to reassemble DNA 

damaged by radiation. 

Manganese antioxidants do not prevent 

DNA damage caused by radiation— 

luckily, the second molecular trick in 

Conan’s tool kit is polyploidy. Polyploidy 

means that when one genome is damaged, 

other undamaged copies can be used to 

repair the broken one. Conan contains 

eight identical copies of its genome per 

cell. The team showed that the organisms 

with the greatest resistance to radiation 

are polyploid. E. coli and Bacillus spores 

typically have only one or two genome 

copies, while baker’s yeast has four copies. 

In Conan, the eight genome copies are 

linked together by interstrand crosslinks 

called Holliday junctions, further 

accelerating DNA repair. “When you get 

a double-strand break caused by radiation 

in the genome, then the repair templates 

for homologous recombination are never 

far away,” Daly said. 

The baker’s yeast strain studied is also 

a polyploid, but this fungus accumulates 

fewer Mn-antioxidants than Conan. By 

comparison, E. coli does not accumulate 

Mn-antioxidants and typically has only 

one or two copies of its genomes. While 

the Bacillus spores accumulate Mnantioxidants, 

they are merely haploids, 

containing only a single copy of the 

genome. In the end, the data showed 

that dried and frozen Conan would 

possibly survive 280 million years when 

buried ten meters below the Martian 

subsurface, the yeast would survive 

48 million years, E. coli would survive 

sixteen million years, and Bacillus 

spores would survive relatively less. 

The forthcoming ExoMars mission’s 

Rosalind Franklin rover plans to drill 

two meters below the surface of Mars and 

collect samples in search of life. While 

the surface of Mars has been frozen and 

desiccated for billions of years, Daly 

theorized that life could still exist not 

far beneath the surface. He explained 

that Mars’ lack of an atmosphere means 

IMAGE COURTESY OF DALY 

These Deinococcus bacteria were used in a new 

study that suggests that if there is or ever was life 

on Mars, it would still exist today. 

that meteorites regularly bombard 

the planet. Upon impact, frozen water 

beneath a crater will melt, and simple 

organic compounds delivered by some 

meteorites could fertilize and fuel 

cellular recovery. If this theory holds 

true, Conan could have a Martian 

doppelganger out there to challenge its 

title as the world’s toughest organism. 

Article IX of the Outer Space Treaty (OST) 

of 1967 is an international agreement aimed 

at preventing harmful cross-contamination 

in the exploration of life across celestial 

bodies. While Conan’s survivability 

suggests that forward-contamination of 

Mars would be essentially permanent over 

mission time-frames of thousands of years, 

this would not be considered harmful under 

the OST because the organisms cannot 

proliferate when frozen and desiccated. 

Harmful backward contamination from 

Mars to Earth is also unlikely because if 

life ever evolved on Mars, it would now 

be anaerobic—able to survive without 

oxygen—and susceptible to the toxic effects 

of Earth’s oxygen-rich atmosphere. 

“It is not considered harmful 

contamination unless these organisms 

were dispersed across the planet and 

somehow found some warmth and water,” 

Daly explained. “There are good reasons 

to think that we can explore the surfaces 

of Mars without harming the science that 

is dedicated to looking for the possibility 

of extraterrestrial life. One can speculate 

that Martian life, if it ever existed there, 

still exists below the surface.” ■ 



FEATURE 

Chemistry 

THE GOLDEN 

Whether you're cooking a meal 

or mixing a drink, chances are 

that you taste your creation 

to figure out if it's right or not. Maybe 

there's too much sugar in the lemonade, 

or your tomato sauce isn't cooked enough, 

or your stir-fry needs more salt. Our 

senses have always helped us decode the 

mysteries of what we eat and drink. But 

now, we can also use chemistry to figure 

out when our favorite refreshments are 

perfect to consume. Researchers from 

the University of Glasgow and the Scotch 

Whisky Research Institute have recently 

designed a way to determine the flavor 

maturity of whiskey by using gold. 

After whiskey is distilled, it is stored for 

years in charred wooden casks to gain its 

characteristic flavor and amber color. The 

type of cask used for whiskey storage and 

the duration of aging can dramatically 

change its flavor profile. This flavor comes 

from chemicals called congeners that the 

whiskey absorbs from its wooden cask. 

Traditionally, casks of whiskey must be 

constantly sampled by a master blender, 

who determines if the flavor is just 

right. Since there are often hundreds or 

thousands of casks to sample, each taking 

so long to age, whiskey distillers are very 

interested in developing a quicker way to 

assess the maturity of their products. 

William Peveler, a chemist at the 

University of Glasgow in Scotland, first 

came across the science of whiskey when 

he saw a related infographic in Chemical 

& Engineering News magazine. He noticed 

that some of whiskey's chemical structures 

looked similar to the chemicals he worked 

with during his doctoral studies, which 

focused on creating gold nanoparticles. 

