YSM Issue 95.1

Yale Scientific

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

MARCH 2022

VOL. 95 NO. 1 • $6.99

12

HAZARDS OF THE HIMALAYAS

CLASH WITH TODAY’S

URBANIZATION PROCESS

MODELING

14

MINDS

HUMANIZING

16

MOUSE MODELS

THE META GUT: CONSERVATIONAL

19

CLUES PROVIDED BY HIPPO POOP

VISUALIZING THE HEART OF

22

PHOTOSYNTHESIS

TABLE OF

VOL. 95 ISSUE NO. 1

COVER

12

A R T

I C L E

Hazards of the Himalayas Clash with

Today's Urbanization Process

Daniel Ma

Nearly half the population of the Himalayas live in areas susceptible to multiple natural hazards. A

new machine learning model lets Yale researchers examine all of those hazards at once.

14 Modeling Minds

Katrina Starbird

Linguistic communication can often seem like a stunning miracle when it works and like an

insurmountable challenge when it doesn’t. Dr. Jara-Ettinger and Dr. Rubio-Fernandez test how

psychology explains this feat.

16 Humanizing Mouse Models

Ryan Bose-Roy

Normal laboratory mice don’t usually get COVID-19, but a team of researchers at the Yale School

of Medicine have created a humanistic mouse model that mimics the severe infection symptoms

in humans. Their work has big implications for the study and treatment of the disease.

19 The Meta Gut: Conservational Clues

Provided by Hippo Poop

Risha Chakraborty and Hannah Shi

Can research on hippo poop change our understanding of biodiversity? Find out how the hippo gut

microbiome may participate in the biological and geochemical processes in the Mara River Valley.

22 Visualizing the Heart of Photosynthesis

Hannah Barsouk and Shudipto Wahed

Yale researchers have reported a novel, high-resolution structure of the protein responsible for capturing

light energy in all photosynthetic organisms. Their findings promise to help unlock longstanding mysteries

about the mechanism of photosynthesis and how it can be used to generate artificial solar fuels.

2 Yale Scientific Magazine March 2022 www.yalescientific.org

CONTENTS

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

4

6

25

34

Q&A

NEWS

FEATURES

SPECIALS

Fishy Driving: Can Fish Navigate Outside of Water? • Eva Syth

Palm Reading Isn't a Myth: What Fingerprints Tell Us About Limb

Development • Odessa Goldberg

Could Carbon Dioxide Be Renewable Energy's Newest Rising

Star? • Maya Khurana

To Diagnose or Not To Diagnose • Gonna Nwakudu

A Holistic Model of Electric Vehicle Carbon Emissions • Tiffany Liao

Stressed Out? You Could Be Aging Faster • Kelly Chen

These Are Not the Genes You're Looking for • Sophia Burick

Delving into Dopamine • Victoria Vera

Halting and Revving the Engines of Sperm Cells • Christopher Esneault

Hello Haloscopes • Isabel Trinidade

Bomb-Sniffing Insects • Elisa Howard

A Sticky Situation... Underwater • Eunsoo Hyun

Can Dogs Distinguish Human Languages? • Breanna Brownson

How Pigs Could Help Us Pee • Kayla Yup

The Precise Choreography of Nature's Master Weavers • Hannah Han

Video Games for the Win • Crystal Liu

Undergraduate Profile: Kate Pundyk (BF '22) • Catherine Zheng

Alumni Profile: James Diao (MY '18) • Yusuf Rasheed

Science in the Spotlight: Science Denial: Why It Happens in Don't

Look Up • Sophia David

Science in the Spotlight: Reviewing The Anthropocene Reviewed • Lucy Zha

Counterpoint: Salamanders Should Not Be Alive • Nathan Wu

Hidden Histories: The Shrewd Family Business That Sold Time • Dhruv Patel

www.yalescientific.org

March 2022 Yale Scientific Magazine 3

&

By Odessa Goldberg

FISHY DRIVING: CAN

FISH NAVIGATE OUTSIDE

OF WATER?

By Eva Syth

Goldfish are able to drive vehicles, suggests a new study

from researchers at Ben-Gurion University of the

Negev, Israel. Yes, you did read that correctly. The

researchers studied the concept of domain transfer methodology,

which refers to when a species applies an existing skill in an

environment outside its own. In this study, the researchers

investigated the ability of goldfish to transfer navigation skills

from aquatic to terrestrial environments.

To carry out this study, the researchers constructed a Fish

Operated Vehicle (FOV), consisting of a rectangular prism-shaped

fish tank mounted on wheels. When the fish swam to an edge of

the tank, the FOV would move in the direction of that edge. To

test the terrestrial navigation capabilities of the goldfish in the

study, the researchers mounted a colored panel on the wall of the

examination room. The goldfish received a food pellet reward

when they drove the FOV to the panel. The researchers found that

even after changing the panel’s location or adding decoy panels,

the goldfish were able to reach the panel consistently.

