YSM Issue 94.1

Yale Scientific

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

MARCH 2021

VOL. 94 NO. 1 • $6.99

20

OUT OF THE BLUE:

ISLANDS OF LIFE

UP IN

12

FLAMES

THE NSP1 PROTEIN: COVID-19’S

14

SECRET BUT FATAL WEAPON

THE UNFINISHED PUZZLE

17

OF ALZHEIMER’S DISEASE

ALUMNI PROFILE:

35

OWEN GARRICK MD ’98

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TABLE OF CONTENTS

VOL. 94 ISSUE NO. 1

More articles online at www.yalescientific.org

& https://medium.com/the-scope-yale-scientific-magazines-online-blog

COVER

20

A R T

I C L E

12 Up in Flames

Anavi Uppal

Climate change has caused forest fires to increase in frequency worldwide. Yale researchers gain surprising

new insight into how forest fire emissions evolve and what that could mean for human health.

14 The Nsp1 Protein: COVID-19’s Secret

but Fatal Weapon

Britt Bistis

Yale scientists find a critical SARS-CoV-2 protein involved in COVID-19 disease progression.

17 The Unfinished Puzzle of Alzheimer’s

Disease

Rayyan Darji

Researchers from the Yale Alzheimer’s Disease Research Unit have investigated the relationship

between two key hallmarks of Alzheimer’s disease in living people.

www.yalescientific.org

Out of the Blue

Alexa Jeanne Loste

Billions of years ago, complex chemical reactions transformed nonliving molecules into the first living

organism on Earth. Yale geophysicists find evidence to support a theory that could explain how.

6 NEWS

From Cells to Thermodynamics • Elisa Howard • 8

22 FEATURES

Robotic Theory of Mind • Veronica Lee • 24

XCL1: Two Folds Are Better Than One • Madison Houck • 26

SPECIALS 31

Scope: How Close is Too Close? • Sophia Li • 32

Alumni Profile: Owen Garrick MD '98 • Xiaoying Zheng • 35

Science in the Spotlight: Black Mirror, Discriminatory Design, and “The New Jim Code” •

Selma Abouneameh • 36

March 2021 Yale Scientific Magazine 3

By Sherry Wang

&

CAN WE REVERSE AGING?

By Christopher Ye

When humans find the Fountain of Youth, it may

ultimately come in the form of a protein shake.

Researchers studying the effect of OSK, a protein

cocktail of “Yamanaka factors” that converts mature cells back

into embryonic stem cells, recently demonstrated that neurons

can be reprogrammed to a more youthful state. This allows for

improved survival and even regeneration of neurons.

The researchers injected viruses to deliver OSK into mice retinal

ganglion cells (RGCs), neurons with projections from the retina

that form the optic nerve. After crushing these axonal projections,

they observed that axons regenerated, RGCs survived, and sight was

restored with no adverse effects like tumor development. Notably,

although regeneration treatment often fails in older individuals, OSK

was beneficial in both younger and older mice. In addition, though

no current treatment can induce regeneration after neurons sustain

damage, the researchers demonstrated that OSK induction even after

crush injury resulted in significant regeneration. The researchers

recovered vision in mice with glaucoma, a leading cause of human

blindness, as well as in mice with vision loss caused by aging. OSK

expression also enhanced regrowth in human neurons in the lab.

Finally, the researchers investigated epigenetic noise, such as

the change in methyl groups on DNA known as methylation.

Accelerated methylation mimics aging, but OSK expression

counteracted this acceleration. As additional evidence,

reduction of ten-eleven translocation (TET) enzymes that

reverse methylation blocked OSK’s beneficial effects. Further

research into how cells store epigenetic information will take

humans closer to the reversal of aging. ■

Huberman, A. D. (2020). Sight restored by turning back the epigenetic

clock. Nature, 588(7836), 34-36. doi:10.1038/d41586-020-03119-1

Lu, Y., Brommer, B., Tian, X. et al. Reprogramming to recover youthful

epigenetic information and restore vision. Nature 588, 124–129 (2020).

https://doi-org.yale.idm.oclc.org/10.1038/s41586-020-2975-4

JUST HOW BADLY HAS COVID-19

AFFECTED COLLEGE STUDENTS?

Just about every college student can relate to memes and

TikToks ranting about online school, what with the huge

workload, lack of social interaction, and accompanying Zoom

fatigue. But amidst increased social pressures and challenges to

academic success, few students have had time to pinpoint just

how badly the pandemic has affected them mentally. Now, a study

published in PLOS ONE provides some answers.

During the first lockdown, an online questionaire was

administered to students at seven different universities

nationwide to capture the pandemic's toll. Results showed that

among college students, certain risk factors were associated

with increased psychological impact: being a woman, being

eighteen-to-twenty-four years old, possessing below-average

general health, experiencing prolonged screen time, and

knowing someone infected with COVID-19. In contrast,

the data suggested that those who were of White or Asian

ethnicity, had higher income, or spent large amounts of time

outside were less susceptible. This allows college students to

better understand how vulnerable they are to the pandemic's

impact in relation to their peers and to what extent they need

to prioritize their mental stability over academic life.

The study ultimately proposes ways for universities to reach

out to the large percentage of the student body with increased

mental health concerns by maintaining healthy mindsets,

supporting safe social interactions, and providing more

personalized approaches to learning. By supporting the mental

health and educational success of students–especially those

who are more vulnerable–universities can circumvent possible

long-term consequences of college students sacrificing their

health and education during these troubling times. ■

Browning, M. H. E. M., Larson, L. R., Sharaievska, I., Rigolon, A.,

McAnirlin, O., Mullenbach, L., Cloutier, S., Vu, T. M., Thomsen, J., Reigner,

N., Metcalf, E. C., D'Antonio, A., Helbich, M., Bratman, G. N., & Alvarez,

H. O. (2021). Psychological impacts from COVID-19 among university

students: Risk factors across seven states in the United States. PLOS

ONE, 16(1). https://doi.org/10.1371/journal.pone.0245327

4 Yale Scientific Magazine March 2021 www.yalescientific.org

The Editor-in-Chief Speaks

HUMANITY IN SCIENCE

As I write this, Yale Scientific Magazine’s 2021 masthead, which took over

in January of this year, is the first in our publication’s history to have never

met in person. Issue 94.1 comes roughly one year from when a pandemic

pushed most of our lives onto Zoom. Since March of last year, we have grown

all too familiar with how an acutely scientific entity—SARS-CoV-2, the airborne

virus with its mRNA core and infamous spike protein—can assert its influence

over society. Science, after all, is intimately connected to the social contexts that

shape it. But Yale Scientific has always known this, has always strived to dismantle

the notion that science exists within an isolated, unfeeling vacuum.

The articles in this issue continue this tradition, investigating science’s response to

issues with immense social significance. Yale researchers have published work that

directly addresses the pandemic we’re all living through, uncovering a key protein that

the SARS-CoV-2 virus uses to wreak havoc on our cells (pg. 14). They have increased

our understanding of devastating situations that affect millions of livelihoods, from

discovering the chemical makeup of the air pollution from wildfires (pg. 12) to

elucidating the relationship between biomarkers of Alzheimer’s (pg. 17). And in our

cover story, scientists used geological modeling to address one of the most contested

questions in all of human history: what is the origin of life on Earth?

Of course, society and humanity also shape science. Elsewhere in this issue, we

highlight a Yale alum who has dedicated his career to using business principles to

combat racial disparities in healthcare (pg. 35). We speak to a Princeton professor

who made waves this Fall with a course dissecting the ways in which racism and

white supremacy permeate technological design (pg. 36). We ponder whether

robots can exhibit “theory of mind,” behavior that lays the groundwork for

human empathy and deception (pg. 24). For the first time, we have also published

a print edition of an article from Scope, our interdisciplinary online blog that

explores science’s social and cultural intersections. In it, we explore the web of

history, public policy, and personal decisions that have legitimized the supposedly

scientific “six-foot” rule in our pandemic discourse (pg. 32).

While our 2021 masthead may be remote for the time being, we are no less

committed to the goals that have driven our publication since 1894. Rather, we will

strive to adapt to an increasingly virtual media environment: improving our website,

publishing exclusive content on our blog and social media, and hosting virtual

events—including our Meet the Profs! webinar series, in partnership with the Yale

Science and Engineering Association and the Yale Alumni Association.

In short: as virtual communication becomes the norm, we remain invested in

the human connections that underlie scientific discovery. We will continue to tell

these stories. And we thank you for listening.

About the Art

Isabella Li, Editor-in-Chief

This issue’s cover encompasses a Yale

group’s approach towards studying

topography to understand the formation

of primordial soup, or else, the origin of

life. In the center of the piece, warm,

radioactive heating thrusts a bundle

of slowly cooling-down mountains

outwards. These structural formations

facilitate ponds of molecules to coexist,

and ultimately, combine.

Sophia Zhao, Cover Artist

MASTHEAD

March 2021 VOL. 94 NO. 1

EDITORIAL BOARD

Editor-in-Chief

Managing Editors

News Editor

Features Editor

Special Sections Editor

Articles Editor

Online Editors

Copy Editors

Scope Editors

Newsletter Editor

PRODUCTION & DESIGN

Production Manager

Layout Editors

Art Editor

Cover Artist

Photography Editor

BUSINESS

Publishers

Operations Manager

Advertising Manager

Subscriptions Manager

OUTREACH

Synapse Presidents

Synapse Vice Presidents

Synapse Outreach Coordinators

Synapse Events Coordinator

WEB

Web Manager

Web Developer

Web Publisher

Social Media Coordinator

Web Designer

SENIOR STAFF WRITERS

Britt Bistis

Anavi Uppal

STAFF

Ismihan Abdelkadir

Selma Abouneameh

Ann-Marie Abunyewa

Tejita Agarwal

Ryan Bose-Roy

Dilge Buksur

Frances Cheung

Rayyan Darji

Krishna Dasari

Elsa Durcan

Matthew Fan

Madison Houck

Elisa Howard

Dana Kim

Malia Kuo

Veronica Lee

Cecilia Lee

Viola Lee

Angelica Lorenzo

Alexa Jeanne Loste

Gonna Nwakudu

Emilia Oliva

Dhruv Patel

Rosie Rothschild

Noora Said

Sydney Scott

Isabella Li

James Han

Hannah Ro

Jenny Tan

Cindy Kuang

Nithyashri Baskaran

Maria Fernanda Pacheco

Meili Gupta

Cathleen Liang

Alex Dong

Brianna Fernandez

Hannah Huang

Christina Hijiya

Tai Michaels

Beatriz Horta

Ishani Singh

AnMei Little

Catherine Zheng

Elaine Cheng

Sophia Zhao

Crystal Xu

Blake Bridge

Jared Gould

Brian Li

Sophia Zhuang

Lauren Chong

Alice Zhang

Sophia Li

Blake Bridge

Jared Gould

Athena Stenor

Anavi Uppal

Sophie Edelstein

Matt Tu

Brett Jennings

Eten Uket

Megan He

Siena Cizdziel

Raquel Sequeira

Yu Jun Shen

Anasthasia Shilov

Georgia Spurriur

Eva Syth

Clay Barton Thames II

Van Anh Tran

Shudipto Wahed

Sherry Wang

Elizabeth Wu

Christopher Ye

Catherine Zhang

Xiaoying Zheng

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

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

06520. Non-profit postage permit number 01106 paid for May 19, 1927

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

any submissions, solicited or unsolicited, for publication. This magazine is

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NEWS

Chemistry / Psychology

LAB GROWN MEAT:

VALID CONCERN OR

UNFOUNDED

DISGUST?

NEGATIVE PERCEPTIONS SURROUNDING

CULTURED MEAT

BY FRANCES CHEUNG

IMAGE COURTESY OF FLICKR

Culturing meat from animal cells is an alternative to

factory farming, a practice that raises ethical, social,

and environmental issues. However, culturing meat

remains controversial, with “unnaturalness” frequently cited

as a concern. Yale researchers led by Matti Wilks conducted a

study to better understand psychological motivators of these

negative perceptions. “We were trying to understand who was

rejecting cultured meat and what kinds of personality traits

were associated with disliking it,” Wilks explained.

After examining correlations between naturalness and

acceptability for several processes—for example, growing

an apple—researchers observed that culturing meat scored

around the average. Next, they found that people with

higher disgust sensitivity and conspiratorial ideation levels

tended to view cultured meat more negatively. Researchers

also examined attitudes and unnaturalness ratings for

specific beliefs about cultured meat, such as the perception

that it is highly processed. Interestingly, the view most

correlated with unnaturalness was related to safety, not

naturalness. Meat grinding—the only step shared with farm

meat production—was rated to be the least natural step of

cultured meat production.

These findings suggest that emotion, rather than logic, may

play a big role in the perception of cultured meat as unnatural.

This may be problematic, as current strategies to ameliorate

such negative opinions focus on rationally educating the

public. “I think the question we should be asking is how can

we make people feel more comfortable with cultured meat,”

Wilks said. In the near future, the researchers hope to find

causal evidence for the role of emotion in cultured meat

perception. ■

Wilks, M., Hornsey, M., & Bloom, P. (2021). What does it mean to

say that cultured meat is unnatural? Appetite, 156, 104960. https://

doi.org/10.1016/j.appet.2020.104960.

EXTRACTING

ARSENIC

PURGING OF STUBBORN CONTAMINANTS

USING EARTH-ABUNDANT MATERIALS

BY SHUDIPTO N. WAHED

IMAGE COURTESY OF PIXY

Drinking water containing arsenic is linked to serious health

issues such as cancer and diabetes. Unfortunately, millions

of people around the world are at risk of water-related

arsenic poisoning. While it is relatively easy to remove arsenic from

otherwise pure water, natural water sources contain other competing

anions, negatively charged molecules. Yale chemists Lauren Pincus

and Predrag Petrović investigated the ability of various transition

metal chitosan complexes (TMCs) to selectively adsorb—stick to—

arsenate and arsenite over phosphate, their biggest competitor.

TMCs are complexes of metal bound to chitosan, a waste

product of the shellfish industry. Previous research demonstrated

that copper(II)-chitosan selectively adsorbs arsenate, but not

arsenite. This study found that iron(III)-chitosan had the highest

rates of selectively adsorbing arsenate and arsenite, reducing

concentrations below World Health Organization benchmarks.

The key is the TMC’s molecular structure: iron(III) and

chitosan formed a less rigid bidentate complex—two bonds

holding iron, as opposed to monodentate—than other studied

transition metals. X-ray spectroscopy data showed that this

diffusion of iron’s positive charge allowed iron(III)-chitosan to

bind more tightly to negatively charged arsenic, whose electron

cloud is more easily distorted than that of phosphorus.

The researchers’ findings address the global need for efficient water

purification systems. “There aren’t many adsorbents that are selective

for arsenic over phosphate,” Pincus said. Importantly, the scientists

are furthering the incorporation of computational techniques in

green chemistry, helping save time and resources. “We can do a lot of

good things by combining computational and experimental work,”

Petrović said. Their research advances an environment-friendly

approach while solving environmental problems. ■

Pincus, L. N., Petrović, P. V., Gonzalez, I. S., Stavitski, E., Fishman, Z.

S., Rudel, H. E., … Zimmerman, J. B. (2021). Selective adsorption

of arsenic over phosphate by transition metal cross-linked

chitosan. Chemical Engineering Journal, 412, 128582. https://doi.

org/10.1016/j.cej.2021.128582


Biomedical Engineering / Geophysics

NEWS

NANOPARTICLES

FOR TREATING

SICK BABIES IN THE

UTERUS

OPTIMIZING CONDITIONS FOR

THERAPEUTIC DELIVERY IN CONGENITAL

LUNG DISEASES

BY VIOLA KYOUNG A LEE

IMAGE COURTESY OF ISTOCKPHOTO.COM

Is it possible to treat babies with congenital lung conditions

before they are even born? Yale surgeons and biomedical

engineers are collaborating on a novel way to use nanoparticles

to deliver therapeutic agents to fetuses in utero. Nanoparticles

can enhance delivery through a variety of mechanisms, such as

protecting drugs until they reach their targets, improving their

bioavailability, or enhancing their cellular uptake.

“We were looking at how to optimize targeting the fetal lung

by using different nanoparticle chemistries, injecting at different

gestational time points, and trying several injection methods,” said

Sarah Ullrich, the lead author of the study and a general surgery

resident at Yale. The study found that to help nanoparticles reach

the lungs of fetal mice, delivery via fetal intravenous injection is

superior to delivery via the amniotic sac.

Nanoparticles provide a potential solution for one of the

diseases Ullrich studies, congenital diaphragmatic hernia.

In this condition, the diaphragm does not form properly,

resulting in the abdominal organs of a developing fetus

being pushed up against the lungs. Many babies born with

congenital diaphragmatic hernia need the help of a machine

that takes over the normal function of the heart and lungs.