He wondered if whiskey could also be 

used to make these nanoparticles, and 

his team tested the hypothesis by using 

a cheap supermarket-brand whiskey in 

their lab. "And it did work, which was 

surprising since things don't always do 

that!" Peveler joked. 

The researchers found that the qualities 

of gold nanoparticles that form in 

different types of whiskey can 

reveal how long it has been 

aged. Their analysis involves 

taking just fifty microliters 

of whiskey—the equivalent of 

one droplet—and mixing in the 

same amount of gold salt. The 

flavor congeners in the whiskey 

reduce the gold salt into gold 

nanoparticles and stabilize 

them against growing any 

larger than a few hundred 

nanometers. These 

particles are so tiny that 

they can’t be seen by the 

naked eye. However, they 

do give the whiskey a visibly 

different color because 

gold nanoparticles absorb 

light very strongly compared 

to many other materials. Gold 

nanoparticles typically absorb 

green wavelengths of light the 

strongest. This means that we 

don’t usually see green light from 

gold nanoparticles—rather, we perceive 

the gold nanoparticles as different tones 

of pink, red, or purple. After just fifteen 

minutes, the final color of the sample 

reveals how aged or flavorful the whiskey 

is. Whiskeys with more flavor congeners 

generally produce more nanoparticles, 

giving the sample a more intense color. 

The researchers' use of gold might 

strike some as strange. "Of course, you 

use gold, and everyone goes, 'Well, gold's 

really expensive. Why are you using 

gold?'" Peveler said. Peveler's group also 

explored using silver for their study since 

silver is cheaper and its nanoparticles 

absorb light even more strongly than gold 

nanoparticles. However, the composition 

of silver is 

different, and the 

researchers found that 

the chemistry of whiskey 

wasn't powerful enough to 

reduce silver into satisfactory 

amounts of nanoparticles. The 

color of the whiskey and silver mixture 

did change, but it took hours or days for 

the reaction to become visible, so Peveler's 

team stuck with gold. And surprisingly, 


Chemistry 

FEATURE 

BY ANAVI UPPAL 

ART BY NOORA SAID 

STANDARD 

t h e gold they used wasn't that 

expensive: the amount 

of gold needed for each 

whiskey test is much less 

than one cent. 

In their research lab, 

Peveler and his team used 

a spectral photometer 

worth thousands of 

dollars to analyze the 

exact colors of these 

whiskey mixtures. 

This instrument 

looks at light on 

a wavelengthby-wavelength 

basis to see 

how much of 

each color 

the whiskey 

absorbs. 

H o w e v e r, 

i t ' s 

possible 

to create a much cheaper version of this 

device that whiskey distillers could use to 

quickly and inexpensively test their own 

samples in-house. This device would use a 

diffraction grating, a clear piece of plastic 

or glass that spreads out white light into 

the rainbow of colors that it is composed 

of. By shining a light through the whiskey 

mixture and looking at it through a 

diffraction grating, you can tell which 

specific colors of light are being absorbed 

or reflected by the whiskey, revealing its 

age. Such a setup could be strapped to a 

smartphone camera and would only cost 

tens of dollars to make. 

In future studies, the researchers hope 

to use gold nanoparticles to measure more 

than just the age of whiskey. "What we 

saw tantalizing hints of in the paper but 

couldn't necessarily pin down in the time 

frame that we were working with was that 

sometimes we measured a whiskey, and 

it gave a really different colored particle, 

or it was a much bigger particle, or a 

different shape," Peveler said. "Sometimes 

we saw spheres. Sometimes we saw a sort 

of triangle plate-like thing. Sometimes 

we saw rods or a star-type shape. My 

hypothesis is that that is linked to the 

different chemistry that is coming out of 

the wood." Ideally, the gold nanoparticles 

would not only allow whiskey distillers to 

determine how much flavor has infused 

the whiskey but also identify the specific 

flavors. For example, they might be able 

to correlate certain particle shapes or 

colors with buttery flavors or with smoky 

undertones. "That's going to be a key 

challenge going forward," Peveler said. 

Through chemistry, it's becoming 

possible to dissect the flavors we encounter 

in our daily lives. "I'm fascinated by this 

kind of stuff: how we taste, how we smell, 

how we perceive flavor, and things like 

that," Peveler said. Peveler has previously 

done similar sensing research that goes 

even beyond food and beverages, such as 

detecting explosives in wastewater and 

sensing liver disease in blood. But as a big 

whiskey fan—and a researcher based in 

Scotland, which is famous worldwide for 

its whiskey—he has particularly enjoyed 

working with it for this project. "It's 

whiskey! It's fun, right?" ■ 

USING GOLD 

NANOPARTICLES 

TO REVEAL THE 

AGE OF WHISKEY 



UNDERGRADUATE PROFILE 

ERIC SUN 

YC ’23 

BY CINDY KUANG 

Eric Sun (MY ’23) is a lot of things: aspiring physician-scientist, 

cancer biology researcher, competitive yo-yo player, longdistance 

runner, and most recently—a 2022 Barry Goldwater 

Scholar. Double majoring in Molecular Biophysics and Biochemistry 

(MB&B) and Statistics & Data Science (S&DS), Eric dedicates his time 

outside the classroom to researching and understanding cancer drug 

resistance, with previous work in epigenetics and DNA damage. 