The results of this successful goldfish navigation led to several

key findings. For example, goldfish are cognitively able to learn

tasks outside their natural environment. Additionally, while you

likely won’t catch a goldfish driver cruising down the highway

alongside you anytime soon, the success of the goldfish navigation

skills in both aquatic and terrestrial environments implies a

potential universality in spatial representation, whether in water

or on land. ■

PALM READING ISN’T A MYTH:

WHAT FINGERPRINTS TELL US

ABOUT LIMB DEVELOPMENT

Come, come! Enter my ancient and mysterious tent where

I can tell you your fears, dreams, and futures with only

a glance at the palm of your hand. Well…maybe not

exactly, but I could tell you about the expression of your gene,

EV11. A group of scientists from the International Human

Phenome Project decided to compare people’s fingerprints to

their genomes. They found forty-three regions of interest but

focused on the EV11 gene, which is involved in regulating how

your limbs develop in the womb. So instead of your future,

fingerprints may actually reveal the length of your fingers or your

risk of leukemia. Fingerprint readings are a serious business.

Certain patterns on your hands, such as skin patterning or

palm creases, are associated with congenital genetic disorders

like Down’s syndrome. These interrelated traits suggest that

genes associated with fingerprint development are pleiotropic,

meaning that the same genes affect multiple traits with different

phenotypes. These scientists plan to further investigate how

exactly this pleiotropic mechanism works. Perhaps fingerprints

could be used as a diagnostic tool in the future. So, I may not

be able to read your future by studying your palms, but by

studying your fingertips, I could tell you about your embryonic

limb development. And that’s pretty cool. ■


The Editor-in-Chief Speaks

MICROSCALE POWER

This year marks the second anniversary of the ongoing COVID-19

pandemic. Heading into 2022, we are grateful for the science and

technology that have allowed us to approach a post-pandemic world.

The first vaccines, composed of tiny strands of mRNA, were critical steps

to overcoming the hardships and suffering caused by the virus. Currently,

researchers are finding novel methods to combat variants and make vaccines

more accessible, missions at both cellular and societal levels. Science as a whole

parallels these themes—the smallest agents can have the largest effects.

In this issue of the Yale Scientific Magazine, our articles highlight the

meticulous nature of the world around us, from the influence of microorganisms

on the greater environment (pg. 19) to the molecular structures that make

photosynthesis possible (pg. 22). In our minds, subtle shifts in personal mental

states can interact with interpersonal communication (pg. 14) while small but

powerful changes can replicate human SARS-CoV-2 infection in mice, shedding

light on how to best treat infection (pg. 16).

Our cover article spotlights an example of the seemingly minor affecting the

largest of phenomena: natural disasters. Researchers developed machine learning

models using factors in urban Himalayan environments to indicate the risk for

natural hazards (pg. 12). These discoveries reveal the power of a single unit in a larger

network and how investigating the minuscule leads to learning about ourselves, the

environment, and potential solutions to global issues.

In this era of pervasive interconnectedness, often too vast to comprehend, we

are reminded that the actions of one do impact the world—beyond one’s uniquely

perceived world. Regarding the pandemic, heroic sacrifices of front-line workers

and individuals doing their part to protect the greater community all contribute to a

continued inhabitance of the “new normal.” We must respect each human existence

as a distinct impression and perspective; each human contribution is undoubtedly

invaluable, especially in scientific endeavors. For example, Kate Pundyk ’22 (pg. 34)

brings a unique perspective on the intersection between social policy and technology,

and James Diao’s ‘18 (pg. 35) integration of machine learning with pathology is already

helping develop wearable medical technologies.

With the beautifully intricate connections between the micro and macro levels

in which society and science operate, we would like to express our most sincere

gratitude to everyone who participates and contributes to the Yale Scientific team—

mentors, staff members, and masthead alike. Our partnership with Yale Science and

Engineering Association and the Yale Alumni Association has also been essential for

our ability to communicate beyond Yale’s campus. Finally, thank you to each and every

reader for giving us the opportunity to share these stories and discoveries.

About the Art

Jenny Tan, Editor-in-Chief

This issue’s cover illustrates just

some of the natural disasters—

flooding and earthquakes—that

occur in the Himalayan region.

A new machine learning model

may help assess the risk of natural

disasters in micro-urbanized

regions and allow for better

preventative measures.