“Our goal with that project is to allow the lungs to grow

enough to have full function while the baby is in utero, by

injecting nanoparticles that deliver therapeutic agents that

promote lung growth,” Ullrich said. Knowing the optimal

particle type and injection method for maximal fetal lung

delivery is therefore essential for this ongoing project. ■

Ullrich, S. J., Freedman-Weiss, M., Ahle, S., Mandl, H. K.,

Piotrowski-Daspit, A. S., Roberts, K., Yung, N., Maassel,

N., Bauer-Pisani, T., Ricciardi, A. S., Egan, M. E., Glazer,

P. M., Saltzman, W. M., & Stitelman, D. H. (2021).

Nanoparticles for delivery of agents to fetal lungs. Acta

biomaterialia, 123, 346–353. https://doi.org/10.1016/j.

actbio.2021.01.024


THE COLOSSAL

EFFECT OF GRAINS

A NEW MODEL EXPLAINS HOW TECTONIC

PLATES WEAKEN PRIOR TO SUBDUCTION

BY YU JUN SHEN

IMAGE COURTESY OF OPEN.EDU

Tectonic plate movements drive many geologic processes

on Earth, from earthquakes to volcanos, yet how

tectonic plates start sinking beneath one another is

not well understood. Yale researchers David Bercovici and

Elvira Mulyukova have proposed a new model in which tiny

mineral grains in rocks mix and shrink at passive margins—

inactive regions where sea floor meets continent—weakening

the tectonic plates and causing sinking known as subduction.

As the near-surface layer of Earth’s mantle cools, it becomes

denser, promoting subduction, but also becomes stiffer,

opposing subduction. On most planets, subduction either

does not occur or stiffening wins out, and plates do not sink.

In contrast, Earth is unique and has a geologically active

surface. Explaining how subduction initiates has attracted

many theories. “The mystery for any rocky planet is if and

when its surface will dive into the mantle,” Mulyukova said.

By developing a new theoretical model that spans three

scales, from massive tectonic plates to individual rocks and

microscopic grains, Bercovici and Mulyukova showed that

tiny mineral grains could determine tectonic plate weakness.

Bercovici and Mulyukova propose that at passive margins,

mineral grains mix and shrink due to the tectonic stress,

which, over a period of one hundred million years, weakens

the plates, making them susceptible to subduction.

“These weak zones don’t heal. They don’t vanish quickly,”

Bercovici said. “We have a mechanism for how to transform

passive, inactive places on Earth into long-lived active plate

boundaries.” By focusing on the action of tiny grains, the

motion of tectonic plates may be predicted, revealing where

their subduction zones form. ■

Bercovici, D., & Mulyukova, E. (2021). Evolution and demise of

passive margins through grain mixing and damage. Proceedings

of the National Academy of Sciences, 118(4).


NEWS

Biophysics

FROM

CELLS TO

THERMODYNAMICS

Measuring the entropy

production of living

matter

BY ELISA HOWARD

A

human being is composed of about 37.2 trillion cells, seven

octillion atoms, sixty thousand miles of blood vessels, three

billion DNA base pairs, and thirty thousand genes. Yet,

despite this profound intricacy, a person originates from a single cell

that splits via the mitotic process of the first cell division. After DNA

replication and the separation of chromosomes, proteins called

microfilaments form a cytokinetic ring, which divides the cytoplasm

and generates two daughter cells. But before the first cell division,

waves within the cellular fluid disseminate for proper formation of

the ring. Such patterns of wave oscillations allow for the application

of thermodynamic principles to measure the metabolic costs

dictating the development of your very being.

In the Laboratory of Living Matter at Yale University, Michael

P. Murrell, Benjamin B. Machta, and Daniel S. Seara introduced

the entropy production factor (EPF) to quantify the irreversibility

of biochemical oscillations, the propagation of signals in various

biological processes, and the associated energetic expense. “The

entropy production factor is a quantity that correctly measures

irreversibility in order to give a total amount of energy consumed or,

equivalently, how much entropy is being produced,” Seara said. The

EPF builds upon the second law of thermodynamics, which states that

the universe tends toward disorder and that entropy—the measure of

energy unavailable for mechanical work—increases over time.

The second law lends itself to a discussion of irreversibility and

time-reversal symmetry, which form the basis of Murrell, Machta,

and Seara’s research. Irreversible processes increase the entropy of the

universe and thus proceed only in the forward direction, as the reverse

direction would contradict the second law. Furthermore, irreversible

processes break time-reversal symmetry, such that the forward

direction is distinguishable from the reverse direction and that time

points unidirectionally. A recording of an explosion, for example, looks

noticeably different when played in the forward versus the reverse

direction. The researchers introduced the EPF to effectively measure

the evolution of a system and its likelihood of returning to an initial

state. “We are using a precise statistical measurement of, for example,

how likely a particle is to move to the right or left at the next time point.

By quantifying this, it intuitively gives you the irreversibility and also

the shortcut to how much energy is being dissipated,” Seara said.

IMAGE COURTESY OF WIKIMEDIA COMMONS

In full, the EPF quantifies the breakage of time-reversal

symmetry that is characteristic of irreversible processes. Thus,

the EPF provides a measure of how much entropy is produced,

or how much energy is dissipated and unavailable for work. “The

statistical measure of how hard it would be to distinguish if the

movie is being played forward or backward is exactly how much

energy is being wasted,” Machta said.

Applying this method, the team used their EPF to quantify phase

transitions of the Brusselator, a model of biochemical oscillations.

With the EPF, they not only measured irreversibility but also the

energetic costs of the Brusselator’s spatiotemporal waves—waves

with both space and time characteristics.

The EPF is a breakthrough in the field of nonequilibrium

thermodynamics, as previous measures of entropy production only

measured changes in single quantities without recognition of the

spatial dimension. “This method is far more inclusive of the degrees

of freedom and information in the system,” Murrell said. The EPF

is particularly extraordinary in its applicability to biological systems

and insight regarding the energetic costs of metabolic processes. “We

are interested in applying this method to relate energetic principles to

fundamental biological events,” Murrell said.

The Yale Laboratory of Living Matter is currently researching an

organism’s first cell division by quantifying the energy dissipation

of biochemical oscillations necessary to form a cytokinetic

ring. “There are traveling waves of proteins for cell division that

propagate across the surface of the cell and are implicated in

properly locating the equator of the cell to divide in a healthy and

robust way,” Seara said. By quantifying irreversibility, the EPF has

the power to unearth the metabolic costs of an organism’s first cell

division. Thus, it may provide insight into human development

from a single zygote to an individual composed of about 37.2

trillion cells, seven octillion atoms, sixty thousand miles of blood

vessels, three billion DNA base pairs, and thirty thousand genes. ■

Seara, D. S., Machta, B. B., & Murrell, M. P. (2021). Irreversibility in

dynamical phases and transitions. Nature Communications, 12(1),

392. https://doi.org/10.1038/s41467-020-20281-2


Material Science

NEWS

A NEW FRONTIER

OF ATOMIC SCALE

REPLICATION

Metallic glass opens new

possibilities in the field

of nanoimprinting

BY EMILIA OLIVA


Science now allows us to replicate designs on the atomic level,

thanks to Yale researchers led by Udo Schwarz and Jan Schroers,

professors of Mechanical Engineering and Materials Science,

and by using a technique called sputter deposition, this breakthrough

could be practical and desirable for mass industrial use.

An efficient way to reproduce nanostructured surfaces could have

a huge impact on areas of technology such as high-density data

storage, photonic devices, water filtration, and electrodes in fuel

cells. Imprinting doesn’t require the use of a clean room, a tightly

regulated space of filtered air to minimize possible contaminants, as

typical nanomanufacturing requires, and the material used to imprint,

metallic glass, has useful properties of durability and strength.

“We had the question: What’s the limit of this? If I can do this to

thirty nanometers, is there anything that stops us?” Schwarz said.

The key to atomic scale replication is the use of bulk metallic

glass, also known as amorphous metal—a material made by

cooling a liquid metal alloy so quickly that the atoms don’t

have time to arrange themselves in a crystalline structure and

instead lie jumbled together. Without a crystalline structure, the

researchers found that the only factor limiting the size of what

they could replicate was the size of the atoms and the distance

between them. The random configuration of atoms in metallic

glass gives it a viscous quality, allowing it to be blown just

like glass, or molded onto nanostructured surfaces. It can be

processed as plastic, but unlike plastic, it is very hard, resistant

to wear and tear, and can conduct electricity.

Once the researchers had shown that there was no limit to the

size of replication except the atoms themselves, they turned their

attention to scaling up the process and making it more efficient.

Instead of pressing the metallic glass to the mold in a process

called thermoplastic forming, the researchers used a technique

called sputter deposition, which doesn’t require high heat or

pressure. They shot argon ions at a metal plate, which loosened

the surface atoms and sent them falling onto the mold below. As

single atoms, they cooled immediately upon hitting the roomtemperature

mold to form a metallic glass on the surface.

“If you use for instance, just gold, then it will still crystallize, so

you still need the right combination of different metals,” Schwarz


said. “The trick is to basically, to have small atoms and large atoms

together so they don’t line up nicely in a crystal, and they don’t

know what to do, and then they just stick in the glass.”

But even still, sputter deposition makes it possible to use many more

metallic alloys than thermoplastic forming for nanoscale imprinting. The

researchers theorize that one hundred million different combinations of

metallic elements could be possible when using sputter deposition while

thermoplastic forming would allow only hundreds of options.

“If you want to do thermoplastic forming, there are some

restrictions on the mold, on the alloy that you can choose, and some,

you know, specific conditions that you have to achieve, let’s say the

temperature or the pressure to do the thermoplastic forming,” said

Zheng Chen, a graduate student who worked on the study.

Because sputter deposition doesn’t require high heat and

pressures, any material that doesn’t react with the metallic glass

could potentially be replicated. For example, biomaterials acting as

molds is a potential application for this technology.

“We think you can duplicate now anything you really want at

the atomic scale,” Schwarz said.

Schwarz hopes to pursue a project to find a way to keep sand and

dirt off of solar panels by reproducing the structure of snake skin,

which has unique nanoscale patterns that force sand to slide off.

Schwarz wants to reproduce these patterns, first by making a mold

with metallic glass and then copying the pattern onto plastic.

Another possible project is to use nanoimprinting with

metallic glass to reproduce nanostructured surfaces that can

act as catalysts for clean energy reactions. These reactions can

be used in applications such as jet fuel.

“Maybe it never goes anywhere, maybe metallic glasses are

totally bad, but because people haven’t tried yet, there are a lot of

intriguing things that could happen because of the disorder [of

the atoms in metallic glass],” Schwarz said. ■

Zheng Chen, Amit Datye, Georg H. Simon, Chao Zhou, Sebastian

A. Kube, Naijia Liu, Jingbei Liu, Jan Schroers, and Udo D. Schwarz.

(2020). Atomic-Scale Imprinting by Sputter Deposition of Amorphous

Metallic Films. ACS Applied Materials & Interfaces 12(47),

52908-52914. DOI: 10.1021/acsami.0c14982.


NEWS

Molecular Biology

SHUTTING

DOWN THE IRE1α

COMPLEX

The Mariappan Lab at

Yale sheds light on a key

cellular pathway

BY RYAN BOSE-ROY

There are more than twenty thousand different proteins

in your body, and each one plays some role in your life.

If you travel to another time zone, clock proteins in your

brain regulating circadian rhythm are briefly overexpressed

and make you tired. If you get sick, proteins called antibodies

are faithfully produced by your immune system to identify the

foreign particles in your body. And if you are ever so lucky

enough to fall in love, then protein hormones like oxytocin

and vasopressin, produced in your pituitary gland, help give

you the feeling of being happy and safe.

The plethora of proteins within us are produced by a cellular

structure that, if not for its intricate folding, would be ten to twenty

times larger than the outer surface of the cell itself. Its name is

the endoplasmic reticulum (ER), and it serves as the production

facility where proteins are assembled, folded, and secreted.

Seeing how crucial proteins are in maintaining metabolism, it is

no surprise that the ER works very hard to keep us alive.

Unfortunately, things don’t always run smoothly: the ER

sometimes over-exerts itself. If you get sick, for instance, each

day, the mature B-cells of your immune system will secrete

up to their own weight in antibodies, which are all processed

in the cells’ ERs. Glucose deprivation and calcium regulation

also affect processes in the ER by triggering responses that

interfere with protein folding. The imbalance between supply

and demand of properly shaped proteins produced by the ER

leads to a phenomenon called ER stress, which may lead to

type 2 diabetes, atherosclerosis, and liver disease.

Fortunately, our cells have a set of proteins that sense ER stress

and respond to stop it. These proteins, collectively called unfolded

protein response (UPR) proteins, play a major role in cellular life

and death decisions—this feature has garnered an intense interest

in the role of UPR proteins in many diseases. However, there is a

lot we do not know about these proteins and their roles.

The most common of these proteins is IRE1α. Initially, IRE1α

calls for molecular chaperones that guide misfolded structures

along the proper pathways for folding, helping the ER return to

its normal functioning conformation. However, if activated for

too long, IRE1α starts to initiate apoptosis, or programmed cell

death, through the signal-regulating kinase 1 (ASK1) protein and

through proteins called caspases. It makes sense that activity is

tightly regulated, but how this happens is unclear. Unveiling the

molecular mechanisms that govern IRE1α activity could help us

understand how UPR proteins are regulated across all eukaryotic

cells, as well as how a number of human diseases develop.

Research conducted by Malaiyalam Mariappan and Xia Li

at the Yale School of Medicine has helped shed light on this

intricate process. Their work describes how UPR proteins are

regulated. “We identified the mechanism that actually turns

off the IRE1α sensor molecule so that cells can get back to

normal, rather than going into cell death,” Mariappan said.

The key, they found, was a protein called sec63, which actively

recruits a protein chaperone called binding immunoglobulin protein

(BIP) to stick to IRE1α like a cap. This capping prevents IRE1α from

binding to itself and forming long, active, peptide chains. Thus, it

forces IRE1α to exist in an inactive state as singular proteins.

Under normal conditions, there is plenty of BIP for sec63

to pick up. During ER stress, BIP preferentially sticks to

misfolded proteins instead of IRE1α, and this lack of capping

allows IRE1α to bind to itself and activate. Active IRE1α

chains initiate cell transcription pathways that produce more

BIP, and it is this self-regulating negative feedback mechanism

that keeps IRE1α in check.

The discovery of sec63 as an inhibitor of IRE1α clustering

is an addition to the Mariappan Lab’s long line of important

findings on regulators of proteins such as IRE1α. “Initially

it was thought that IRE1α was an independent protein that

sensed ER stress and sent signals to the nucleus… but we were

the first to report that it’s actually part of a big complex with

protein translocation channels,” Mariappan said.

Elucidating the role of sec63 as a recruiter for BIP opens

up a host of new questions. “Still in this field, there’s a lot

of mystery, especially in ER stress and the unfolded protein

response field,” Li said. “I just want to know how it all works.” ■

Li, X., Sun, S., Appathurai, S., Sundaram, A., Plumb, R., & Mariappan,

M. (2020). A molecular mechanism for turning off IRE1α

signaling during endoplasmic reticulum stress. Cell Reports,

13(33). doi:10.1101/2020.04.03.024356


Neuroscience & Genetics

NEWS

THE

MOLECULAR NATURE

OF PTSD

The transcriptomic

landscape of PTSD in

postmortem tissue

In studying psychiatric disorders, researchers must account for

both the environmental and biological components that may play

into a condition’s presentation. In post-traumatic stress disorder

(PTSD), the environmental component is written into the name—

trauma. But much still needs to be uncovered surrounding the

biological mechanisms, which was the goal of an article published in

Nature Neuroscience in January of this year, led by researchers in the

Department of Psychiatry at the Yale School of Medicine. Researchers

dove into the transcriptomic organization of postmortem tissue in

the PTSD-diagnosed brain, meaning they analyzed the collection of

messenger RNA (mRNA) transcripts present in a cell—known as the

transcriptome—to understand the molecular mechanisms underlying

this disorder. This investigation illuminated sex differences in PTSD

expression, unexpected correlations with other disorders, and several

genes of interest in the pathophysiology of PTSD.

The paper homed in on four subregions of the prefrontal cortex (PFC),

a region of the brain highly implicated in emotion regulation, chosen

because of previously observed differences between PTSD patients and

healthy patients in this area. Not unlike other psychiatric conditions,

PTSD does not have a clear-cut cause. A range of trauma types can

contribute to its emergence and may even have an impact at the molecular

level. “We would predict differences in molecular profiles for different

traumas,” said Matthew Girgenti, a research scientist at the Yale School

of Medicine. “I do think that the trauma type has an effect on how and

when you develop PTSD,” Girgenti said, bringing to light the complex

interplay of environmental and biological factors. This interplay may also

be present in sex differences in PTSD, as the traumas that most often lead

to PTSD diagnoses in men and women are vastly different, the former

being combat trauma and the latter being sexual trauma.

Researchers found that sex, in fact, had the greatest effect on

molecular variance in PTSD. All subregions of the PFC displayed

transcriptomic differences between men and women, with women

additionally showing more differentially expressed genes (DEGs)

between the PTSD and control groups. The identified genes are

involved in GABAergic signaling, which is significant given that

GABA serves as a major inhibitory neurotransmitter implicated

in traumatic stress. One of these genes, ELFN1, was identified as a

key player in the observed sex differences. ELFN1 was significantly

downregulated, meaning there was significantly less of the transcript

in PTSD patients in females but not in males. Another key gene,

UBA7, was also downregulated in females in multiple subregions. This


IMAGE COURTESY OF FLICKR

BY GEORGIA SPURRIER

gene is involved in inflammatory and immune processes, which have

been implicated in the pathophysiology of many psychiatric disorders.