Growing up in northern Virginia, Eric was always excited by 

the proximity of the National Institute of Health in Maryland: 

“You see experiments in the textbook, and you’re like – how do 

you actually do that?” Eric said. 

At sixteen years old, Eric cold-emailed NIH principal investigators 

hoping for a summer laboratory experience and ultimately joined 

Philipp Oberdoerffer and Mirit Aladjem’s labs, where he spent the 

next two years. There, he studied the 

epigenetics 

behind the DNA damage response, 

primarily 

how different types and 

modifications of histones 

(which are what DNA 

wraps around in the cell’s 

nucleus) could dictate or 

inform the environment 

in which DNA repair 

processes occur. 

He continued 

pursuing this 

interest in 

epigenetics at Yale, 

where he joined 

Andrew Xiao’s lab 

in the fall of 2019 

as a first-year. “I felt 

that the projects that 

were ongoing were really 

fascinating, 

PHOTO COURTESY OF SOPHIA LI VIA ERIC SUN 

and there was great mentorship 

from the MD/ 

PhD students in the lab that have helped me tremendously 

through the last couple years, especially navigating the pathway 

of applying for an MD/PhD,” Eric said. 

Despite initial setbacks due to COVID-19, Eric’s work on 

cancer drug resistance—specifically targeted therapies in the 

context of lung adenocarcinoma—has made great progress. He 

focuses on epidermal growth factor receptor (EGFR) mutant lung 

adenocarcinoma, a subclass of non-small cell lung cancers, and 

how these cancers ultimately develop resistance against therapies 

that are initially greatly effective. 

Currently, in the clinic, patients with EGFR mutant lung 

adenocarcinoma are treated with specific targeted therapies called 

tyrosine kinase inhibitors, one of which—Osimertinib—is used as a 

first-line treatment for EGFR mutant lung adenocarcinoma patients, 

and is the focus of Eric’s research. These patients are sensitive to 

these targeted therapies because these inhibitors bind to mutated 

EGFR but not wild-type EGFR, effectively only targeting and killing 

the cancer cells and not wild-type healthy cells. 

“The problem is, patients often develop resistance in just a 

matter of months,” Eric said. “In the clinical setting, we see 

tumors initially regress but then expand again and metastasize 

further, so understanding why tumors become resistant has been 

a major question in the field.” 

Eric’s project particularly questions how oncogene amplification 

is involved in resistance, notably how two copies of an oncogene 

can amplify to fifty copies or even one-hundred copies and how 

the cell can then exploit that upregulation to develop therapeutic 

resistance. Through mining sequencing data, including rich clinical 

trial data from the National Cancer Institute, as well as hands-on 

imaging, genomics, and assay work at the bench in different cell 

line models, Eric has studied the acquisition of resistance through 

various approaches. “We have a lot of data from 

various aspects, from patient data to cell line 

models, suggesting a common mechanism 

of oncogene amplification that drives 

Osimertinib resistance,” Eric said. 

Eric reflected on the Barry Goldwater 

Scholarship and how the award has 

influenced him as a researcher. “I take 

pride in that it’s an affirmation that 

I’m doing the right things,” Eric said. 

“Really, I’ve been mentored really 

well, and it’s a testament to the faculty 

and the professors that I’ve been able 

to get to know at Yale who really 

supported me both in the classroom 

and in my research.” 

After graduation, Eric plans to pursue an 

MD/PhD, stating that though he really enjoys 

research, he also really loves spending time in the 

clinic to see how his research interfaces with clinical issues. 

“I don’t think science lives in a vacuum; you don’t do science just 

for science. You see patients, you see what their challenges are, 

you see patients fail treatment with a drug or develop resistance, 

and then you go back to the bench and ask: now how do you 

understand this?” Eric said. 

Regarding advice for aspiring researchers, Eric stressed a confident 

mentality. “Just don’t be afraid in general. Reach out to people, screw 

up an experiment, those are small things in the grand scheme of 

everything. If you’re afraid, you aren’t even going to try,” Eric said. 

Without a doubt, Eric’s passion and enthusiasm for science and 

medicine will not just better the research community but will also 

continue to inspire everyone around him for years to come. ■ 


ALUMNI PROFILE 

JONATHAN ROTHBERG 

GSAS ’91 

BY SOPHIA BURICK 

J 

onathan Rothberg GSAS’ 91, the pioneer of nextgeneration 

DNA sequencing, has always had a scientific 

bent and entrepreneurial spirit. His father, a chemical 

engineer, built his own company and turned the basement of 

their family home into a laboratory. Conversations around the 

dinner table often revolved around business. 