Anasthasia Shilov, Cover Artist

MASTHEAD

March 2022 VOL. 95 NO. 1

EDITORIAL BOARD

Editor-in-Chief

Managing Editors

News Editor

Features Editor

Special Sections Editor

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PRODUCTION & DESIGN

Production Manager

Layout Editors

Art Editor

Cover Artist

Photography Editor

BUSINESS

Publisher

Operations Manager

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OUTREACH

Synapse Presidents

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Synapse Events Coordinator

WEB

Web Managers

Head of Social Media Team

Social Media Coordinators

SENIOR STAFF WRITERS

Hannah Barsouk

Ryan Bose-Roy

Rayyan Darji

Krishna Dasari

Alex Dong

STAFF

Tejita Agarwal

Luna Aguilar

Gaukhar Alzhanova

Ryan Bose-Roy

Kelly Chen

Patryk Dabek

Sophia David

Danielle de Haerne

Chris Esneault

Odessa Goldberg

Saacchi Grewal

Bella Guzman

Sydney Hirsch

Elisa Howard

Eunsoo Hyun

Hannah Han

Elisa Howard

Cindy Kuang

Sophia Li

Dhruv Patel

Maya Khurana

Iva Knezevic

Catherine Kwon

Tiffany Liao

Elizabeth Lin

Cynthia Lin

Crystal Liu

Daniel Ma

Anjali Mangla

Cindy Mei

Chloe Nield

Gonna Nwakudu

Dhruv Patel

Himani Pattisam

Alexandra Paulus

Jenny Tan

Tai Michaels

Maria Fernanda Pacheco

Madison Houck

Alex Dong

Sophia Li

Cindy Kuang

Ethan Olim

Tori Sodeinde

Breanna Brownson

Hannah Han

Kayla Yup

Anna Calame

Hannah Huang

Meili Gupta

Catherine Zheng

Ann-Marie Abunyewa

Brianna Fernandez

Malia Kuo

Anasthasia Shilov

Jenny Wong

Jared Gould

Lauren Chong

Sophia Burick

Shudipto Wahed

Krishna Dasari

Lucy Zha

Rayyan Darji

Hannah Barsouk

Risha Chakraborty

Bella Xiong

Katherine Moon

Emily Shang

Anavi Uppal

Abigail Jolteus

Elizabeth Watson

Raquel Sequeria

Anavi Uppal

Kayla Yup

Yusuf Rasheed

Noora Said

Sydney Scott

Hannah Shi

Georgia Spurrier

Katrina Starbird

Eva Syth

Zeki Tan

Connie Tian

Isabel Trindade

Victoria Vera

Sherry Wang

Norvin West

Nathan Wu

Sophia Zhao

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

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NEWS

Chemistry / Medicine

COULD CARBON

DIOXIDE BE

RENEWABLE

ENERGY’S NEWEST

RISING STAR?

BY MAYA KHURANA

TO DIAGNOSE

OR NOT TO

DIAGNOSE

BY GONNA NWAKUDU

IMAGE COURTESY OF THE ECONOMIC TIMES

IMAGE COURTESY OF PXHERE

Carbon dioxide has long been branded an irredeemable

chemical waste, but new research is showing that it can

be extremely useful if harnessed correctly.

A study by graduate student Conor Rooney and his colleagues

at the Wang Lab in Yale’s Department of Chemistry highlighted

alternative uses for this chemical waste. In their experiments,

carbon dioxide was converted using electricity and water such

that it could undergo bond formation with a nitrogen-containing

molecule. “Carbon-nitrogen species are [very common] in

a lot of the valuable chemicals that we rely on in our economy,”

Rooney said. “If we can take carbon from CO 2

instead of from [a]

fossil fuel byproduct, then we’re able to make these carbon-nitrogen

bonds in a sustainable fashion.”

The research team was able to synthesize a common class of

chemicals known as N-methylamines with electrochemical

reduction, a process that “hasn’t really been done [before],”

Rooney said. But what is most exciting about the transformation

of carbon dioxide into fuels is that it can create a green

source of energy. Carbon dioxide would be converted using

an energy source, which, in the case of electrochemical reduction,

is electricity. The reaction would, in turn, produce

an energy-dense fuel that could then be used to further fuel

the reaction. “It’s an energy storage idea to have a circular

carbon economy,” Rooney said.

Moving forward, the Wang Lab will continue to investigate

ways to create a circular carbon economy by researching sustainable

methods to synthesize more carbon-nitrogen species.

In the meantime, it is time to rebrand carbon dioxide as a promising

resource that could play a prominent role in the future of

sustainable energy. ■

After the opioid epidemic peaked between 1990

and 2013, one challenge healthcare professionals

continue to face is how to treat patients on long-term

opioid therapy (LTOT) who are at risk of addiction.

To better comprehend this challenge, Dr. William Becker

and his team at the VA Connecticut Healthcare System and

Yale School of Medicine invited medical specialists from the

U.S. and Europe to discuss new diagnostic criteria for patients

on LTOT for whom the benefit of the therapy is no longer outweighing

the harm, but who may not meet criteria for opiate

use disorder (OUD).