Another goal of this research was to explain on a molecular level

the high comorbidity, or simultaneous presence, of PTSD and major

depressive disorder (MDD). Surprisingly, despite nearly fifty percent

of newly diagnosed PTSD patients having comorbid MDD, their

transcriptomic profiles were found to be quite dissimilar. While there

were a high number of DEGs present in the PFC regions of MDD brains,

the overlap with PTSD was minimal. The researchers identified one

gene, GADD45B, that PTSD and MDD brains had in common across

both sexes; GADD45B therefore serves as a molecular intersection

between these two disorders. Overall, however, the results indicate

a non-significant overlap, and the researchers concluded that these

disorders are more dissimilar than previously thought.

So, what can explain the high tendency for PTSD and MDD to

occur together? “PTSD is still stress, and any amount of stress can

lead to some type of depression,” Girgenti said. “Having PTSD

makes you prone to many comorbidities including depression.”

Interestingly, the PTSD transcriptome did significantly correlate

with other neuropsychiatric disorders, such as schizophrenia,

bipolar disorder, and autism spectrum disorder, implicating that the

molecular pathologies of these disorders overlap to some degree.

This research demonstrates important progress in our understanding

of the molecular mechanisms involved in PTSD and how these may

interact with sex and other diagnoses. Unfortunately, there are currently

no medications specifically designed to treat PTSD. However, the gene

networks identified here may play an important role in developing a

treatment. “Therapeutically targeting those systems [GABAergic and

inflammatory] is most likely to succeed,” Girgenti said. “We hope to

identify genomic targets that are changing in PTSD and find current drugs

we can repurpose to target those.” The genomic landscape of the PTSD

brain brought to light by this research may have important implications

for therapeutic interventions as well as for gaining a deeper understanding

of the impact of traumatic stress on the brain. ■

Girgenti, M. J., Wang, J., Ji, D., Cruz, D. A., Alvarez, V. E., Benedek, D., Brady,

C., Davis, D. A., Holtzheimer, P. E., Keane, T. M., Kowell, N., Logue, M. W.,

McKee, A., Marx, B., Mash, D., Miller, M. W., Scott, W. K., Stein, T., Ursano,

R., … Duman, R. S. (2021). Transcriptomic organization of the human

brain in post-traumatic stress disorder. Nature Neuroscience, 24(1),

24–33. https://doi.org/10.1038/s41593-020-00748-7


FOCUS

Environmental Science

UP IN

FLAMES

Retrieving clues about air pollution from forest fires

BY ANAVI UPPAL

Orange skies and choking smoke

covered California last summer.

Wildfires aren’t rare in this state,

but climate change has been making them

increasingly severe—2020 was the worst

Californian wildfire season on record. Recent

research on wildfire patterns can offer insight

into what kinds of pollutants they release into

the atmosphere and may tell us more about

how they impact our health and our planet.

Researchers from the Department of

Chemical and Environmental Engineering

at Yale University found that forest fire

emissions evolve in surprising ways over

time. Associate professor Drew Gentner

and his lab focus on studying air quality

and atmospheric chemistry, particularly

the chemical transformations that organic

compounds undergo in the atmosphere, and

what their ultimate impact might be. The

Gentner lab collaborated with Environment

and Climate Change Canada to take part in a

flight campaign that focused on studying oil

sands emissions in Canada.

The team’s goal was to sample a

forest fire’s emissions to study how the

composition of its smoke plume evolved

over time and distance. “Forest fires are an

important factor in global air quality and

the air quality of local regions, so the field

is conducting more and more projects to

study wildfire smoke,” Gentner said.

Catching Fire

The flight campaign—an airplanebased

measurement program—was

initially focused on studying oil

sands emissions and not forest fires.

But when a forest fire coincidentally

erupted during the campaign, a plane

was quickly dispatched to sample its

emissions. “I think it was in the back of

their mind that, if this happens, we're

going to go, and once they heard about

it they capitalized on the opportunity,”

said Jenna Ditto, a former doctoral

student at Yale in the Gentner lab. “This

type of sampling definitely needs quick

thinking, and you have to be ready.”

The aircraft flew in zig-zag lines called

transects along the emission plume as

it traveled downwind and sampled it in

five different places. Sample one was

taken closest to the fire, while sample

five was the farthest. The farther that the

sample was from the wildfire, the older

those emissions were.

The plane was outfitted with

instrumentation that measured gases,

particles, and weather conditions in

real time, while also collecting offline

samples for later laboratory analysis.

These offline samples were collected on

small filters or glass tubes filled with

absorbent materials that trap a mixture

of compounds from the atmosphere.

Once collected, the samples were

frozen at around negative thirty degrees

Celsius to prevent chemical reactions

from altering them during storage. When

the team did an initial compound class

analysis to see what materials they were

dealing with, they found a surprising

result: the quantity of compounds

called CHONS—which contain carbon,

hydrogen, oxygen, nitrogen, and sulfur—

increased in particle-phase samples taken

the furthest from the forest fire. “We saw

that and thought: that's very interesting,

we've never seen this before. Why is

that happening? Let’s look more into the

functional groups,” Ditto said. Compound

class analysis is usually done as just a first

step to get a sense for what the data looks

like, but it fortuitously led the team to

some interesting results.

12 Yale Scientific Magazine March 2021


Environmental Science

FOCUS

They also found that the quantity of CHO

(carbon, hydrogen, oxygen) compounds

decreased from samples one to four, moving

away from the fire—the fifth sample was

contaminated by emissions from a nearby

oil sands facility, and was not considered.

This seemed to indicate that these CHO

compounds were the precursors for the

CHONS compounds that were increasing

in quantity. “It's interesting because we

previously didn't really know about the

formation of these CHONS compounds,”

said Megan He, a current junior and

Environmental Engineering major at Yale

College who co-authored the study.

Human Health

The discovery that CHONS compounds

are a major component of forest fire

emissions is important for future studies

on how biomass burning affects human

health. For forest fires in particular,

understanding what compounds form

as emissions evolve downwind helps us

determine exactly what we are breathing

in. “If you're a couple hundred miles

downwind of a fire, you're not really

exposed to the same type of chemical

components as you would be if you were

ten miles away from the fire,” Ditto said.

However, the results of this study are not

just limited to wildfires. They could also

apply to developing areas that burn biomass

for fuel. Biomass burning emits nitrogen

species and fossil fuel combustion emits

sulfur species, which are similar to those

that were present in this particular forest

fire plume. Therefore, the chemical reactions

that created CHONS in the forest fire

could be representative of similar chemical

processes that occur in developing regions.

Getting a better picture of what compounds

are being formed when something is burned

can help create better models that in turn

help to inform environmental policies. “If

you were a part of the government, it would

be helpful to know what the health impacts

of the different compounds are,” He said.

Looking to the Future

Moving forward, the team believes that

more studies should be done on how the

compounds they observed in the fire

plume affect the environment. Looking

at their light absorption properties could

yield important results, since having a

lot of light-absorbing particles in the air

changes how incoming solar radiation

interacts with the planet—which, in

turn, affects the climate.

Looking at oil sands emissions, such as

those that contaminated the fifth sample,

could also be an insightful next step.

This was not only the original purpose

of the flight campaign, but is also the

focus of He’s current research. Oil sands

are untapped sources of petroleum fuel

in Canada, and the facilities built on

top of them drill down to extract and

then process that oil. In addition to the

natural evaporations from the sands,

this process releases a lot of emissions.

“Previous studies have shown that the

enhancement of secondary organic

aerosol formation from these emissions

is at a similar magnitude to those that

are downwind of major cities, such as

Houston or Toronto,” He said. “This

remote area where it's just trees and oil

sands facilities has emissions that are

comparable to major megacities, so that

just shows how important they are in the

grand scheme of things.”

Undergraduate Researchers Blaze Forward

This study was particularly special in

that it involved undergraduate students in

frontline air pollution research. In

addition to He, Tori Hass-Mitchell, a

former Yale undergraduate and current

Yale PhD student, contributed to this

research. “I was really excited about the

chance to involve undergrads in research

that's at the forefront of the field, and for

them to interact with leading scientists

from places like Environment and

Climate Change Canada,” said Gentner.

As someone who is passionate about

air quality research, He emphasized

how much she enjoyed the rigor of the

research process and the opportunity to

apply what she had learned inside the

classroom to the real world. “As we saw

last year with Australia, forest fires in

general are increasing, and they're just

going to keep becoming more frequent,”

He said. “There's so much of a mystery

surrounding what is burned and what's

in the air, so I just want to keep figuring

out what it is that we're breathing right

now, and what's coming into our bodies.

I guess long story short, it's just the

mystery of it that I love, and we have the

tools to actually solve those mysteries.”

Climate change is worsening, and it’s

more urgent than ever that we find ways

to mitigate humanity’s negative impacts

on the environment. The research that is

done in labs can have a powerful impact

on current worldwide problems, and new

voices—such as He’s and Hass-Mitchell’s—

on topics like air quality can get us closer

to finding solutions for them. ■

A R T B Y A N M E I L I T T L E

ANAVI UPPAL

ABOUT THE AUTHOR

ANAVI UPPAL is a first-year student and prospective Astrophysics major in Pierson College. In

addition to writing for YSM, she is one of Synapse’s outreach coordinators, and teaches science to

elementary schoolers through Yale Demos.

THE AUTHOR WOULD LIKE TO THANK Drew Gentner, Jenna Ditto, and Megan He for their time

and enthusiasm about their research.

FURTHER READING

Ditto, J. C., He, M., Hass-Mitchell, T. N., Moussa, S. G., Hayden, K., Li, S., . . . Gentner, D. R. (2021).

Atmospheric evolution of emissions from a boreal forest fire: The formation of highly functionalized

oxygen-, nitrogen-, and sulfur-containing organic compounds. Atmospheric Chemistry and Physics,

21(1), 255-267. doi:10.5194/acp-21-255-2021.



FOCUS

Virology & Molecular Biology

THE NSP1

BY BRITT BISTIS

ART BY ELAINE CHENG

PROTEIN:

COVID-19’S

SECRET

BUT FATAL

WEAPON

The role of the

SARS-CoV-2 Nsp1

protein in the deadliness

of COVID-19

While Moderna and Pfizer's

mRNA vaccines prevent sickness

with COVID-19, they do not

help people who have already become sick

with the novel coronavirus, SARS-CoV-2.

These prophylactic measures target the most

famous protein encoded by the SARS-CoV-2

genome: the spear-shaped spike protein

that transverses the viral protein coat and

punctures the host cell, allowing the virus

to inject its genetic information. The spike


protein enables the infection to occur, but

what is it about the novel coronavirus that

poisons our cells and makes us sick?

SARS-CoV-2—like many other viruses

such as influenza A and SARS-CoV, the

agent responsible for the SARS outbreak

in 2003—contains an mRNA transcript

that encodes its viral proteins. Among

them is nonstructural protein 1, or Nsp1.

As its name would suggest, nonstructural

protein 1 is not a structural building block

o f

t h e

v i r a l

particle.

T h e main

function of the viral

protein Nsp1 is to stop the host c ell

from expressing its own genes. Produced

early after viral infection, this protein

starts reshaping the cellular environment

to accommodate viral proliferation. A



FOCUS

previous study found that, in SARS-CoV,

Nsp1 is also necessary for viral replication,

making it a vital component of sickness

progression and a strong candidate for

target therapeutics against coronaviruses.

With the COVID-19 outbreak,

coronavirus research became

critical, and scientists applied

what was already known about

an earlier coronavirus, SARS-

CoV, to make hypotheses

about SARS-CoV-2. Yale

Molecular Biophysics

and Biochemistry

professor Yong Xiong,

whose research group

studies how viruses

suppress and escape a host's

immune system, hypothesized

that SARS-CoV-2 Nsp1 is likely

critical for disease progression

and poisoning host cells.

To test this hypothesis, his

collaborator, associate professor

Sidi Chen, investigated twentyseven

of the twenty-nine proteins

encoded by the SARS-CoV-2

genome. Chen

t r a n s f e c t e d

each protein

individually

into human

l u n g

epithelial

cells and

found that

out of the

t w e n t y - s e v e n

S A R S - C o V - 2

proteins tested, Nsp1

caused the most

severe decrease in

cell viability. To

confirm that Nsp1

is the linchpin of

this phenotype, a new

population of cells

was transfected with a

mutated, defunct copy of

Nsp1. This group of cells

remained healthy, leading

Xiong and Chen to conclude in a

recent paper published

in Molecular Cell that

SARS-CoV-2 Nsp1 is “one of

the most potent pathogenicity

protein factors of SARS-CoV-2

in human cells of lung origin.”


Shifting Gears

After Xiong and his collaborators

knew with greater certainty what leads to

pathogenicity, they began to investigate

how Nsp1 led to this cell sickness. Nsp1

infection causes a large-scale shift in

the host cell's transcriptome, with

the expression of 9,262 genes

being altered as a result of this

protein’s presence in the cell. By

sequencing cellular mRNAs and

quantifying the amount of each

mRNA transcript present using

mRNA-seq, the research team was able to

determine which host genes were affected

by Nsp1 expression. Nsp1 expression led

to the decreased expression of 5,394 genes,

the majority of which are related to protein

synthesis, cellular metabolism, and the

immune system. To express the proteins

encoded in their own genome, cells

need the protein-production machinery,

the ribosome, and energy to translate

their mRNA transcripts into proteins.

By suppressing genes involved in these

processes, Nsp1 shuts down cellular protein

synthesis—hijacking the host cell, rerouting

resources to build viral machinery,

and dampening the cell's immune response

to allow the infection to occur.

The connection between Nsp1 expression

and the genes it upregulates is less clear than

those it downregulates. Nsp1 upregulates

the expression of 3,868 genes that encode

transcription factors that regulate higherorder

chromatin structure, homeobox

genes that are most known for driving body

patterning, DEAD-box genes that regulate

RNA metabolism, and regulators that drive

cell fate determination. How upregulation of

these genes might affect the pathogenicity of

SARS-CoV-2 is not yet understood. "Logically,

Nsp1 programs the cellular transcriptome

in order to redirect cellular resources to the

virus, but there is nothing specific that jumps

out to us," Xiong said. It is also unclear how

Nsp1 alters gene expression on a molecular

level as Nsp1 has no nuclear activity, meaning

that it never enters the host cell nucleus where

all the cell's genetic information is stored.

The Two-Pronged Approach

In the case of SARS-CoV, Nsp1 has

been shown to bind to the 40S, the small

ribosomal subunit, to block translation

of mRNA into protein and promote

cleavage and degradation of cellular mRNA.

However, the molecular mechanisms of

these activities remained unexplained.

Recent advancements in cryogenic electron

microscopy (cryo-EM) and Xiong’s role in

bringing this technology to Yale has made it

possible to use these clues from SARS-CoV

to look at SARS-CoV-2 activities at the

atomic scale.

Xiong used cryo-EM to investigate

how Nsp1 inhibits protein synthesis.

By freezing proteins down to cryogenic

temperatures (approximately below

negative 150 degrees Celsius), Xiong was

able to capture proteins in their native form

and image these native structures at the

resolution of 2.7 angstroms, about the width

of a water molecule. His lab found that the

C-terminus, or back end, of the Nsp1 protein

tightly binds to the mRNA entry channel

on the 40S subunit, while the N-terminus

interacts more loosely with subunit’s head

domain. “Think of a body with a neck and

head. Around the neck is the mRNA path,

where it is loaded and translated,” Ivan

Lomakin, an associate research scientist in

the Bunick lab and expert in human protein

synthesis, explained. “Part of Nsp1 binds

to this path. The other portion binds to the

head, which is a moving part that would

otherwise enable mRNA to slide along

the channel.” While the C-terminus

of Nsp1 physically sits in the entry

channel at the neck and

binds to the

ribosomal

RNA and

r i b o s o m a l

proteins uS3 and

uS5, the rest of the

Nsp1 molecule interacts with the

head domain of the ribosome.

The exact effect of this is unknown since

the N-terminus does not bind tightly to the

ribosome, so the cryo-EM image could not

precisely determine how the N-terminus

makes contact with the 40S subunit. Nsp1

also competes with some initiation factors

critical for eukaryotic translation for binding

to the 40S subunit and locks the 40S subunit

in a “closed” conformation, which is the state

where the ribosome is unable to load mRNA.

In addition to preventing mRNA from

loading onto the ribosome, previous studies

focusing on SARS-CoV have shown that Nsp1

prompts the cutting of host cell mRNA. mRNA

stability is determined by many structural

features within the mRNA transcript, which


FOCUS


OUR HOPE IS THAT WHAT

WE LEARN FROM THESE

INTERACTIONS WILL GIVE

US SOMETHING ON THE

TREATMENT FRONT.

contains caps, tails, and sequences that can

loop back on themselves and provide stability.

By prompting cutting of the mRNA transcript,

Nsp1 targets the host cell transcript for rapid

degradation. How Nsp1 does this remains a

completely open question.