After earning his bachelor’s in Chemical Engineering from Carnegie 

Mellon University in 1985, Rothberg arrived at Yale to complete a PhD 

in Biology. In the lab of Yale professor emeritus Spyros Artavanis- 

Tsakonas, he investigated the molecular basis of nervous system wiring. 

While still a student at Yale, Rothberg founded his first company, 

Curagen. Curagen was one of the first movers in the genomics industry 

in the 1990s. They invented a new field dubbed global proteomics, 

which entails identifying and analyzing all the proteins in a sample. 

“We were the first ones to map out all the protein interactions in a yeast 

cell, which got featured on the cover of Nature,” Rothberg said. 

When his son had difficulties breathing after birth, Rothberg was 

frustrated that genome sequencing technology was not fast enough to 

provide him with genetic answers regarding his son’s condition. 

While in the hospital, Rothberg saw 

an InfoWeek magazine cover 

featuring the new Pentium 

semiconductor chip. In 

that moment, inspiration 

struck. He could 

apply the concept of 

transistors—which are 

used in circuits in large 

quantities to switch 

or amplify electrical 

signals in a massively 

parallel way—to DNA 

sequencing. “I could 

interrogate a sequence of 

bases, but this time, instead 

of doing it in one test tube, I 

could do it thousands of times or 

millions of times in parallel,” Rothberg 

said. While still working at Curagen, Rothberg 

founded his second company, 454 Life Sciences, to develop this 

revolutionary technology. Rothberg’s method became known as 

next-generation sequencing and is still used today. 

Shockingly, Rothberg was fired by the boards of Curagen and 454 

for this idea. The company’s board believed the completion of the 

Human Genome Project had rendered the technology obsolete and 

sold 454 Life Sciences for 140 million dollars. 

Still convinced that next-generation DNA sequencing was the 

future, Rothberg founded Ion Torrent. This time, he would have to 

do something different. Instead of just using the general concept 


PHOTO COURTESY OF ALEX DONG VIA JONATHAN ROTHBERG 

of massively parallel analysis derived from transistors on a chip— 

sequencing the DNA at many different spots simultaneously— 

Rothberg approached the issue more directly, creating a 

semiconductor chip that could 

directly sequence DNA in 

a massively parallel way. 

Out of this idea came 

the Ion Torrent chip: a 

semiconductor chip 

capable of sensing the 

chemistry of DNA 

PHOTO COURTESY OF ALEX DONG VIA JONATHAN ROTHBERG 

synthesis through 

pH changes, allowing 

the user to rapidly 

sequence DNA. “We 

were really on a great 

path to a thousand dollars 

genome by just going to newer 

factories or foundries and making 

denser chips,” Rothberg said. 

Rothberg sold Ion Torrent to Life Technologies for 725 million 

dollars—five times the amount 454 Life Sciences was sold for. 

Ironically, almost exactly ten years after he was fired for the 

idea, President Barack Obama awarded Rothberg a National 

Medal of Technology and Innovation for his work on nextgeneration 

sequencing. 

After Ion Torrent, Rothberg wanted to transition to 

parallel entrepreneurship—helping several different 

startups develop at once. To do this, he launched a startup 

accelerator called 4Catalyzer. Rothberg has three key 

criteria that startups under 4Catalyzer must meet: each 

startup must solve a problem that affects the life of someone 

they love, use artificial intelligence, and take advantage of 

semiconductors or the concept of large-scale integration 

behind semiconductors. One of 4Catalyzer’s startups, Detect, 

played a major role in the COVID-19 pandemic. Detect’s mission 

was to develop an at-home COVID test with sensitivity comparable to a 

PCR test. The test they developed was sometimes demonstrated to be ten 

thousand times more sensitive than the at-home alternative of antigen 

tests. Now, Detect is applying their technology to other ailments. “It will 

be for universal testing, and they’ll do STIs, COVID, and flu. They’ve 

raised about 160 million dollars for the company,” Rothberg said. 

Many of the companies under 4Catalyzer, like Detect, are headed by 

Yale graduates, and Rothberg is always eager to work with the latest 

talent coming out of Yale. For Yalies looking to try their hand at scientific 

entrepreneurship, Rothberg’s advice is simple. “Find somebody that 

compliments you. If you’re good at business, find someone good at 

science. I think that raises your probability of success the greatest—just 

finding a complement that you can work with,” Rothberg said.■ 


EATING TO EXTINCTION 

BY DINESH BOJJA 

SCIENCE 

IN 


THE WORLD'S RAREST FOODS AND 

WHY WE NEED TO SAVE THEM 

Every day, our dining halls are filled with countless choices: dozens of 

types of pizza, chicken tikka masala and aloo gobi, Cajun fish tacos, 

and cheese quesadillas. But if we take these foods back to their base 

ingredients, that variety vanishes. In fact, only three plants—rice, wheat, and 

maize—account for half of all calories consumed globally. This expanse of 

diverse food options masks a dramatic loss in true food biodiversity and the 

increased homogenization of agriculture and food production. 

In his book Eating to Extinction: The World’s Rarest Foods and Why We 

Need to Save Them, Dan Saladino discusses the uniformity of modern food 

production, driven by a steep demand for low-cost, high-quantity food 

species. For example, half of the world’s cheese is made from bacteria and 

enzymes produced by the same company. The same breed of pig controls the 

international pork trade. And only one of the 1500 types of bananas dominates 

the global market. Saladino attributes this trend—sacrificing variety for 

surfeit—to a few concurrent factors: shifts in land usage, the introduction of 

chemical fertilizers and pesticides, and a rise in genetic modifications for crops 

and livestock alike. Dubbed the “Green Revolution,” this shift in the 1960s 

and 1970s was marked by unparalleled crop prosperity and food production, 

enough to sustain the world’s growing population. Overall yields of staple 

crops skyrocketed, but other wild crops were driven to near extinction. 

While there may be more food produced overall, this marks a dangerous 

trend. A decline in food biodiversity increases the risk of pests and diseases 

disrupting global food security. For example, one fungus, Fusarium 

graminearum, has led to billions of dollars of damage by infecting wheat 

crops in Europe, Asia, and the Americas. Saladino runs through countless 

examples of mass-produced foods overshadowing traditional species, from 

Cosmic Crisp and Red Delicious apples overpowering the apple market 

to slaughterhouse chickens, eliminating the need for traditional breeds or 

historically used but now obsolete species. A loss of diversity comes with a 

loss of culture, identity, and history. 

It is not too late to reverse the trend, however. From scientific seed repositories 

in Norway to government-run food conservation efforts, thousands of different 

crops, animals, and fruits have been painstakingly preserved in hopes of future 

reintroduction and production. Thankfully, corporations also have recognized 

the need for increased food biodiversity, and twenty of the world’s biggest food 

businesses have pledged to preserve traditional foods. 

But the real hope is in the hands of farmers daring to continue their 

tradition, even in the face of agricultural giants. A “chocolate lab” in 

Venezuela specializes in producing traditional chocolate made from Criollo 

cacao. A village of resilient fishermen holds steadfast to their roots of selling 

wild Atlantic salmon. A group of millers on the Orkney Islands work with 

agronomists to bring back nutritious Bere barley. Even on the individual 

level, every effort is the chance to bring another species back from the brink 

of extinction. With a stroke of encouragement and support, the opportunity 

to restore food biodiversity is within reach. ■ 


ATOMS AND ASHES 

A GLOBAL HISTORY OF 

NUCLEAR DISASTERS 

Ever since scientists first split the atom in 1938, nuclear power has both 

fascinated and terrified millions. Today, ten percent of world energy 

is supplied by almost 440 nuclear reactors. In the US, closer to twenty 

percent of electricity comes from nuclear power. Regarded as a highly efficient, 

low-emission energy source, nuclear energy is an attractive option for many 

countries seeking to reduce their carbon footprint while meeting population 

needs. Yet, nuclear disasters like Chernobyl have shown the risks of working 

with radioactive material. Considering the industry’s troubled history raises 

the question: Just how safe is nuclear energy? 

In his new book Atoms and Ashes: A Global History of Nuclear Disasters, Serhii 

Plokhy, Harvard University professor of Ukrainian History, explores the dangers 

of nuclear power through six of the worst nuclear disasters: the 1954 Castle 

Bravo hydrogen bomb test, the 1957 Kyshtym nuclear waste tank explosion, the 

1957 English Windscale reactor fire, the 1979 Three Mile Island partial reactor 

meltdown, the 1986 Chernobyl reactor meltdown, and the 2011 Fukushima 

disaster. 

Plokhy expertly creates a picture of the international nuclear industry. “The 

story told here is a global one,” he writes, examining “not only the actions 

and omissions of those directly involved but also the ideologies, politics, 

and cultures that contributed to the disasters.” For example, the Castle Bravo 

accident sets the stage for later chapters by introducing the pressures of the 

Cold War, government efforts to cover up disasters, and the inevitability of 

human error when dealing with emerging science and technology. 

Plokhy complements his well-researched piece with a skillful narration. 

Meticulously selected testimonies bring every accident to life, making the 

historical events all the more palpable and impactful. Discussing the Fukushima 

meltdown, Plokhy anchors his narration around plant superintendent Yoshida. 