How Does SARS-CoV-2 mRNA Escape?

“The two-pronged approach on inhibiting

cellular protein production is just half the

story. The other half is how viral mRNA

escapes,” said Xiong. With such a well-defined

notion of Nsp1 blocking and cutting host cell

mRNA, an important question remained:

how does the viral mRNA escape this

mechanism and translate its own genome?

Xiong explains that the answer likely lies in

the 5’ untranslated region (UTR) of the SARS-

CoV-2 genome, a portion of the mRNA strand

upstream of the protein-encoding segments.

“We have a clue from the literature already.

Some viruses harbor a mutation that prevents

mRNA cutting," he said. These genes harbor

an internal ribosome entry site (IRES) that

directly binds to the 40S subunit and

enables protein translation

initiation without the

normally required 5’

mRNA cap and cellular

initiation factors.

Previous studies

found that SARS-

CoV relies on its 5'-

UTR for evading the Nsp-1-mediated

translation block. SARS-CoV-2 may use an

"IRES-like" mechanism where the 5'-UTR

enables translation without the initiation

factors blocked by Nsp1 binding to the

ribosome. In addition, viral 5'-UTR could

cause the Nsp1 C-terminus to dissociate

from the mRNA entry channel of the

40S subunit, effectively unplugging the

protein from the channel and allowing the

ribosome complex to form and to load

mRNA. However, the exact mechanism by

which SARS-CoV-2 evades the translation

shutdown still remains to be demonstrated.

Nsp1 as a Therapeutic Target

The new COVID-19 vaccines are designed

to prevent us from getting sick with

ABOUT THE AUTHOR

COVID-19, but they do not cure the many

who already are sick. Moreover, there

is insufficient information as

to whether these vaccines

guard against other related

coronaviruses.

Scientists already

speculate that, like the

flu vaccine, we may

need booster shots

regularly to protect

against evolving SARS-

CoV-2 strains. Although coronaviruses

do not mutate as rapidly as the flu, there

are already multiple new and more

infectious forms of the novel coronavirus,

and COVID-19 is the third coronavirus

outbreak to occur in the last two decades.

Unfortunately, it seems that coronaviruses

will not be leaving the human population soon,

and therefore it is critical that, in addition to

vaccination prevention, there also be effective

treatment options. Nsp1 is a particularly

attractive target due to its largest role, among

all viral proteins, in affecting cell viability.

Xiong’s research on how Nsp1 leads to

pathogenicity through host cell translation

suppression suggests it may be an effective

therapeutic target. “Our hope is that what

we learn from these interactions will give

us something on the treatment front,”

Xiong said. While more research needs

to be done on the molecular interactions

between Nsp1, the ribosome, and the viral

mRNA transcript before therapies can

begin to be developed, Nsp1 seems to be a

promising future drug target. ■

BRITT BISTIS

Britt Bistis is a senior majoring in Molecular Biophysics and Biochemistry. She works

in the Noonan lab investigating the role of high-confidence autism risk gene CHD8 in

corticogenesis at a cell type-specific resolution. Outside of the lab she can be found

volunteering with special needs students and in science outreach programs or horseback

riding.

THE AUTHOR WOULD LIKE TO THANK Professors Yong Xiong and Ivan Lomakin for their time and

commitment to their research.

REFERENCES

Kamitani, W., Huang, C., Narayanan, K., Lokugamage, K.G., Makino, S. (2009). A two-pronged strategy to

suppress host protein synthesis by SARS coronavirus Nsp1 protein. Nat Struct Mol Biol, 16(11), 1134-1140.

DOI: 10.1038/nsmb.1680

Wathelet, M. G., Orr, M., Frieman, M. B., & Baric, R. S. (2007). Severe acute respiratory syndrome

coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. Journal of

virology, 81(21), 11620–11633. https://doi.org/10.1128/JVI.00702-07.

Yuan, S., Peng, L., Park, J. J., Hu, Y., Devarkar, S. C., Dong, M. B., Shen, Q., Wu, S., Chen, S., Lomakin, I. B., &

Xiong, Y. (2020). Nonstructural Protein 1 of SARS-CoV-2 Is a Potent Pathogenicity Factor Redirecting

Host Protein Synthesis Machinery toward Viral RNA. Molecular cell, 80(6), 1055–1066.e6. https://doi.

org/10.1016/j.molcel.2020.10.034



THE

UNFINISHED

PUZZLE OF

ALZHEIMER’S

DISEASE

Investigating the

relationship between two

hallmarks of Alzheimer’s

Neuroscience

FOCUS

BY RAYYAN DARJI

ART BY NOORA SAID

Memory loss. Frustrated struggles to piece together

past events. Forgetting the names of loved ones.

These are likely some of the first symptoms that

come to mind upon hearing the word “Alzheimer’s.”

As a neurodegenerative disease, Alzheimer’s is characterized by a

progressive loss of neuronal function that ultimately results in neuron

death. This degeneration is responsible for the deterioration in cognitive

and functional abilities associated with disease progression.

The devastating toll of Alzheimer’s—a currently incurable and extensively debilitating

illness—touches thousands of American families every year, with over six million current cases

in the U.S. alone. As the population ages, the number of Americans living with this condition is

projected to reach 13.8 million by the year 2060. Yet, despite afflicting so many people, the complex

puzzle of Alzheimer’s disease and the quest for how to treat it remains largely unfinished.

The progressive accumulation of a protein fragment known as amyloid-beta (Aβ) in brain

regions important for cognition has long been believed to be the underlying cause of

the neurodegeneration, neuronal death, and cognitive decline seen in Alzheimer’s.

However, components of this hypothesis have been critically questioned, such as

the scientific community’s understanding of the role of Aβ in Alzheimer’s and its

relationship with other neuropathological hallmarks.

Beyond Aβ, synaptic loss, or the reduction of connections between neurons, has been described

as the strongest neuropathological correlate with cognitive impairment in Alzheimer’s. Up until

now, however, there had been no known publications investigating this relationship in living

people, as previous work focused almost exclusively on postmortem analyses.



FOCUS

Neuroscience

To fill in these gaps, a group of researchers

at the Yale Alzheimer’s Disease Research

Unit (ADRU) recently conducted an in

vivo positron emission tomography (PET)

imaging study, imaging the brains of living

humans to investigate the relationship

between Aβ deposition and synaptic density

in the early symptomatic stages of Alzheimer’s.

Because PET is an imaging technique that

uses radioactive tracers, this allows scientists

to detect and analyze Aβ deposition in people

living with Alzheimer’s disease.

“The synaptic density PET tracer came out

very recently, and now we can look in vivo at

a live brain to study the relationship between

synapses and Aβ,” said Christopher van Dyck,

director of the ADRU and a co-author of the

paper. There were two tracers used in this

study: one that allows for the measurement of

synaptic density and a second that allows for

the quantification of Aβ in the brain.

Although the clinical presentation of

Alzheimer’s spans a broad range

of cognitive and functional

deficits, the focus of this

study was on the early

s t a g e s

of the disease, which are known as the

prodromal and mildly symptomatic stages.

Importantly, while Alzheimer’s can only be

definitively ascertained after death through

an autopsy of the brain, it can still be clinically

diagnosed using a thorough clinical history,

neurological examinations, and magnetic

resonance imaging (MRI), which can help

rule out other contributing causes that could

generate similar symptoms. “The autopsy

report demonstrating those Aβ plaques,

that was the gold standard diagnosis of

Alzheimer’s for a long time, but you can

still clinically diagnose Alzheimer’s disease

without autopsies today,” van Dyck said.

Aβ Deposition and Synaptic Density

While the full physiologic role of Aβ is still

unknown, it is understood that pathologic

Aβ forms from the sequential division of a

protein called amyloid precursor protein.

These Aβ protein fragments then aggregate

and ultimately form larger Aβ fibrils

outside of cells. This insoluble

fibrillar Aβ is what comprises

amyloid plaques, the large

deposits of Aβ outside of

cells that are characteristic

signs of Alzheimer’s.

O v e r

time, the

deposition

of fibrillar

Aβ in the brain

is thought

to approach a

plateau. “I like to

think of it as sort of an

equilibrium; it reaches

a point where you’re

accumulating amyloid

at the same rate as

you’re clearing it, and

fibrils are aggregating

at the same rate they’re

being cleared,” said Ryan

O’Dell, first author of

the paper and a fourthyear

resident in the

Yale Department of

Psychiatry.

A l t h o u g h

the presence of

Aβ deposition

is certainly a

pathologic hallmark

of Alzheimer’s, Aβ plaque buildup is generally

not well correlated with measures of either

disease severity or symptom duration. “Even

in early studies when we only had autopsy

reports to base off of, amyloid plaques tended

to correlate relatively poorly with any index

of disease severity,” van Dyck said. These

observations are likely due to the deposition

of Aβ reaching the aforementioned ceiling, at

least in later stages of the disease.

With the advent of Aβ PET imaging

and the ability to longitudinally track the

in vivo accumulation of Aβ over time, the

definition of this “plateau” has become

more refined. Specifically, the continued

accumulation of Aβ has been demonstrated

through the early, prodromal stages of

Alzheimer’s, with minimal accumulation

by the time of conversion to dementia.

Therefore, the authors postulated that in

the earlier stages of Alzheimer’s—when Aβ

is still accumulating—there would be an

observed association with measures of disease

severity, including synaptic loss. In addition,

they hypothesized these associations would

be strongest in brain regions characterized by

early synaptic loss, such as the hippocampus.

In this study, the primary analysis focused

on the relationship between Aβ deposition

and synaptic density in the hippocampus, a

brain region that plays an important role in

the consolidation of long-term memories

and that is marked by early synaptic loss

in Alzheimer’s. “Synaptic density is the

best correlate of cognition, which makes it

important to being able to look at a person

with Alzheimer’s disease and evaluate how

well their memory and cognitive function

are working,” van Dyck said.

Participants were placed into three distinct

groups after completing a series of clinical

interviews, cognitive tests, and brain scans.

The study enrolled fifty-seven individuals—

nineteen who were cognitively normal

(CN), fourteen with amnestic mild cognitive

impairment (aMCI; an earlier prodromal

stage) due to Alzheimer’s, and twenty-four

with mild Alzheimer’s dementia (a more

advanced, albeit still mild clinical stage). An

important distinction between the CN group

and the aMCI and dementia groups was

that all CN participants were characterized

by an absence of Aβ deposition, as assessed

by the Aβ PET imaging, while all aMCI

and dementia participants were classified

as positive for brain amyloid. Additionally,

and as expected, participants with aMCI

18 www.yalescientific.org

Neuroscience

FOCUS

exhibited less severe cognitive impairment

than those with dementia.

Relationship Between Aβ Deposition and

Synaptic Density

Consistent with the researchers’ primary

hypothesis, there were statistically significant

results demonstrating an inverse association

between global Aβ deposition and

hippocampal synaptic density within aMCI

participants, but not within participants with

dementia. These findings lend support to

the model that Aβ continues to accumulate

in the early stages of the disease before

approaching a plateau, a point at which Aβ

may uncouple as a primary contributor to

the ongoing neurodegenerative processes,

including synaptic loss.

However, the authors recognized that the

study’s overall findings are limited by its small

sample size and the lack of longitudinal data

gathered over a longer time. Including this

kind of data could allow for a more powerful

analysis of the relationship between Aβ

deposition and synaptic density across the

Alzheimer’s disease clinical continuum.

Extending Our Understanding of Aβ and

Synaptic Density

Although this study showed an inverse

relationship between global Aβ deposition

and hippocampal synaptic loss in the

early, prodromal stages of the disease, this

relationship was not generally observed

across other brain regions. This opens the

door to future molecular imaging studies

of Alzheimer’s.

Thus, while past postmortem and in vivo

imaging studies have shown that Aβ is not

generally well correlated with disease severity,

other pathologic proteins associated with

Alzheimer’s, such as the hyperphosphorylated

tau protein, may have a more specific

regional relationship with synaptic density.

Ongoing PET imaging studies at the ADRU

are investigating this relationship between

synaptic density and structures known as tau

tangles, and this direction is promising.

Modifications to the current study could

also allow for a more comprehensive

understanding of the relationship between

Aβ deposition and synaptic density across the

clinical continuum of Alzheimer’s. “We are also

interested in longitudinal work, which is one of

the limitations of this study, because this would


The group members of the Alzheimer’s Disease Research Unit (ADRU), taken in 2019.

allow us to measure these markers of synaptic

density, of amyloid, over time… allowing us to

see not only how those individual proteins and

measures change over time but also how their

relationship changes over time,” O’Dell said.

Additionally, these investigations into the

longitudinal relationship between synaptic

density and other pathologic hallmarks of

Alzheimer’s are currently being expanded

into the preclinical, or symptomatically silent,

stage of the disease. “The other big project

that is really exciting is looking at a preclinical

model of Alzheimer’s,” O’Dell said. “These

would be participants who are younger than

our typical cohort, maybe in their fifties or

ABOUT THE AUTHOR

sixties, and have no subjective or objective

cognitive impairment, but who are biomarker

positive, confirmed by either PET imaging or

fluid biomarker testing, for these pathologic

amyloid and tau proteins.”

Alzheimer’s disease is devastating; it

progressively destroys the control center of

the human body to the point that it can no

longer function normally. But there is much

optimism in the advancing field of Alzheimer’s

research. Research like this helps shed light

on the complex relationship between Aβ and

synaptic density in this disease, bringing us

closer to fitting one more piece in the complex,

unfinished puzzle of Alzheimer’s disease. ■

RAYYAN DARJI

RAYYAN DARJI is a first-year student in Grace Hopper interested in studying neuroscience on the premed

track. In addition to writing for YSM, Rayyan is involved with Alzheimer’s Buddies, Yale Muslim

Students Association, and Refugee and Immigrant Student Education.

THE AUTHOR WOULD LIKE TO THANK Ryan O’Dell and Christopher van Dyck for taking the time

to speak and discuss their research with him.

FURTHER READING

PHOTOGRAPH COURTESY OF CRYSTAL XU

O’Dell, R.S., Mecca, A.P., Chen, MK., Naganawa, M., Toyonaga, T., Lu, Y., Godek, T.A., Harris, J.E., Bartlett,

H.H., Banks, E.R., Banks, Kominek, V.L., Zhao, W., Nabulsi, N.B., Ropchan, J., Ye, Y., Vander Wyk, B.C.,

Huang, Y., Arnsten, A.F.T., Carson, R.E., & van Dyck, C.H. (2021). Association of Aβ deposition and

regional synaptic density in early Alzheimer’s disease: a PET imaging study with [11C]UCB-J. Alzheimer’s

Research & Therapy, 13(11). https://doi.org/10.1186/s13195-020-00742-y

Mecca, A.P., Chen, MK., O’Dell, R.S, Naganawa, M., Toyonaga, T., Godek, T.A., Harris, J.E., Bartlett, H.H.,

Zhao, W., Nabulsi, N.B., Vander Wyk, B.C., Varma, P., Arnsten, A.F.T., Huang, Y., Carson, R.E., & van Dyck,

C.H. (2020) In vivo measurement of widespread synaptic loss in Alzheimer’s disease with SV2A PET.

Alzheimer’s & Dementia, 16(7), 974–82. https://doi.org/10.1002/alz.12097


FOCUS Earth Sciences

OUT OF THE BLUE

ISLANDS OF LIFE

How biological systems may have originated in warm little pools

BY ALEXA JEANNE LOSTE

If you were to take apart a cell and

examine each of its components—

from the mitochondrial powerhouse

to the Golgi packaging center—none of

them, on their own, could be classified

as living. Zoom in even closer, and you'll

find an unfathomably complex network

of chemistry: clusters of macromolecules

whizzing past each other, transforming

in spectacular collisions to reach more

energetically favorable states.

Life is an emergent property. Every living

thing consists of billions upon billions

of nonliving things, engaging in highly

specific interactions that sustain the larger

system. How, exactly, they do so is at the

heart of the origin of life problem—the

transition from the abiotic to the biotic,

from macromolecules to the cell.

Forming a living system requires a vast

array of chemical reactions, which in turn

need to be propelled by a robust energy

source. In a groundbreaking experiment

in 1952, Stanley Miller and Harold Urey

electrified an "organic soup" of methane,

ammonia, and hydrogen, elements thought

to have been present in the early Earth’s

atmosphere. In this miniature simulation

of the ancient world, simple organic

molecules and naturally occurring amino

acids emerged, demonstrating how the

most fundamental building blocks of life

could have come to be. However, their

system could not form polymers—the

more complex chains of molecules that

make up essential structures in living

organisms. This provoked questions of

which environmental conditions would

be most suitable for polymerization, and,

importantly, which among these systems

could have existed on the Archaean Earth.

There are two leading theories in the

abiogenesis, or origin of life, debate: some

researchers conjecture that life originated

in warm little ponds, while others argue

that it was born out of hydrothermal

vents—cracks in the deep-sea floor where

tectonic plates diverge. The former theory

is popular among scientists since the "wet

and dry" seasonal cycles available to warm

little ponds have been shown to polymerize

long chains of nucleotides, while the

latter set of conditions has experimentally

produced much shorter chains. However,

up to now, the debate has favored the

hydrothermal vents theory, largely because

of a glaring Achilles' heel in the warm little

pond theory: geologists have had good

reason to suspect that the ancient Earth was

completely covered in water.