“Yoshida was sitting behind his desk, [...] when things around him started 

shaking. [..] ‘My mind should have been panicking. But strangely, [it] was 

telling me to keep calm and start planning,’ recalled Yoshida,” Plokhy writes. In 

this manner, Plokhy builds an entertaining, well-informed historical thriller. 

Atoms and Ashes shows that science and technology alone cannot cause or 

BY XIMENA LEYVA PERALTA 

T H E 

SPOTLIGHT 

prevent nuclear disasters. Many political, social, and cultural factors are involved 

in regulating nuclear energy. New international legislation was established through 

international cooperation to prevent future nuclear accidents, making it easier to 

exchange technology and enforce rigorous standard safety measurements. 

Though the impacts of nuclear disasters should not be disregarded, their 

rate and severity are lower than accidents in the coal, gas, and hydropower 

industries. While not perfect, nuclear fission reactors are the most efficient 

zero-emission energy source. As Plokhy recognizes, “the major accidents 

involved [...] technologies developed in the 1950s and 1960s, [offering] some 

hope that the [industry’s] major errors [are] behind us.” Better policy-making 

and increased funding for research and development promise a safer future 

for nuclear energy. Moreover, they open the door to a promising, carbonfree, 

potentially safer option to power the second half of this century: nuclear 

fusion, fusing atoms instead of splitting them apart. ■ 

IMAGE COURTESY OF WIKIMEDIA COMMONS 



COUNTERPOINT 

Life on Mars Was 

Its Own Undoing 

Has life existed on Mars? If so, how would 

it have affected Mars’s climate? There has 

been ample research on Earth’s early life 

forms and their effect on the planet. Scientists 

have been particularly interested in methanogens, 

microorganisms that consume hydrogen (H2) and 

carbon dioxide (CO2) and generate methane (CH4) 

as waste. Both CO2 and CH4 are greenhouse gases, 

which trap heat in the atmosphere and lead to 

temperature increases, but CH4 retains twenty-five 

times more heat than CO2. Therefore, methanogen 

metabolism increased global temperature and, as a 

result, made Earth habitable to other organisms. 

However, a recent study in Nature Astronomy 

found that if methanogens ever existed on early 

Mars during the Noachian period (about four 

billion years ago), they would have had an opposite 

cooling effect. This is because early Mars had a 

CO2-dominated atmosphere, as opposed to early 

Earth’s nitrogen-dominated atmosphere. Collisions 

between CO2 and H2 molecules absorb more heat 

energy than CO2-CH4 collisions or CH4 alone. 

Since the existence of methanogens would have 

drastically changed the climate, it is important to 

evaluate whether the early Mars environment could 

support methanogenic life. The researchers concluded 

that Mars’ subsurface environment was probably 

favorable to microbial life. Mars’ crust is covered by 

regolith, a loose, heterogeneous layer made of dust, 

sand, and broken rocks. At that time, regolith may 

have sheltered microorganisms from ultraviolet and 

cosmic radiation. Simultaneously, brine, highlyconcentrated 

salt water, would have filled the porous 

layer and provided an aqueous environment. 

In addition to an aqueous solution and shelter 

from radiation, the land must also have been free 

of surface ice to sustain life. Ice-free regions allow 

gases to exchange from the atmosphere, which 

microorganisms need to survive. Ice coverage 

depends on surface temperature and the brine 

freezing point. Researchers estimated the surface 

temperature on early Mars by modeling H2 and 

CH4 concentrations combined with the latitude 

By Crystal Liu 

ARTIST’S IMPRESSION OF MARS FOUR BILLION YEARS AGO. 

IMAGE COURTESY OF ESO/M. KORNMESSER. 

and elevation of any given geographical area. They 

found that before any life forms existed, the average 

surface temperature ranged from 216 to 294 K (-57 

to 21°C). Brine’s freezing point, however, is largely 

unknown. As salt concentration increases, the 

solution’s freezing point decreases, which is why 

we salt the road before a snowfall to prevent snow 

from settling. Brine likely consisted of other ions 

besides sodium and chloride, which would also 

have altered the freezing point. Estimates of early 

Mars brine freezing points from existing literature 

range from 203 to 273 K (-70 to 0°C). 

Researchers ran three models, estimating the 

probability of methanogenic life with brine freezing 

points of 203, 252, or 273 K. If brine had a lower freezing 

point, more area would be ice-free and habitable. With 

a freezing point of 203 K, one hundred percent of Mars’ 

surface would have been ice-free, whereas simulations at 

273 K generated a median of only 0.15 percent ice-free 

area. In all three cases, some parts of Mars would have 

been habitable to methanogens, typically in lowlands at 

low-to-medium latitudes. It is important to note that 

this study only shows that early Mars satisfied every 

condition for methanogenic life rather than confirming 

the existence of life. However, the studies’ findings will 

inform the search for traces of life in fossil records. 

If methanogens had really existed, their metabolic 

activity would have significantly changed Mars’ 

climate, leading to new equilibrium temperature 

and atmospheric composition. The study estimates 

a reduction of 33 to 45 K. As a result, the fraction 

of ice-free regions would have dropped, and 

habitability would have been compromised. Even 

in places with no ice coverage, methanogens would 

have been forced deeper into the crust, which was 

warmer but scarcer in essential gases. Somewhat 

counterintuitively, if Mars had a lower brine freezing 

point, more methanogens could have existed in the 

first place, but they would have induced a larger drop 

in temperature and lower habitability at the steady 

state. Unlike on Earth, where the first life forms 

facilitated the emergence of later organisms, life on 

Mars may have been its own undoing. ■ 


HIDDEN 

HISTORIES 

NETTIE STEVENS 

BY ANJALI 

DHANEKULA 

ART BY 

MALIA KUO 

Nettie Maria Stevens was born on July 7, 1861, in 

Cavendish, Vermont, where her family had lived for 

several generations. Still feeling the aftereffects of the 

Civil War, women in the US generally had few educational and 

professional opportunities. However, in part because of her 

father’s accumulated wealth, Stevens attended public schools, 

eventually graduating from Westford Academy at the age of 

nineteen. Stevens was a dedicated student, earning praise from 

teachers and peers alike. 

After graduation, Stevens became a high school teacher to 

save money to continue her education. Later, she attended Bryn 

Mawr College and pursued a graduate scholarship in biology. 

After just six months at Bryn Mawr, Stevens performed such 

brilliant work that she was awarded a fellowship to conduct 

research abroad. She studied at the Zoological Station in Naples, 

Italy and the Zoological Institute of the University of Würzburg 

in Germany. After earning her doctorate at Bryn Mawr, she 

continued to teach and research at the college until her death 

due to breast cancer in 1912. 

Stevens studied morphology, the study of the forms of 

living organisms, and cytology, the study of the structure and 

function of plant and animal cells. Her research focused on sex 

determination, how biological sex and sex characteristics are 

determined in organisms. At the time of Stevens’ research, there 

were two major schools of thought on sex determination. Some 

believed sex was determined by external factors and others 

believed that sex was determined at the point of fertilization, 

not by the surrounding environment. Over the course of her 

research, Stevens noticed that male mealworms produced 

sperm with either a large chromosome (now known as the 

X chromosome) and sperm with a small chromosome (now 

known as the Y chromosome), but female mealworms only 

produced eggs with large chromosomes. She concluded that 

chromosomes, specifically on the paternal side, are responsible 

for sex determination. 

Despite Stevens publishing her groundbreaking discoveries, many 

credit Edmund Wilson, a geneticist who worked in the same fields 

as Stevens, for the finding. While Stevens and Wilson worked on 

chromosomal sex determination simultaneously, they arrived at 

the conclusion independently. In fact, Thomas Hunt Morgan, a 

mentor to Stevens who did not accept the theory of chromosomal 

inheritance at the time, is often credited with discovering the genetic 

basis for sex discrimination. Morgan even went on to win a Nobel 

Prize in 1933 “for his discoveries concerning the role played by the 

chromosome in heredity.” 

Stevens is not the only female scientist whose contributions to 

science were not recognized as her own until long after her death. 

Others include Rosalind Franklin, who co-discovered the helical 

structure of DNA, and Esther Lederberg, who discovered a virus 

that infects E. coli bacteria, a widely used tool in the current study 

of genetics. This pattern indicates the Matilda effect: the repeated 

dismissal of scientific discoveries made by women in science. 

Stevens’ discoveries about sex determination are the basis for many 

advancements in research on Turner syndrome and Down syndrome, 

as well as developments in the chromosomal basis of heredity. 

Although Stevens dedicated much of her life to her education and 

research, making crucial contributions to the field of genetics, the 

highest position she ever reached was as an associate in experimental 

morphology at Bryn Mawr College. Thomas Hunt Morgan described 

her as more of a lab technician than a true scientist. Reporters at the 

time stressed Wilson’s discovery over Stevens’, even though Stevens 

stated her conclusions more explicitly. 

Without Stevens’ discoveries, it is impossible to know where 

the field of genetics would be today. Yet, like many other female 

researchers, her work has been consistently undervalued. There is 

limited research available on how to diminish gender bias in scientific 

fields. However, by continuing to acknowledge the contributions of 

female scientists, we can work to create a world where the Matilda 

effect does not exist—a world in which we celebrate Nettie Maria 

Stevens for her achievements. ■ 



SYNAPSE 

Essay Contest Winner 

P 

LLING TEETH 

I 

turned sixteen last May, meaning, I 

have officially entered the “wisdom 

teeth removal” era of my life. 

According to my last dentist visit, I have 

3 lovely molars waiting for me in a couple 

of years' time. That got me thinking, why 

do we even have wisdom teeth? 