Reimagining the Water World

An article published in Nature Geoscience

by Jun Korenaga, Yale professor, and

Juan Carlos Rosas, a former postdoctoral

researcher at Korenaga's lab and currently

a researcher at the Ensenada Center for

Scientific Research and Higher Education

in Mexico, challenges the hydrothermal

vent paradigm. By modeling changes

to the depth of the seafloor due to

radiogenic heating, or the heat produced

by radioactive decay in the Earth's mantle,

the researchers found a surprising result:

the internal heat may have caused seafloor

shallowing, allowing for the emergence

of landmasses from under the sea. The

presence of these islands implies that the

warm little ponds may have existed as

theorized, containing the "organic soup"

that eventually birthed life.

The existence of subaerial landmasses,

or land exposed to the atmosphere, is

subject to the dynamics of plate tectonics.

Korenaga explained that when the layers

of earth beneath the crust of two tectonic

plates converge, the older, heavier plate

can subduct under the other into the

mantle, bringing water along with it.

Therefore, over time, the net effect is that

the earth absorbs water. Reversing that

process, scientists predict that oceans

during the Archaean era had much greater

volumes of water than they do today,

submerging all continental landmasses

and providing the rationale for the "water

world" view of ancient Earth.

Overcoming Seafloor Subsidence

Korenaga and Rosas approached the

problem from a different layer—the

seafloor topography. Presently, geologists

observe a phenomenon known as seafloor

subsidence—the lowering of the seafloor

as its tectonic plate becomes colder and

denser, moving away from the mid-ocean

ridge where it originated. This is the process

by which volcanic islands are gradually

submerged and become seamounts.

However, the Yale team predicted that

sufficient internal heating could overcome

the cooling effect, leading seamounts to

resurface as the seafloor shallows.

It so happens that there was a source of

additional heat under the Earth's surface:

Every living thing consists of billions upon

billions of nonliving things, engaging in highly

specific interactions that sustain the larger

system.


the radioactive decay of trace elements in the

mantle. Some elements radioactively decay

naturally with time, releasing atomic energy

and a small amount of heat in the process.

Currently, the concentration of radioactive

elements in the mantle is relatively low,

such that only a moderate amount of

heat is produced. However, Korenaga and

Rosas found that, by reversing the clock

on the present-day mantle concentrations

of potassium, uranium, and thorium,

the much higher concentrations that

existed during the Archaean would have

sufficiently increased radiogenic heating to

induce seafloor shallowing.

The Case for Warm Little Ponds

The argument for hydrothermal vents is

based on the extremely reactive conditions

formed at mid-ocean ridges where tectonic

plates diverge. The high temperatures from

magma heating provide a robust energy

source around which rich ecosystems and

complex reactions can thrive. Nevertheless, it

has been suggested that the concentrations of

chemicals necessary for reactivity would have

been extremely low given the massiveness

of oceans. "The ocean is, intrinsically, a

difficult place for life to emerge," Korenaga

said. Additionally, because the formation of

peptide bonds between amino acids to form

proteins is a dehydration reaction, this would

be difficult to accomplish with water as the

medium. Therefore, some scientists would

consider dry land essential to initiate life.

The evidence for land above sea


level provides the necessary geological

environment for warm little ponds to exist.

In addition to concentrating chemical

compounds more effectively, these ponds

would be exposed to a variation in annual

rainfall. The seasonal wet and dry conditions

could have driven bond formation in RNA,

which is widely accepted to have been the

original information-carrying molecule in

all organisms, before DNA had evolved.

Its ability to store and pass on information

would subject it to the Darwinian theory of

natural selection, leading to the evolution

of organisms and life as we know it.

Building Bridges, Traversing the Divide

While Korenaga and Rosas' work fits

another piece into the puzzle of the origin of

life, the specifics of the prebiotic chemistry

involved remain to be understood.

ABOUT THE AUTHOR

Earth Sciences

Abiogenesis lies at the intersection of

Earth sciences and inorganic chemistry.

According to Korenaga, his research focus

lies within the more straightforward of the

two problems, involving building models

of the Archaean Earth using physical and

chemical principles that are already wellunderstood.

"The abiological to biological

bridge remains a huge question," Korenaga

said. He explained that once the first

organism had been formed, one could trace

a line down to the currently existing species

by Darwin's theory of evolution.

Korenaga shared that one of the limitations

of the field is a lack of communication between

scientists from the geological and chemical

disciplines. "As science matures, people start

to specialize in a very narrow discipline,” he

said. "Many of the people working on the

origin of life problem are not very aware of

our contemporary understanding of geology,"

he said. He plans to continue refining the

understanding of early Earth conditions

by accounting for more components and

interactions and testing model predictions

against geological records. Communication

with prebiotic chemists is also a priority,

since an understanding of the early Earth

would provide knowledge of the relevant

environmental conditions.

Korenaga spoke about the loftiness of the

abiogenesis project and how filling the gap

between physical and biological systems

seems inconceivable at the moment. "I

probably won't see the result in my lifetime,"

he said. Nevertheless, by opening up a new

paradigm for islands on the ancient Earth,

their research contributes to the larger

international endeavor. "Once we understand

the transition from abiological to biological

stuff, it’s probably as big as Darwin’s discovery

of biological evolution," he said. ■

A R T B Y E L A I N E C H E N G

ALEXA JEANNE LOSTE

ALEXA JEANNE LOSTE is a first-year prospective Molecular Biophysics & Biochemistry major in

Ezra Stiles College. In addition to writing for YSM, she is a project head for GREEN at Yale, a

member of the Environmental Education Collaborative, the STEM Panel Chair for the Conference

Committee of the Women's Leadership Initiative, and a copy desk staffer at the Yale Daily News.

THE AUTHOR WOULD LIKE TO THANK Jun Korenaga for his time and enthusiasm in sharing his research.

FOCUS

FURTHER READING

Pearce, Ben K. D., Ralph E. Pudritz, Dmitry A. Semenov, and Thomas K. Henning. 2017. “Origin

of the RNA World: The Fate of Nucleobases in Warm Little Ponds.” Proceedings of the National

Academy of Sciences of the United States of America 114 (43): 11327–32.

Rosas, Juan Carlos, and Jun Korenaga. 2021. “Archaean Seafloors Shallowed with Age due to

Radiogenic Heating in the Mantle.” Nature Geoscience 14 (1): 51–56.


FEATURE

Virology

LEARNING THE

LANGUAGE OF A VIRUS

BY ANGELICA LORENZO

ART BY ELAINE CHENG

USING MACHINE LEARNING TO PREDICT WHICH VIRAL

MUTATIONS ESCAPE THE HUMAN IMMUNE SYSTEM

Viral escape, the strategy a virus

adopts to evade the human

immune system by mutating

just enough to avoid recognition and

destruction by host antibodies, is one

of the biggest challenges virologists face

while developing effective vaccines. It is

why a vaccine for HIV and a universal

vaccine for influenza have yet to exist.

Furthermore, it is why current vaccines

approved for emergency use against

SARS-CoV-2 may ultimately prove

ineffective against new strains of the

virus such as the the more contagious

B.1.1.7 and P.1 variants.

In an effort to predict which viral

mutations could result in successful escape,

a team of MIT researchers made use of a

machine learning technique originally

intended for natural language processing

to construct computational models of

three different surface

proteins: influenza A hemagglutinin,

HIV-1 envelope glycoprotein, and SARS-

CoV-2 spike glycoprotein.

In a recent article published in Science,

Brian Hie, an electrical engineering and

computer science graduate student at

MIT, along with senior advisors Bryan

Bryson, an MIT assistant professor of

Biological Engineering, and Bonnie

Berger, head of Computation and Biology

at MIT’s Computer Science and AI Lab,

explore how natural language components

such as grammaticality, or syntax, and

semantics, or meaning, can be used to

better understand viral evolution.

So, why a language model? To begin,

techniques for studying viral escape fall

into two main categories: experimental

and computational. One highthroughput

experimental technique

known as a deep mutational scan (DMS)

makes every possible amino

acid change to a

protein and

t h e n

measures the effect of each mutation by

analyzing some property of that protein,

such as cellular binding or infectivity.

While a DMS is effective in analyzing

mutations on a singular amino acid,

it becomes impractical—and quite

expensive—to analyze the escape

potential of combinatorial mutations.

To put it into perspective, proteins are

made up of chains of polypeptides with

between fifty to two thousand amino

acid residues, each of which can be one of

twenty unique amino acids. Considering

this complexity, testing every possible

combination of mutations in a laboratory

setting would be unfeasible.

Alternatively, machine learning models

can use statistics and algorithms to draw

patterns from large collections of data

without being explicitly told what patterns

to learn. “In natural language, that

corresponds to completing sentences and

modeling grammar and semantic similarity

or semantic change,” Hie said. For viral

escape, semantic change is analogous to

antigenic change, where the virus mutates

its surface proteins, and grammaticality

relates to adhering to biological rules in

order to survive and replicate.

Training the algorithm to model

viral escape rather than human

language involves feeding it sequences

of viral amino acid data instead of

English sentences. While machine

learning language models of proteins

previously existed, none of them looked

at both protein fitness and function

simultaneously and, therefore, could

not predict escape nearly as well as the

MIT model, which captures both fitness


Virology

FEATURE


A SARS-CoV-2 virus binds to a receptor on a host cell.

and function through the language

components of grammaticality and

semantic change.

Viral fitness, more specifically

replicative fitness, refers to a virus’s ability

to bind to a host cell, infect it, and produce

infectious offspring inside the host cell.

In the language model, viral fitness

corresponds to grammaticality while

protein function is captured by semantic

change, or the ability of the virus to alter

its surface proteins enough to evade

neutralizing antibodies. Mutating viruses

must sufficiently change their proteins

so as not to initiate an immune response

but not so much that they are unable to

fold into the correct conformation and,

therefore, lose function. Thus, the host

immune system will lose the original

ability to recognize the viruses as foreign

invaders, and the viruses will be able to

successfully enter and infect host cells.

The model was given the task of

identifying viral mutations with high

grammaticality and high semantic

change, which are characteristics of high

escape potential. Operating on amino

acid data alone and without human

instruction, the model was able to

execute this task, known as constrained

semantic change search (CSCS), by

ranking mutations based on fitness and

function. Mutations with higher scores

corresponded to viruses that were both

grammatical—able to preserve fitness

by following biological rules—and had

experienced high semantic change—were

antigenically different from the original

wildtype sequence. The results of the

model’s rankings were then validated by

comparing it to the results of a DMS.

“We started [this project] in response

to the pandemic and out of curiosity

of how we can better understand viral

evolution,” Hie said. While Bryson

and Hie usually focus their work on

tuberculosis research in Bryson’s lab,

they transitioned to studying viral

escape. "When you’re in a pandemic,

you learn about the pathogen that is

wreaking havoc,” Bryson said.

Initially, the researchers trained their

model using influenza A and HIV data.

“Once we validated the model on influenza A

and HIV, by then the data had been released

for SARS-CoV-2, and we were able to run

it… The timing was perfect,” Hie said.

In addition to scoring mutations

based on grammaticality and semantic

change, the researchers also created

visual representations of each protein

structure that showed escape potential

in different regions of each protein.

Different sections of the proteins were

color coded according to high escape

potential or high escape depletion.

Visualizing and quantifying escape

potential is significant in identifying

which areas of a protein should be

targeted by drugs. “Our whole idea is

that we look for areas that are depleted

by our predictions for escape, and we’re

suggesting that [vaccine developers]

target those areas,” Berger said.

For example, areas such as the receptor

binding domain (RBD), a region of a

virus located on its surface proteins that

allows the virus to attach to and enter

host cells, has high escape potential.

This means that targeting RBDs may

be less effective due to the fact that they

have a high possibility of mutating and

avoiding immune defenses. “For COVID,

we found this subunit domain—the S2

domain—is low on depletion, whereas

the N-terminal domain and receptor

binding domain have high escape

potential,” Berger said. This finding

suggests that because the S2 domain is

less likely to mutate, it is characterized

as a good target of antibodies instead of

the receptor binding domain.

This idea of identifying areas of escape

depletion raises the question that many

immunologists are trying to solve:

“How do you design immunogens for

regions of a protein instead of a whole

protein or a whole inactivated virus?”

Bryson asked. Immunogen design is

something immunologists must keep

in mind while developing vaccines. The

Pfizer-BioNTech and Moderna vaccines

currently being distributed in the United

States target the entire SARS-CoV-2 spike

protein rather than particular subunits.

Because new variants such as B.1.1.7

and P.1 have successfully mutated their

spike proteins, current vaccines may not

be as effective against them, as areas of

the protein may be unrecognizable to

neutralizing antibodies.

Given that the language model was

successful in learning viral dynamics

from sequence data alone, the researchers

can now search for possible mutations

on top of the SARS-CoV-2 variants that

have already emerged. “This can tell

us what are the best experiments to go

test to anticipate potential even further

escape,” Bryson said.

As new data for SARS-CoV-2 is being

generated in real time, the researchers

consistently retrain the model and publish

the results on their GitHub repository.

Considering the model’s successful

performance, the researchers hope that

the Centers for Disease Control and

Prevention will adopt their model as a tool

for understanding viral epidemics. If this

happens, as new strains of SARS-CoV-2

surface, the model could predict more

variants on top of the current mutations,

which would give scientists a narrow set of

experiments to test the efficacy of current

vaccines on and allow for modification of

the vaccines as needed. ■

IMAGE COURTESY OF U.S. CENSUS

A scientist prepares to administer a COVID-19 vaccine.

Hie, B., Zhong, E. D., Berger, B., & Bryson, B. (2021). Learning the language of viral

evolution and escape. Science, 371(6526), 284-288.



FEATURE

Robotics

BY VERONICA LEE | ART BY CECILIA LEE

ROBOTIC

THEORY

OF MIND

THE FUTURE OF ROBOTS

IS MORE HUMAN THAN

WE EXPECT

With self-driving cars, powerful

AI-like facial recognition

powering our smartphones,

and machine learning inside of

transportation apps like Uber, it seems

like we already live in a world run by

robots. However, many still believe that

there remains a clear division between

“human” and “non-human.” Sure, robots

may be able to drive along a street or

play a specific song when asked, but

humans claim the realm of emotion and

empathy for ourselves. But recent robotic

innovations suggest that such traits may

not be so unique to humans after all.

PhD student Boyuan Chen and

Professor of Mechanical Engineering and

Data Science Hod Lipson at Columbia

University are among the researchers

seeking to demonstrate just that—starting

by giving robots the ability to predict

behavior based on visual processing alone.

“We’re trying to get robots to

understand other robots, machines, and

intelligent agents around them,” Lipson

said. “If you want robots to integrate into

society in any meaningful way, they need

to have social intelligence: the ability to

read other agents and understand what

they are planning to do.”

Theory of mind, the ability to recognize

that others have different mental states,

goals, and plans than your own, is an

integral part of early development in

humans, appearing at around the age

of three. Allowing us to understand the

mental state of those around us, theory

of mind acts as the basic foundation for

more complex social interactions such as

cooperation, empathy, and deception.

In children, it can be observed in

successful participation in “false-belief”

tasks, such as the famous Sally-Anne test,

in which the participant is asked questions

to see if they understand that two fictional

characters, Sally and Anne, have different

information thus different beliefs. If a child is

able to recognize that different information

is known to different people, this is a strong

indicator that they possess theory of mind.

As children develop further, they naturally

develop the social skills needed to navigate

the world around them.

“We humans do this all the time in

lots of subtle ways,” Lipson said. “As we

communicate with each other, we read

facial expressions to see what the other

person is thinking.”

It is this very ability that Chen and Lipson

hope to one day give to robots. To do so,

however, they must first start with the basics

of theory of mind. After all, what comes

so easily to us as humans is not so easily

produced in robots. In their recent research,

they sought to find evidence that theory

of mind is preceded by something called

“visual behavior modeling.” In essence, they

wanted to see if robots could understand and

predict the behaviors of another agent purely

from visual analysis of the situation.



Robotics

FEATURE

In their experiments, the researchers

used a simple setup with a physical

robot “actor” and “observer,” in which

the observer, via a camera above,

had a complete visual of the actor’s

surroundings, including a green dot and

sometimes a barrier object. The actor

robot would only pursue the green dot if

it was visible from its point of view. If a

barrier was blocking the view of the green

dot, the actor robot would not move. Most

importantly, the observer robot had no

prior knowledge of the actor’s intentions

to pursue the green dot or the coordinates

of any of the objects in the setup. The only

information given to the observer robot

was the raw camera view. Everything

else would have to be discovered and

understood by the robot.

Such an experiment differed from

other research in the field because

the observer robot used purely visual

inputs and explicitly modeled the longterm

expected behavior of the actor.

Previous experiments gave the observer

robot symbolic information, such as

the coordinates of the actor robot and

green dot, that would make the observer

robot’s job much easier. Furthermore,

Lipson and Chen carried out their

experiments in the real world, rather

than in simulations, which added new

challenges but ultimately gave their

findings more substance for application

in existing technologies.

After being trained with 2,400 inputoutput

image pairs of the actor robot’s

actions given different scenarios, the

observer robot was presented with a new

scenario and asked to produce a single

image showing the predicted long-term

path of the actor robot. The researchers

hypothesized that the observer robot

could only be successful if it had the

ability to visualize the point of view of the

actor robot and understand from limited

information that the actor robot was

pursuing the green dot only when it was

in its field of vision—in other words, if the

observer had theory of mind.

To Chen and Lipson’s delight, the

observer robot had a 98.5 percent success

rate in predicting the path of the actor

robot. This means that the observer robot

was able to understand the actor robot’s

point of view, learn its intentions, and

predict its trajectory from visual analysis

alone. In other words, the observer

robot understood that the actor robot

had different information and thus a

different way of thinking and behaving.

Interestingly, such results hint at how

our ancestors may have evolved theory

of mind, and that they too perhaps once

used a purely visual system to predict the

behaviors of other beings.

“This was a very remarkable finding,”

Lipson said. “This is the first step

towards giving machines the ability

to model themselves, for them to have

some type of self-awareness. We’re on a

This is the first step towards

giving machines the ability

to model themselves, for

them to have some type of

self-awareness.

path towards more complex ideas, like

feelings and emotions.”

From their findings, Chen and Lipson

are optimistic about how robotic theory

of mind can help create more reliable

machines. For example, driverless cars

will be much more effective if they can

read the nonverbal cues of other cars and

pedestrians in their surroundings. Chen

also reflects on a funny story from his

stay at an intelligent hotel in China, in

which a robot delivered the wrong food

to his room and could not recognize its

mistake. According to Chen, such errors

could be avoided if robots were trained

with some social awareness and ability

to understand what other agents—in this

case, their customers—are thinking.

Ultimately, the researchers hope to

create a machine that can model itself,

leading to introspection and selfreflection

that can advance the social

integration of robots into human society.

In the short term, however, they are

working on making the experimental

situations more complex for the observer

robots. For example, what will happen

if two robots are modeling each other at

the same time? If there is some type of

challenge introduced, will they take part

in manipulation and deception?

Of course, both Chen and Lipson

understand that giving such capabilities

to robots is a double-edged sword. Both

agree that discussion about the ethics of

AI are important across all fields, not just

science. For example, issues of privacy

and surveillance, risks of manipulating

or influencing human behavior, and the

distribution of access to such powerful

technologies are all very important as we

move forward with AI.

However, Chen remains optimistic

about the future of robots and how they

will contribute to our lives.

“I’m so excited about this area of

research,” Chen said. “Even though

people may be afraid that AI will become

a threat to humans, I really view it as a

tool and resource that will be used to

improve our quality of life. Eventually,

it will become just like electricity—so

integrated into our lives that we can’t

even feel it.” ■

Chen, Boyuan, Carl Vondrick, and Hod Lipson. "Visual Behavior Modelling for Robotic

Theory of Mind." Scientific Reports 11, no. 1 (2021). doi:10.1038/s41598-020-77918-x.



FEATURE

Biochemistry

XCL1: TWO FOLDS ARE BETTER THAN ONE

BY MADISON HOUCK

ART BY ANASTHASIA SHILOV

About twenty years ago, when Brian

Volkman was still a postdoctoral

student, he was approached by

a colleague who was studying HIV and

looking to characterize a protein he had

encountered in his studies on the immune

system. The protein, now referred to as XCL1,

was identified as having an important role in

the immune system’s response. Essentially,

Volkman was tasked with determining how

the protein folds in three dimensions, like

how a piece of paper folds to create an origami

shape. Using nuclear magnetic resonance

(NMR), he started to uncover the structure

of XCL1, which would in turn tell him and

his colleague a lot about its function. When

he got his first batch of data back, he was at

a loss; it was uninterpretable and seemed to

suggest that the protein was unfolded, or had

no consistent structure.

It was only after running many more

tests under many different temperatures

and salt concentrations that Volkman

came to a startling conclusion: The

XCL1 protein had two folds.

We now know that one fold of XCL1

tells white blood cells where to go in

the body in order to fight off invaders.

The other fold also directs an immune

response, through a different mechanism,

but can also directly fight off invasive cells.

Because of these alternative forms, one

protein can have a much greater impact on

the body’s overall immune response.

But back then, not much was known about

the protein’s form or function. As Volkman

says, anyone who has taken a biochemistry

class as an undergraduate will tell you that

a protein folds in a single specific way that

is most thermodynamically favorable. The

structure of this protein then determines its

specific function in the body. This principle

is one of the core tenets of biochemistry,

and Volkman’s work was challenging

everything his field believed in.

“It took years to reach the point where

I felt confident enough to know what was

happening and write the paper. Even now,

almost twenty years later, there are people,

experts in biochemistry, who if you asked

them, ‘Can a protein do this?’ They would

say, ‘No, no, we know that’s not the case,’”

Volkman said. “That’s the hardest part—

looking at some data, some evidence, and

realizing that it’s the opposite of what you

learned in your biochemistry class and

wondering what’s right: what you learned

in the textbook or what you’re looking at

on the page in front of you.”

After Volkman’s work was finally

published, the term “metamorphic

protein” was coined. Because of this,

he considers XCL1 to be one of the first

metamorphic proteins.

But his work with XCL1 didn’t end there.

Volkman received several National Institutes

of Health grants to continue his research. “I

like to think that [Anthony] Fauci has been

supporting this over the years,” Volkman

said, laughing. With this level of funding,

he continued to study XCL1 until he met an

interested graduate student, Caci Dishman.

Acacia “Caci” Dishamn met Volkman

early in her MD/PhD program at

the Medical College of Wisconsin,

where he was her advisor. She was

specifically excited about his research in

metamorphic proteins because it went

against what she had been taught for her

entire undergraduate career. Dishman


Biochemistry

FEATURE

IMAGE COURTESY OF ISTOCK

Origami crane symbolizing how proteins fold from a twodimensional

sheet to a three-dimensional structure.

said early on in her conversations with

Volkman she could see that this would

be “paradigm-defying work.”

She compiled preliminary data that

other postdocs and graduate students had

collected about the evolutionary ancestry of

XCL1 and combined it with her own work,

eventually being published as the first author

on a recent paper about how XCL1 came to

be. Volkman says that Dishman’s drive to

push the project forward was the reason they

found something genuinely new that they

wanted to share with a broader audience.

Dishman’s work had two main findings.

First of all, it was discovered that XCL1’s

simultaneous evolution of two folds wasn’t

an accident. When many scientists look

at metamorphic proteins, they come to

the conclusion that one fold must be an

evolutionary artifact, like an appendix in

humans. The prevailing belief was that XCL1

and other similar proteins only had two folds

because they were unfinished with their

evolutionary journey and someday would

return to only having one fold. However,

when Dishman and Volkman modelled the

ancestry of the protein, they found that XCL1

started out with one fold. Over time, it evolved

to have two folds but primarily occupied the

old fold in a ratio of about nine to one. As

more time passed, the ratio became one to

nine, now primarily occupying the new fold.

If the protein was evolving to only occupy the

new fold, as was the conventional belief, the

next step would see only the new fold.

That wasn’t the case. The protein is

now present in a ratio of one to one,

found equally in both forms, and is able

to spontaneously and randomly switch

between folds under conditions within the

human body. This protein wasn’t the result


of an ill-timed snapshot or an evolutionary

mistake; rather, it was evolution’s creative

improvement to the immune response.

But how does a protein evolve from having

only one fold to having two folds? Dishman’s

next goal was to make changes in the amino

acid sequence of a chemokine protein like

XCL1 until it expressed two folds. At first,

she made small changes, trying to isolate the

specific amino acids that were important.

After making about fifteen individual

changes, one or two at a time, it didn’t seem

like her approach was going to work. It was

only when she had the idea to employ three

sets of changes at once, eleven in total, that

the protein finally became metamorphic.

Dishman says that was both the most

challenging part of the project and the most

rewarding. “When I finally figured out that

set of mutations that caused XCL1 to become

metamorphic, I was so excited,” she said.

“I had collected data for an experiment

overnight, and I went in the next morning,

and the protein I had made was metamorphic,

and I was just so amped.” Dishman added,

“People in the lab were starting to be like

‘Caci, I don’t know if you’re going to do this.

You’ve been trying for a while. You might

want to stop.’ But finally I got it.”

Why is all of this important? First of all,

now that we know that XCL1 isn’t an accident,

biologists across the world can search for

more metamorphic proteins and learn about

their functions. One important application

is the creation of targeted therapies for

diseases: If a metamorphic protein can cause

a genetic disease, finding and understanding

its structure is the next step in developing a

treatment. Essentially, if one fold of a protein

causes a disease, a powerful therapy would

be to determine how to switch to only the

other fold of that protein.

Now that they have an “instruction

manual,” Dishman and Volkman are

attempting to create metamorphic proteins

with specific functions for biological sensors,

self-assembling materials, and components

of molecular machines. The level of control

researchers have with metamorphic proteins

is much greater than that with a regular

protein—an “active” fold could be engineered

only to occur in certain conditions. This would

allow researchers to turn a protein “on” by

changing the environment. The applications

of metamorphic proteins are far-reaching,

and will likely have a significant impact on the

fields of biochemistry and bioengineering as

more developments are made.

If Volkman and Dishman had believed

in convention over their own data or listened

to critics, such advancements would not be

possible. It is only through their willingness

to defy commonly held beliefs and their

unwavering perseverance that we can even

imagine these treatments and technologies,

let alone develop them in years to come. ■

“That's the hardest part—looking

at some data, some evidence, and

realizing that it's the opposite

of what you learned in your

biochemistry class and wondering

what's right: what you learned in

the textbook or what you're looking

at on the page in front of you.

”

Dishman, A. F., Tyler, R. C., Fox, J. C., Kleist, A. B., Prehoda, K. E., Babu, M. M., ... & Volkman, B. F.

(2021). Evolution of fold switching in a metamorphic protein. Science, 371(6524), 86-90.


FEATURE

Psychology

TESTING THE MARSHMALLOW TEST

HOW IMPORTANT IS CHILDHOOD SELF-CONTROL IN ADULTHOOD?

BY DANA KIM

A

few months ago, moms from all over the world flooded

TikTok with videos of their toddlers being put to the

“marshmallow test,” in which a marshmallow was placed in

front of a child with the promise that they would receive two treats

if they did not eat it while the parent left the room. The claim was

that children who displayed enough self-control for a greater reward

would have the self-discipline to become successful as adults.

Leah S. Richmond-Rakerd, assistant professor of Psychology at

the University of Michigan, and Terrie Moffitt, professor in the

Department of Psychology and Neuroscience at Duke University,

tested this theory in their recent paper. Richmond-Rakerd

explained that the results of this study could help people age more

healthily by better understanding the effects of childhood selfcontrol

on decisions made later in life. “We were interested in

whether people with better self-control also age more slowly and

are better prepared to manage their health, financial, and social

demands of later life,” Richmond-Rakerd said. This life skill may

be more important now than ever before.

Richmond-Rakerd and Moffitt conducted their longitudinal study

using data collected from the Dunedin Study, a prospective study of

a birth cohort of over one thousand babies followed from birth to

age forty-five. The study members’ self-control was measured at ages

three, five, seven, nine, and eleven using a multi-occasion and multiinformant

strategy in which reports were collected from parents,

teachers, and even the children themselves. This differs from most

approaches: Other studies of self-control use behavioral tasks, but the

accuracy of the findings from these less-holistic experimental models

is highly contested in how well the findings actually predict behavior

in the real world. The reporting system instead identifies behavior in

the children’s day-to-day lives, such as how well they are able to wait

their turn to play a game or how frustrated they get when something

doesn’t go their way. In the study of the participants’ adulthood, aging

was measured, biologically and socially—how quickly they were

doing so across different organ systems, in addition to their financial,

health, and social skills. Did the participants have sufficient financial

knowledge? How strong was their social network?

The study found surprising results. Although childhood selfcontrol

has long-lasting implications, there is still an opportunity to

prepare ourselves for aging even when we are forty. Moreover, for the

participants, self-control was not confounded by IQ, education, or

cognitive skills as expected. This is an optimistic finding; it tells us that

social skills such as financial literacy are teachable. “Early beginnings

matter, but adulthood matters too,” Richmond-Rakerd said. “We found

that adults who exercise better self-control developed more health,

financial, and social reserves for old age—even if they didn’t have so

much self-control in early life. This is encouraging because it opens up

middle age as a potential intervention window. A lot of research has

focused on intervening in childhood, and our results indicate that the

early years are certainly important, but middle age may also be a good

time to revisit the opportunity to gettter prepared for later life.”

ART BY CATHERINE ZHANG

The study results may also have implications on our social security

system. The results shed light on a concerning pattern: People are

beginning to struggle with their physical fitness and health at an earlier

age. “Those rules for when you can retire and when you can get support

for your retirement were developed years and years ago when in the U.S.,

the median age of death was sixty-five. What we have now is that people

are living longer but they’re also falling apart younger,” Moffitt said. This

opens up an essential conversation of the importance of chronological

age compared to that of biological age.

To conclude, Moffitt gave a more concrete example. “There are factory

workers who have had really intense, heavy-duty, physical labor all their

lives. By the time they’re fifty-five, they are pretty worn out and they

should be able to retire. Whereas someone like me, a college professor

who has sat in a comfy office with air conditioning and worked on a

computer, I could really work until I’m seventy-five,” Moffitt said. ■

Richmond-Rakerd, L. S., Caspi, A., Ambler, A., D’Arbeloff, T.,

De Bruine, M., Elliott, M., . . . Moffitt, T. E. (2021). Childhood

self-control forecasts the pace of midlife aging and preparedness

for old age. Proceedings of the National Academy of Sciences,

118(3). doi:10.1073/pnas.2010211118


Protection of

the world’s

animals presents

many challenges, but

conservation’s newest

defense weapon actually

works from space. One of

the problems conservationists

and zoologists face is tracking

the location and movements of

the animals they are studying.

Isla Duporge, a Zoology Ph.D.

candidate at Oxford University,

and Olga Isupova, assistant

professor of Artificial Intelligence at

the University of Bath, led a team that

found a niche in the field of satellite

imagery technology using their

creativity to assist the conservation

fight for African elephants. Duporge

focuses on Addo Elephant National

Park, an elephant reserve in South Africa. There,

the large population of elephants allows for a more controlled

environment in which to test elephant detection software. Though

the technology for studying large animals in a homogeneous

environment has existed for quite some time, the novelty in Isla’s

approach lies in the application of machine learning.

The Isupova lab’s neural network (NN) was applied by passing a

satellite’s gaze over a particular area such that the contrast between

the animals and the surrounding landscape could be used to count

animal populations. A NN is a type of machine learning where the

makers of the study use a computer algorithm that takes in mass

amounts of data—in this case, images of the savannah. First, the

satellite takes in images of the savannah as input. Within these

images, the study makers identify the elephants. This is the training

phase; after a while, the NN sees what study makers have previously

identified as elephants and “learns” that a grey blur is actually an

elephant. The NN then produces an output based on whether or

not the data fulfills the requirements (Does the image contain an

elephant?). This is an example of supervised machine learning: the

study makers input the first large dataset manually in hopes that

when the NN encounters new information, it can correctly identify

elephants as elephants and leave non-elephants unmarked.

The study concluded that the NN program had a success

rate of around seventy-three percent for identifying elephants

against a homogeneous background and a seventy-eight percent

success rate for a heterogeneous background. Compared with

the normal human success rate of seventy-seven percent and

eighty percent, this is an astounding rate of accuracy. With this

new technology, workers on reserves would be able to spend less

time monitoring the animals and dedicate more time towards

habitat conservation, protection of the species from disease,

and advocacy efforts. The satellite used, Worldview3, has a wide

range of vision and is also capable of completing a full loop

around the Earth in less than twenty-four hours. The satellite

also boasts a range of 680,000 square kilometers roughly every

twenty-four hours. Due to the magnitude of area the satellite

is able to process, miscounting or double-counting, which are

common human errors, are far less likely to occur.


deep learning for preservation

Computer Science

BY CLAY THAMES

ART BY ELAINE CHENG

FEATURE

“While

the technology

has been used for identifying herding animals like

elephants, our NN is capable of identifying one elephant even

if it was alone. The NN can actually identify the crowd of

animals as has been done with penguins in the past and then,

from that large concentration, tell how many elephants are

there by marking them individually,” Isupova said.

The ramifications of this research? “The first step in

conservation is knowing where the animals are and how many.

From there, conservationists in Africa can use this data to

identify where large elephant populations are in the wild so that

they can be protected,” Isupova said. Elephants are frequently

subject to poaching, so keeping an accurate tally of how many

are present is vital data in order to protect them from poachers.

This research could potentially be applied to other animals

that are more endangered than African elephants as well.

“My professor is now working on wildebeests, and others are

working on cattle,” Duporge said.