Retired now, wisdom teeth’s original 

function was to grind down hearty, rough 

food. According to Herman Pontzer, 

an evolutionary anthropologist at Duke 

University, the myth of the prehistoric 

diet consisting mostly of meat isn’t true. 

Instead, early humans ate what they could 

forage from their environment, which 

heavily varied depending on location, 

season, and climate. In an article for 

National Geographic, Leslie Aiello, 

president of the Wenner-Gren Foundation 

for Anthropological Research in New 

York City says this, “What bothers a lot of 

paleoanthropologists is that we actually 

didn’t have just one caveman diet, The 

human diet goes back at least two million 

years. We had a lot of cavemen out there.” 

Even so, all paleoanthropologists seem 

to agree on one thing; The diet of early 

human beings was coarse and rough. 

Enter, the adaptation to have a third 

set of molars. Wisdom teeth grew in with 

the function to provide more chewing 

power. Now, with softer foods and the 

inventions of cutlery, wisdom teeth are 

obsolete. If anything, they are quite a 

literal source of irritation. This is due to 

human jaws becoming much smaller over 

time. Without the extra space, wisdom 

teeth become blocked by surrounding 

teeth. This can result in bone and 

jaw disruption, as well as damage to 

neighboring teeth. To avoid these side 

effects, many young adults undergo a 


Essay Contest Winner 

SYNAPSE 


procedure to have 

them removed. Annually, Americans 

remove around 10 million wisdom teeth. 

This adaptation, while useful at the time, 

has been outgrown for thousands of years. 

It goes to show that some solutions work 

better in the past and are best left there. 

Although optimization isn’t contained to 

biological changes, it is in human nature 

to find the “better” solution. According 

to Applied Psychology: Health and Wellbeing, 

“Optimal functioning, which may 

be in physical, cognitive, emotional, and/or 

social terms, emphasizes the importance of 

a person’s inner strength, state of resilience, 

virtue, and the maximization in capability” 

People most often self-optimize to achieve 

self-fulfillment and inner satisfaction. 

I share this human need to optimize; I 

myself have terrible handwriting. 

It started in third grade 

when my mom told me 

"teachers will take off points 

KATE KIM is a junior at James Hillhouse 

High School in New Haven, 

CT, where she enjoys swimming 

for the East Haven/New Haven 

girls' swim team and participating 

in the student council as class president. 

She loves painting, writing, 

and opening SAT books (but not 

studying in them). Through her 

writing, she aims to capture her life 

experiences as a recording for her 

future self. 

Kate Kim is the winner of the 2022 

Yale Synapse Essay Contest for 

high school students 

for messy writing". From then on, I was 

living a double life. Picture chicken scratch for 

personal notes transcribed into calligraphy 

for official assignments. Even now, I have 

separate notebooks for in-class notes and 

for homework. But like wisdom teeth, 

the solution my eight-year-old self came 

up with seems to have run its course. 

The strategy slows me down. I 

have piles of notes waiting for me to 

transcribe them, I get lost in lesson material 

after rewriting notes from weeks prior and 

I'm pretty certain I have acute Tendinitis. 

One could argue that my strategy was 

never an optimized solution to my issue. 

“Why didn’t I just learn to write neater from 

the start?” I asked myself while rewriting my 

notes. It was then that I realized understand 

that optimization comes in stages. 

My handwriting solution may have not 

been the best solution, but it was one that was 

a quick fix to my needs when I was eight. My 

issue lay within the fact that I never sought a 

better solution, becoming comfortable with 

a fix that I outgrew years ago. 

Now, I grapple with the consequences: 

Deciphering the scrawl of my handwriting, 

late nights revising pages upon pages of 

work, and practicing neat handwriting in 

the limited free time a high school junior 

has. Maybe it's time I do my own operation 

and remove the problem at its root. ■ 

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Interested in getting involved with 

Yale Scientific 

for writing, production, web, 

business or outreach? 

Learn more at 

yalescientific.org/get-involved 

AD_YALE_SC_ENG_Half_winter_2023.qxp_8 1/31/23 7:55 AM Page 1 

YSEA Wants You! 

The Yale Science and Engineering Association is 

where students and alumni connect to... 

• Connect with STEM luminaries from around the world through the YSEA Speaker Series 

• Support top-notch undergraduate research through the YSEA grants program 

• Provide meaningful STEM experiences to high school students at science fairs and 

robotics competitions around the world 

• Salute the achievements of distinguished Yalies with prestigious YSEA Awards 

• Foster STEM journalism by sponsoring Yale Scientific Magazine and Yale Undergraduate 

Research Journal 

• Have fun at networking events, speaker receptions, and other activities 

BE PART OF ENGAGING AND IGNITING THE YALE STEM COMMUNITY. 

Join us at: ysea.org 

Photo courtesy of Yale’s Graduate Society of Women Engineers

YSM Issue 95.4

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