To sum up Duporge’s research findings in one sentence: The

future of conservation comes from space. While the original

purpose of the NN developed by Duporge’s team was elephant

identification, it’s possible that as technology and satellite

imaging improve, the same process could be applied to smaller

animals or more heterogeneous landscapes. Though the use

of satellite imagery may be costly, its benefits far outweigh the

costs—offering reduced resources concentrated on finding the

elephants, comparable accuracy to that of traditional conservatory

counting methods, and rapid identification of the target species

in unknown locations. As conservationists continue to battle to

protect animals, this particular research can shine like the North

Star, guiding more conservation efforts that begin in space. ■

Duporge, I., Isupova, O., Reece, S., Macdonald, D. W., &

Wang, T. (2020). Using very-high-resolution satellite imagery

and deep learning to detect and count African elephants in

heterogeneous landscapes. Remote Sensing in Ecology and

Conservation. doi:10.1101/2020.09.09.289231


FEATURE

Physics

THE MAGIC NUMBER

BEHIND THE UNIVERSE?

Unfortunately for fans of The Hitchhiker’s Guide to the

Galaxy, the answer to life, the universe, and everything

is not forty-two.

It’s actually closer to 1/137.

This “magic number,” as physicist Richard Feynman puts

it, approaches the value of the fine structure constant α, a

dimensionless constant that specifies the strength of interactions

between electromagnetic forces and charged elementary particles,

such as electrons or muons. It’s a number that necessitates

precision. In fact, according to astrophysicist Biman Nath, if the

fine structure constant was even four percent smaller or larger,

stars would be incapable of sustaining the nuclear reactions that

ultimately create carbon-based life as we know it.

The constant is a critical component in predicting the Standard

Model of particle physics, a theory created in the

1970s that describes the interactions between

fundamental particles and therefore describes

the basic laws of physics. The Standard Model

can predict a property of the electron—

its magnetic moment—with high

accuracy, which is measured very well

experimentally. However, to compare

the measurement and the theory, the

fine structure constant’s value is needed,

as it is a parameter of the theory. The

comparison between measurement

and theory could result in a difference

between the two—a discrepancy that

could point to potentially new physics or

new particles that we haven’t seen yet.

Researchers Saida Guellati-Khelifa and Pierre

Cladé in the Kastler Brossel Laboratory (the LKB)

in Paris have made the most precise measurement of this

constant to an astonishing eleven decimal points: 1/137.035999206,

with a relative accuracy of eighty-one parts per trillion. The precision

is almost unbelievable—this value is three times more precise than

the previous most precise measurement of the constant, which

was measured by the Müller group at the University of California,

Berkeley.

Using a specially designed set up, the LKB calculated α using

the recoil velocity of the rubidium atoms when absorbing a

photon. This velocity measurement relates directly to the

mass of rubidium atoms, which is the limiting factor when

calculating high precision values of α.

They began with cooling the rubidium atoms with lasers. “If we

reduce the velocity distribution, we enhance the wave behavior

of the matter,” Guellati-Khelifa said. Clear wave behavior is

critical to observing the wave patterns—atomic fringes—that

are the key to measuring the recoil velocity. These atoms were

launched into an atomic elevator, essentially a vacuum chamber

BY MALIA

KUO

IMAGE COURTESY

OF WIKIMIEDIA

COMMONS

REACHING A NEW LEVEL OF PRECISION FOR THE FINE STRUCTURE CONSTANT

that the researchers used to position the atoms and cancel out

factors as significant as gravity or the Earth’s rotation, which

could affect their velocity measurements.

Here’s where it gets a little insane. The LKB chose atoms

that would occupy two stable atomic levels. They used

lasers to “split” the atom wave packet in half and created a

superposition between those two levels; one half would remain

with a velocity of zero while the other that was prepared into

the second atomic level would gain recoil velocity. A split

second later, they would use another laser pulse to recombine

these atomic halves or wave packets into one. They measured

the phase shift between these two different wave patterns to

determine the recoil velocity and therefore the rubidium atom

mass needed to calculate the fine structure constant.

The LKB found that their measurement of the

fine structure constant was in better agreement

with the experimental value of the Standard

Model than any before. Effectively, it places

limitations on the structure of electrons.

Moreover, it sets the stage for potentially

new physics, though the team is

excitedly waiting on results of a similar

experiment with the muon, which—if

it has a similar discrepancy as

their results—could provide

the basis for new physics

or a new particle. In the

meantime, they will

continue improving their

measurement of the fine

structure constant. Cladé

projected that they might

change the isotope of rubidium from Rb-87 to Rb-85 to

check their measurements for systematic effectsand to cool the

atomic cloud to ten or even one hundred times smaller to check

their measurements even further.

When asked what her favorite part of the experiment was,

Guellati immediately displayed the graphs of the atomic fringes

found from the wave patterns. “When we started the project, it

was my third version. It’s exactly like a clockmaker, a very high

technology clockmaker. You have to control everything. And what

was most exciting was when we first observed the most beautiful

atomic fringes in the world. When you see these measurements,

you think, ah, my clock worked very precisely,” Guellati said. ■

ART BY ANMEI LITTLE

Morel, L., Yao, Z., Cladé, P. et al. Determination of the finestructure

constant with an accuracy of 81 parts per trillion.

Nature 588, 61–65 (2020). https://doi.org/10.1038/s41586-

020-2964-7


COUNTERPOINT

DR. FAUCI, ARE WE

THERE YET?

BY DILGE BUKSUR

Since December 31, 2019, when COVID-19 was first reported

to the World Health Organization, the world has been

waiting to hear positive news about a COVID-19 vaccine.

At last, we have more than three successful vaccines. But success

as described by the news may not tell the full story. Surprisingly,

Yale professors Jason L. Schwartz and David Paltiel, along with

professors from Harvard University, found that the real success

of these vaccines can only be determined by the efficiency of their

implementation. Their research considered specific issues related

to vaccine distribution using a mathematical simulation that

accounted for various factors, like the speed of manufacturing

and distribution and the extent of vaccine delivery.

The Susceptible-Exposed-Infectious-Removed (SEIR) model

they used is one of the simplest mathematical models of the

possible progression of an infectious disease. It illustrates the

infectious spread through different stages. Initially, researchers

used a population size of one hundred thousand people where

they assumed 0.1 percent of the people would be exposed to

the virus and another nine percent recovered. To better reflect

the parameter of vaccine efficacy in this model, the researchers

took into account differing vaccine types, such as a preventative

vaccine, a disease-modifying vaccine, and a composite vaccine

that bears the features of both. To account for pace, researchers

assumed 0.5 percent of the population could be vaccinated in a

single day, since this was the daily percentage reached during

influenza vaccination efforts in the US.

Researchers also used alternative values to achieve a more

nuanced modelling. For example, coverage is a parameter that

is concerned mainly with the more social side of the vaccination

process. It measures public acceptance of the vaccine as well as

the availability of the vaccine. For this parameter, researchers’

base-case value was fifty percent, which led to the conclusion that,

under these assumptions for pace, it would take one hundred days

to reach the fifty percent target coverage. Additionally, the model

included epidemic severity scenarios (total number of infections,

deaths, and intensive care unit use) and the natural history of the

COVID-19 virus—which relates to the biological structure of the

virus and how it is predicted to spread over time.

Data from the study can significantly pave the way for future

public health measures. They exhibited that the efficacy of the


vaccines displayed in clinical trials plays a less significant role

when compared to implementation and the epidemiological

environment into which it is introduced. If Rt, the effective

reproductive number of the virus, is lower, a low-efficacy

vaccine can have a greater impact on the decrease in infections

than a high-efficacy one. When this rate is higher, implying

that the public health measures are not properly followed, even

the most successful vaccines fall short in decreasing infections.

The results also displayed another significant conclusion

regarding the social reality of vaccination. “Logistics of

infrastructure—such as getting the proper amounts of freezers

and doses to the exact places they need to be—has a vital role in

accelerating the effectiveness of the vaccines,” Schwartz said on

Newsmakers, a podcast series by the journal Health Affairs. He

highlighted that the governments should put ample time and

effort into helping educate the public and inform them about the

importance of these vaccines. Educational messaging should rely

heavily on communicating why vaccination is beneficial as well as

finding strategies to gather states, local administrations, healthcare

providers, and scientists to spread information on vaccine safety.

This way, we can get past the social reality dilemma.

Though we have a long way to go in achieving flawless

vaccine production, distribution, and deployment processes,

Schwartz stressed in his podcast interview that we have reached

historic progress with promising vaccines in record time. He

also expressed positivity on governmental efforts to invest in

production and distribution of vaccines. Now, all we need to do is

to put more energy towards public education and transportation

of the vaccines. With attentive governmental endeavors and

continuous efforts to follow public health measures, we will defeat

this pandemic that has turned our lives upside down. ■

Paltiel, A. D., Schwartz, J. L., Zheng, A., & Walensky, R. P. (2021).

Clinical Outcomes Of A COVID-19 Vaccine: Implementation

Over Efficacy. Health Affairs, 40(1), 42–52. https://doi.org/10.1377/

hlthaff.2020.02054

Schwartz, J. L. (2020, November 24). “All hands on DECK” - preparing

for the distribution of COVID-19 Vaccines Health Affairs Podcast

https://www.healthaffairs.org/do/10.1377/hp20201202.663555/full/


SCOPE

Public Health

HOW CLOSE IS TOO CLOSE?

NUMBERS IN THE TIME OF COVID-19

BY SOPHIA LI

ART BY CECILIA LEE

This article was originally published in Scope, YSM’s interdisciplinary

blog. For more pieces that put science in conversation with society, visit

https://medium.com/the-scope-yale-scientific-magazines-online-blog

338 days have passed since the first case

of COVID-19 was recorded in New

Haven. Ninety-four days until firstyears

are allowed back on Yale’s campus.

Only 2n+2 the number of guests allowed

in a suite at a time (n being the number

of permanent residents). A minimum

of six feet social distancing, gatherings

only allowed in “outside, well-ventilated

environments” with a maximum of ten

people. And the dreaded, all-too-familiar

two-week quarantine.

Over the past year we have been

inundated with statistics, guidelines,

and mandates that dictate our behavior,

deeming them as “safe” or “unsafe.” We

have internalized these numbers and

repeated them like mantras—but where

exactly did these guidelines come from?

COVID-19 is an airborne disease spread

by droplet transmission. In October

2020, the Centers for Disease Control and

Prevention (CDC) stated that COVID-19 is

transmitted through sneezing, coughing,

and/or speaking. These behaviors,

according to a 2007 study by researchers in

the Department of Mechanical Engineering

at the University of Hong Kong, can

produce “a million droplets of up to 100 μm

in diameter” and “several thousand larger

particles [are] formed predominantly from

saliva in the frontal part of the mouth.” Even

just talking for five minutes can generate

as many droplet nuclei as a cough can.

Quantifications of droplet transmission

distance are important data that inform

safety guidelines disseminated to the public.

COVID-19 is spread in two main ways:

droplets, which are larger, visible, and

fall to the ground

rapidly, and aerosols,

which are small and

can stay suspended in

the air for extended

periods of time. In

scientific literature, the

definitions of droplets

and aerosols are never

truly standardized

and the terms “droplet

transmission” and

“aerosol transmission”

have different

characterizations in

different studies. Thus,

exact details of viral

transmission can be

difficult to determine.

Furthermore,

parameters such

as humidity and

initial gust force can

affect particle travel

distance, and accurate predictions can

only be modeled with a select group of

parameters in scientific laboratories.

Studies on the fluid dynamics of

aerosols have been used to determine

the physical properties of droplet disease

transmission. Small droplets evaporate

more rapidly but have a slower falling

rate and can become bioaerosols—small

particles that hang in the air and are

capable of transmitting disease—whereas

larger droplets fall faster but evaporate less

quickly. Accordingly, the transmission

ability of a droplet relies heavily on the

size of the droplets being emitted.

W. F. Wells first defined this relationship

in 1934 in the Wells evaporation-falling

curve, which models the distance traveled by

droplets based on droplet size, evaporation

rate, and falling rate. On a graph with the

x-axis as droplet diameter and y-axis as

time, Wells draws two curves: one that

measures the time it takes for a droplet to

evaporate, and the other that measures

the time it takes for a droplet to reach the

ground. From this model, which assumed

unsaturated air at eighteen degrees Celsius,

Wells postulated that droplets larger than

one-hundred μm would fall to the ground

within a radius of two meters (six feet).



Public Health

SCOPE

However, the 2007 University of

Hong Kong investigation revised the

travel distances of droplets in indoor

environments by modifying the

Wells evaporation-falling curve. The

researchers used mathematical models

to relate droplet travel velocity to the

rate of mass and heat transfer and

droplet displacement. Ultimately, they

found that droplet travel distance was

profoundly affected by compounding

variables such as air currents and relative

humidity, establishing that droplets

from sixty to one hundred μm in size

could travel for more than six meters

in certain humidities if originating at

a velocity of fifty meters per second.

Additional studies conducted in 2014

and 2016 by the Bourouiba Group, which

focuses on research at the interface of

fluid dynamics and epidemiology at the

Massachusetts Institute of Technology,

have speculated that droplets originating

from violent respiratory events

(coughing or sneezing) could travel for

more than seven to eight meters.

Thus, it is challenging to quantify the

scenarios in which COVID-19 transmission

can occur, and varying datasets can make

it impossible to construct adequate safety

guidelines. To complicate matters further,

viral payload within droplets as well as

air pollution levels—pollutants can help

the virus remain suspended in the air—

also affect transmissibility of the disease.

During the COVID-19 pandemic, the

CDC and World Health Organization

(WHO) have set different guidelines on

the distance healthcare workers should

have from patients, at two meters and one

meter, respectively. How did the CDC and

the WHO come up with such guidelines,

and why are they so different?

IMAGE COURTESY OF PIXABAY

The CDC recommends six feet of social

distancing between individuals to limit COVID-19

transmission.

The data informing WHO guidelines

originated from research from the twentieth

century, which measured infection rates from

rhinovirus colds and bacterial meningitis.

This data persisted as a worldwide guideline

for the COVID-19 pandemic.

Yet, the CDC, a United States federal

agency, conducted multiple rounds of

research on viral droplet transmission and

came up with a different set of guidelines.

In 2007, the CDC published a manual

for healthcare workers detailing droplet

transmission rates. They found through

epidemiological and experimental

modeling that there is a high risk of

transmission if one is within a three-foot

radius of the patient, producing similar

results to the research informing WHO

guidelines. However, they noted that

during the 2003 global SARS outbreak,

there were reports of droplets traveling

up to six feet while retaining their

infectious capabilities. As a result, they

established that “it may be prudent to don

a mask when within six to ten feet of the

patient.” Research completed during the

2009 H1N1 flu virus outbreak, however,

revised CDC guidelines such that a “close

contact is defined as working within six

feet of the patient or entering into a small

enclosed airspace shared with the patient.”

This definition has been maintained and

continues to inform American guidelines

during the COVID-19 pandemic.

Yale has also developed its own

guidelines regarding safe practices for

students on campus, from lowering its

student capacity to suggesting guidelines

for social distancing. By limiting

gatherings to no more than ten people,

mandating an hour time limit between

uses of music rooms, and placing indoor

signs marking six-foot distances, Yale has

taken recommendations from the CDC

and State of Connecticut and modified

them to fit a university setting. But Yale

faces a unique challenge: how do you

balance student safety with the creation

of an “authentic” Yale experience?

In an email correspondence, Natenin

Cisse (MY ’22), a Yale Public Health

Education for Peers representative, said:

“There are plenty of signs and stickers

throughout [Yale libraries] to ensure that

people are socially distanced. Library

COVID-19 viral particles.

IMAGE COURTESY OF PIXABAY

workers also monitor the rooms to enforce

social distance. Of course, this isn’t the

same as a usual school year, but going to

the library to study with friends is still

feasible and enjoyable as usual, so this is

one way Yale has effectively preserved our

student experience while also ensuring our

safety.” With their guidelines, Yale seeks to

contain any positive COVID-19 cases and

prevent large, super-spreader events.

Nonetheless, no guidelines can be

completely effective. Due to varying

scientific data and the impossible task

of modelling every droplet transmission

scenario, many regard social distancing

and CDC guidelines to be inadequate.

There is still discussion over whether

or not six feet of social distancing

is enough to prevent COVID-19

transmission. On July 6th, 2020, a

group of 239 scientists from more than

thirty-two countries wrote to the WHO

urging them to expand their guidelines

beyond one to two meters and scale it

up to “several meters, or room scale.”

Although the guidelines were never

changed, it still posed a robust counter

to the magic number “six.” Thus, it is

up to the discretion of the individual

to determine what behaviors they are

comfortable with—even if it means ten

feet between you and your neighbor at

the grocery store—because guidelines

are, after all, only guidelines. ■

The full list of sources for this article

is available at https://medium.com/

the-scope-yale-scientific-magazinesonline-blog



ANNA ZHANG

(DC ’23)

UNDERGRADUATE PROFILE

BY LAUREN CHONG

PHOTO COURTESY OF ALEX DONG

Anna Zhang (DC ’23) is well known for her accomplishment

as a Forbes 30 under 30 honoree on the Art & Style

list, but her combination of artistry, innovation, and

creativity extends to the personal as well as the professional in

life. From creative photography to inspiring app ideas, Zhang

has photographed for Keds and Fujifilm, started a publication

to share the stories behind youth leaders, and designed a mobile

gaming app that advocates kindness rather than violence.

Zhang credits her passion for photography for pushing her

to start her journey in all of her projects. First experimenting

with landscape photos, she soon decided to try her hand at

concert photography. After cold-emailing over forty artists’

management and record labels, Zhang finally received a photo

pass to photograph Magic Man. Soon after, she was approved to

photograph other concerts and grew her portfolio from there.

“I started a music blog on which I shared my concert photography,

and this blog ultimately transformed into my magazine, Pulse

Spikes. I founded Pulse Spikes because there weren’t many

publications at the time that spotlighted young people’s work, and

as a photographer, I was particularly interested in people’s stories,”

Zhang said. “To bring Pulse Spikes to life, I had to create a website,

which is what prompted me to learn how to code.”

Pulse Spikes has featured artists and entertainers including

notable names such as Lana Condor, the star of the Netflix

movie To All the Boys I’ve Loved Before, and Riverdale actress

Lili Reinhart. With over twenty thousand readers per issue

and fifteen million social media impressions, Pulse Spikes is a

well-established publication made by youth for youth.

“It’s definitely a lot of work, but I just love hearing the stories

of different people around the world. I also get to collaborate

with other incredible young artists and writers who are

passionate about Pulse Spikes and sharing these stories to the

rest of the world,” Zhang said.

During the COVID-19 pandemic, Zhang decided to rebrand

Pulse Spikes and expand its mission. Rather than focusing

on arts and entertainment as the publication has done in the

past, she hopes to highlight the voices of young people around

the world, whether it’s an interdisciplinary artist sparking

conversations around environmental justice or an author

celebrating women of color.

“It’s easier in some way to do entertainment stories because there

are managers, publicists who reach out to you with pitches and

story ideas. But there are also incredible people who don’t have

publicists to reach out on their behalf or advocate for them. We

want to try to uplift the voices that are not traditionally heard in

the media, rather than those that are already heard,” Zhang said.

Zhang hopes to find an intersection between the arts and

computer science. She’s already well on this path, having ideated the

award-wining game Brightlove. As the winner of the 2019 Google

Play Change the Game Challenge, she served as the Creative

Director of Brightlove when bringing the game to life. Brightlove

aims to award players for positive actions, and all the objectives

circle back to kindness and standing up against injustice.

With over ten thousand downloads on the Google Play

store and a spot in an exhibition at the National Museum of

American History, Brightlove is a product of her spontaneity.

“I just thought of it one day when I realized the number of

games that reward violence. I don’t think innovation necessarily

has to come from a ‘I’ve never seen this before’ sort of an idea—I

think it can come from elements that have existed separately in

the past and combining them in a different way,” Zhang said.

Zhang hopes to continue her creative weaving of multiple fields

in one by majoring in Computing and the Arts at Yale. While she

is still exploring her potential career interests, she ultimately hopes

to put innovative ideas into the world that bring people together.

“I’m just in the same boat as everyone else. I don’t really

know what I want to do career-wise, but my general interests

are in the intersection between technology and art. I’m not

too sure what the future holds, but I am excited about all of

the possibilities.” ■


OWEN GARRICK

(MD ’98)

ALUMNI PROFILE

BY XIAOYING ZHENG

IMAGE COURTESY OF OWEN GARRICK

Growing up in a majority Black and minority neighborhood,

Owen Garrick (MD ’98, MBA) had always been aware

of the health disparities that disproportionately affect

minority communities. When he began college, Garrick began to

deepen his interest in medicine in hopes that he would play a role

in addressing these disparities. As Garrick continued exploring

the intersections between medicine, public health, and business,

he began exploring different avenues to make healthcare more

equitable, merging his diverse interests to make a difference for his

family and community in their access to quality healthcare.

Fascinated by people and social sciences, Garrick majored in

Psychology at Princeton. Although he describes his undergraduate

experience as typically pre-med, it is clear that he diverged from

the traditional route. During these years, he began to develop

a broad interest in the business side of healthcare, gravitating

toward summer analyst positions outside traditional research and

clinical experiences. After college, Garrick opted to take two gap

years to work as a financial analyst in New York City and then at

his cousin’s construction company while living in the Caribbean.

It wasn’t until medical school when Garrick’s interest in business

became more central to his medical career. Between his first and

second year at the Yale School of Medicine, Garrick found an

intersection between medicine and business as an intern at Merck

in the Vaccine Division, where he helped write the first commercial

analysis for the human papillomavirus (HPV) vaccine. As Garrick met

doctors who were working on marketing strategies for pharmaceutical

companies, he started seeing a clearer path for himself. “Help launch a

drug that cures two million people, right? That’s the inflection point I

had in terms of my career, away from clinical practice more toward the

business side of healthcare,” Garrick said. “It made me realize that I can

do something a little different and still make an impact on healthcare.”

At the time, medicine and business functioned relatively

independently of one another. Although Garrick met physicians

at Merck who worked on marketing and business, he said very

few had both an MD and an MBA. Garrick would attend events

at the Yale School of Management before the combined MD/MBA

program existed. But this did not stop Garrick from pursuing his

passion for utilizing business to impact healthcare. When asked

about the difficulties that pursuing this path entailed, Garrick

responded simply, “I just decided I’m going to make this work.”

Today, Garrick has struck a balance between his interests in medicine,

business, and public health while staying true to his original goals. He

dedicates his time to bridging health disparities among underserved

ethnic and racial groups through his work with Stanford Precision

Health for Ethnic and Racial Equity Center (SPHERE) and as CEO

of Bridge Clinical Research, a contract research organization that

specializes in research and development in a variety of therapeutic areas.

Recently, Garrick has launched a collaboration between Bridge

Clinical Research and SPHERE, which is one of five National

Institutes of Health centers focused on using precision medicine to

address health concerns specific to underserved racial and ethnic

groups. Recognizing that health disparities that affect certain racial

and ethnic groups result from environmental as well as genetic

differences, the study focuses on the enrollment of sickle cell

disease patients in precision health research as well as the effects of

the race of the physician on a patient’s view on the research.

Sickle cell disease (SCD) is a hereditary blood disorder that

primarily affects populations in Mediterranean, the Middle East,

the Caribbean, and South and Central America. When groups

uniquely affected by a disorder such as SCD are not participating in

precision health research, it negatively impacts the potential of new

treatment options and innovations. The study hopes to address the

issue of historical underrepresentation of demographic groups in

clinical and biomedical research. Through merging his interest in

business and passion for bridging healthcare disparities, Garrick

has become a leader in cutting-edge research that brings to light

systematic barriers in biomedical research today.

Garrick believes in the importance of taking initiative to explore

new avenues in hopes of addressing the problems he is passionate

about. “If you see something wrong in the world, or missing in

the world, the opportunity to create the solution is really, really

fascinating, right?” Garrick said. “It’s fun; it’s fulfilling. And you

might fail at it a few times, but you have to get comfortable with

failing and learn how to fail fast. The successes will come.” ■



BLACK MIRROR, DISCRIMINATORY

DESIGN, AND "THE NEW JIM CODE"

BY SELMA ABOUNEAMEH

If you’ve ever watched the Netflix series Black Mirror, you’re well acquainted

with the on-screen consequences of artificial intelligence gone rogue, invasive

medical technologies, and intrusive surveillance methods. The show acts as

a satirical commentary on both the role that technology plays in our society

and the role society plays in creating technologies that have unintended, often

destructive outcomes. After all, whose problems are technologies meant to solve,

and whose problems do “innovative solutions” exacerbate?

This is just one question that Ruha Benjamin, sociologist and associate

professor of African American Studies at Princeton University, posed to

students in her course, "Black Mirror: Race, Technology, and Justice,” taught

in Fall 2020. The course drew its inspiration from her most recent book, Race

After Technology: Abolitionist Tools for the New Jim Code.

In her work, Benjamin analyzes how the history of racial coding—a system

that facilitates white supremacy—is deeply intertwined with discriminatory

design. She walks readers through examples of discriminatory design—beauty

algorithms that favor whiteness, soap dispensers that fail to recognize dark

skin, and rating systems used to track social standing—prompting us to think

about the social systems that allow these technologies to exist in the first place.

Benjamin gives a name to the employment of technologies that, regardless of

intent, amplify racial hierarchies: “The New Jim Code.”

“The New Jim Code” isn’t simply defined by the existence of discriminatory

technologies. Benjamin structures her book around four major components that describe

this era: engineered inequity, default discrimination, coded exposure, and technological

benevolence. The strongest part of her analysis is her reliance on storytelling to engage

readers and stress the tangible consequences of discriminatory design.

When asked what message she hoped her students took away from her course,

Benjamin articulated the importance of human experience. “[W]e have to take

stories as seriously as we do statistics… speculation is not just what happens in

books, films, and science fiction, but… the technologies that we use and build are

PHOTOGRAPH COURTESY OF RUHA BENJAMIN

the materialization of someone’s imagination,” she said. Through her analysis of lived

experience and pop culture references, readers are able to recognize the racialized

social hierarchy that decides whose problems get solved.

Benjamin concludes her book with an important chapter describing ways to fight the New Jim Code. We must both recognize the oppressive

social systems that have led to a “default” of discriminatory design and act to dismantle them. A large part of this responsibility lies with students:

the future leaders of STEM fields that have been defined by long histories of racism. Benjamin is an advocate for STEM education reform in this

regard. “I’d love more STEM students to understand that their disciplines are located in a hierarchy of knowledge where some ways of codifying and

understanding the world… trump and displace other humanistic and experiential ways of knowing,” Benjamin said. “Part of working in solidarity

with people and communities who are most harmed by unjust systems means engaging in the varied forms of knowledge they bring to the table.” ■

SCIENCE IN TH



THE SURGEON'S CUT

BY TEJITA AGARWAL

IMAGE COURTESY OF ON TAP SPORTS NET

Van der Pool, J. & Cohen, A. (Executive Producers). (2020). The

Surgeon's Cut [TV Series]. Netflix.

It is not easy to sit with a pregnant woman while monitors all around you

tell you her fetus’s heart is slowing; her child is dying.

This is the situation fetal surgeon Kypros Nicolaides of King’s College

Hospital found himself in. His own heart racing, he pushed blood directly

into the fetus’s heart just in time, saving its life. Over the course of four

episodes, Netflix’s The Surgeon’s Cut follows and humanizes Kypros and

three other surgeons, each revolutionaries of their fields. Like life, the show

starts with pregnancy and birth, where Kypros works his miracles.

When he performs surgeries, Kypros asks his patients to hold his arm, so they feel

they are on a team with him. He says his role as a surgeon is to serve as a guide, leading

the parents through complex operations, some of which he developed himself.

The second episode follows Mayo Clinic neurosurgeon Alfredo Quinones-

Hinojosa, fondly referred to as Dr. Q. While Kypros is enthralled by the beginning

of life, Dr. Q says the brain holds our humanity. He compares surgery to a dance: the

brain dances with the rhythm of the heart, and his body dances as his feet and hands

control careful surgical movements. In these moments, when he commits the sacred

act of opening someone’s skull, he feels intimately connected to his patient’s soul.

Dr. Q sees each surgery as an obstacle, and his past empowers him to face these

obstacles with determination. Dr. Q left Mexico at nineteen and became a farm

worker, a cleaner, then a welder, all while learning English at night school. Seven

years after leaving the farm, he began medical school at Harvard University.

While the brain holds our humanity, the liver is where our souls are—at least

according to Nancy Asher, a transplant surgeon at the University of California,

San Francisco. She is artful, impatient, and in constant pursuit of excellence. “I

think you have to have fearlessness tempered by fear of failure,” Asher says while

describing the job of a surgeon. Her impact extends beyond the operating room:

she invests in mentorship for women in surgery, she is an activist against organ

trafficking, and she has published a large body of research.

A surgeon’s greatness depends on something beyond solely technical skill,

and like Asher, Devi Shetty’s impact is immeasurable. Devi Shetty is a heart

surgeon in India. Describing his work as Mother Teresa once did, Shetty

says that when God created babies who had holes in their hearts, He saw

the mistake and sent Shetty to help them. Shetty has worked hard to develop

a relationship with rural India, and the hospital he created can now offer

operations to thousands of patients who otherwise could not afford them.

The Surgeon’s Cut gives us a glimpse into the trials and excitements of

surgery—from birth to death, from fetus to brain, from liver to heart. The show

reveals who these surgeons are at their cores: creators, visionaries, and artists. ■

E SPOTLIGHT



INTO THE

NEWSROOM

TEACHING THROUGH TIKTOKS

By Ann-Marie Abunyewa

IMAGE COURTESY OF @HANKGREEN1 ON TIKTOK

Ever wondered what our appendix actually does? Or why you

feel like sneezing when you pluck your eyebrows? How about

why the spider in your bathroom only has six legs? Well,

Hank Green has an answer for that. You might have encountered

Hank on his CrashCourse channel, which he co-founded with

his brother John, while you were cramming for that high school

biology test. Now he’s migrated to TikTok, where he shares some of

his hot takes and answers some of the scientific questions that may

(or may not) be on your mind—all while maintaining his everfamiliar

eccentric personality between two of his largest platforms.

Hank Green is one of many creators on TikTok who use their

platforms to talk about science. In his most popular TikToks, his

followers submit videos asking any question on their minds, and

Hank directly posts his responses on his page. The TikToks with

the most views match his high-energy YouTube persona and use

lightheartedness and sarcasm to point out that he is not always right

and should not be the only scientific authority his viewers consult.

You might also remember the aesthetic whiteboard illustrations

and the infamous “Periodic Table Song” from AsapScience’s YouTube

channel. Well, Greg and Mitch, the channel’s creators, have also brought

their platform from YouTube to TikTok. Still, their style of disseminating

information is a little different. Some of their most popular videos

are reminiscent of the illustrative visuals they are known for on their

YouTube channel. But others involve social commentary on STEM,

dance breaks with captions calling attention to our reckless destruction

of the planet, and Greg and Mitch’s everyday thoughts and hot takes.

Hank, Greg, and Mitch never seemed to have sacrificed their

personas on TikTok. Of course, their long-form content on YouTube

can’t necessarily be translated onto TikTok. Instead, TikTok allows

their audiences to see a more personable side that may not have

been portrayed in the same way on their main YouTube channels.

TikTok’s sixty-second time limit better accommodates short tidbits

than complex concepts. This allows them to focus more on aspects

that enable them to better connect with their audience—like Q&As

or talking about their personal lives.

As for creators that have built their platforms solely on TikTok,

Darrion Nguyen (@lab_shenanigans) and Hailey Levi (@

chaoticallyscience) are worth checking out. Many of Darrion’s TikToks

use sounds from reality shows to help playfully illustrate concepts

helpful for studying biochemistry while others showcase some of his

after-hours antics as a research technician. One of Darrion’s most

popular videos shows him pasting images of James Watson, Francis

Crick, and Maurice Wilkins in his Mean Girls-inspired Burn Book.

He alludes to how they snubbed Rosalind Franklin of her deserved

recognition for identifying the double helix of DNA. The humor and

classic references that Darrion incorporates are starting points for a

social commentary on science and science history.

Meanwhile, Hailey is a PhD student who creates videos to prove

that science isn’t as dull or out-of-touch as it is sometimes portrayed

to be. Her most recent posts showcase her having fun during her

after-hours, whether she is switching on the vortex mixer to Gloria

Estefan and Miami Sound Machine’s “Conga” or doing the Perfect

Match trend with her lab mates. But she also puts out advice on

starting graduate school and uses her platform to talk about being

a person of color in STEM. Periodically, she educates viewers on

prominent black women in STEM. She empowers her audience

based on the importance of seeing other black women making

significant strides in fields in which they’re underrepresented. From

Hailey’s content, you feel like you’re connecting with a supportive

peer mentor and easy-going friend.

What do all of these creators have in common? They have all found

ways to make attention-grabbing videos that promote science—

but not exactly in a format that is as high-stakes as your nine AM

chemistry class or as passive as your asynchronous math class.

Because these creators only have sixty seconds, the points that they

communicate must be incredibly concise and clear. Moreover, they

sprinkle in their personalities and humor to make learning STEM

more engaging and more fun. Maybe Hank’s status as a Gen-X

member makes his TikToks more entertaining as he attempts to

understand the questions coming from his majority Gen-Z audience.

Meanwhile, Darrion’s use of pop culture helps boost his relatability

in his videos. It is no wonder that TikTok has become a popular

destination for access to science and scientific news. ■

Brown, G. & Moffit, M. [@asapscience] (n.d.) AsapSCIENCE

[TikTok profile]. TikTok. Retrieved February 24, 2021

Green, H. [@hankgreen1] (n.d.) Hank Green [TikTok profile].

TikTok. Retrieved February 24, 2021, from https://www.tiktok.

com/@hankgreen1?lang=en

Levi, H. [@chaoticallyscience] (n.d.) Hailey [TikTok profile].

TikTok. Retrieved February 24, 2021, from https://www.tiktok.

com/@chaoticallyscience?lang=en

Nguyen, D. [@lab_shenanigans] (n.d.) Darrion Nguyen [Tik-

Tok profile]. TikTok. Retrieved February 24, 2021, from https://

www.tiktok.com/@lab_shenanigans?lang=en


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