Specialists who favored the creation of new diagnostic criteria,

like Becker, want to shine light on the unique circumstances these

patients face. “We did have a substantial minority of experts who

said… there should not be a different entity,” Becker said. “We’ve

heard from these experts that if we create a new diagnosis, it

may… have the unintended consequence of stigmatizing people

who have opioid addiction to non-medical sources of opioids.”

In continuing this conversation, Becker strives to incorporate

more specialists from diverse racial backgrounds, as well as

patient voices. “There has been a strong movement in bringing

persons with lived experiences into clinical research,” he said. “It

hasn’t happened much… in terms of thinking of creating diagnostic

entities, but it probably should.”

Nevertheless, Becker is excited for this conversation to lead

to new ways of tackling patient needs. “We have to be proactive

earlier,” Becker said. “We can identify this early, give it a name,

and then develop protocols for getting appropriate treatment to

patients sooner rather than waiting until more adverse consequences

develop.” ■


Environment & Technology / Psychology

NEWS

A HOLISTIC MODEL

OF ELECTRIC

VEHICLE CARBON

EMISSIONS

STRESSED OUT?

YOU COULD BE

AGING FASTER

BY TIFFANY LIAO

BY KELLY CHEN

IMAGE COURTESY OF AAA LIVING

IMAGE COURTESY OF WIKIMEDIA COMMONS

Electric vehicle companies like Tesla and Rivian are

making waves in the automotive industry, with Tesla

expected to surpass General Motors’ vehicle sales by 2023.

However, as the electric vehicle (EV) industry has erupted into

the spotlight, concerns regarding the indirect emissions from

the EV life cycle have emerged. While it is clear that tailpipe

emissions from combustion engines are significantly reduced

with EV adoption, the effects of indirect emissions from the full

life cycle of an EV can be difficult to capture.

Researchers at the Yale School of Environment, led by postdoctoral

researcher Paul Wolfram, have applied an integrative

approach, combining supply-demand concepts of economics

with ecology to accurately capture the effects of indirect emissions.

“Combining engineering and economics methods allows

us to capture more of the dynamics that life-cycle cost models

themselves can’t, such as market cycle and supply-demand mechanisms,”

Wolfram said.

The group found evidence contradicting concerns around the

“dirtiness” of battery life cycles stemming from raw materials

mining and a material-intensive manufacturing process. The effects

of the latter can be mitigated by recycling. The electricity

emissions of battery electric vehicles (BEVs) overall are still far

less than fossil fuel emissions. Furthermore, once the external effects

of carbon on the public are priced into both fossil fuel and

electric vehicles, EVs become the more cost-efficient option.

Ultimately, Wolfram’s work serves as a reminder that curbing

climate change requires multiple moving parts. “It’s a ripple effect—carbon

emission reduction in every sector from manufacturing

to car transport will lead to a much faster transition to

electric vehicles,” Wolfram said. ■

In popular culture, we commonly believe that stress

makes one age faster. A simple Google image search of

“stress and aging” returns pictures of presidents from

when they first started their term to a couple of years later,

the difference being a head full of gray hair.

Previous research has proven this idea to be true in patients

with high stress, including those with post-traumatic

stress disorder, trauma histories, or other mental illnesses.

Now, researchers from Yale’s Department of Psychiatry, including

psychiatry resident Zachary Harvanek, have shown

that stress makes even healthy populations age faster. Using

GrimAge—an epigenetic clock or biochemical test that correlates

with chronological age, disease, and mortality—the

researchers found that stress might contribute to accelerated

aging even before contributions from chronic illnesses start

taking a toll. In this study, most participants were white and

between 18-50 years old.

How can we slow down the effects of epigenetic aging when

stress is a pervasive element in most of our lives? “People who

have stronger emotion regulation or stronger self-control

seem to be more resilient not just to the psychological effects

of stress but also to the physical effects,” Harvanek said.

Future research could involve investigating the impact of

race and culture on epigenetic aging and testing whether

methods that build emotion regulation actually lessen the

psychological and physical effects of stress. And what can

communities like New Haven and Yale do to help with these

stress-causing factors? “The more important thing is going

to be providing those sorts of resources,” Harvanek said. ■



NEWS

Biochemistry

THESE ARE NOT

THE GENES YOU’RE

LOOKING FOR

Filtered editing opens doors to new

possibilities in genome editing

BY SOPHIA BURICK

Since its inception in the early 2000s, genome editing has been

revolutionizing biotechnology. Methods like CRISPR/Cas9

empower scientists with “genetic scissors” that allow them to

make remarkably precise edits to DNA—the genetic instructions in

cells that control cell function, development, and reproduction.

This technology has widespread applications, from engineering to

genetic diseases to globally threatening plant pathogens. However,

CRISPR/Cas9 is greatly limited by its inability to distinguish

between genetic sequences that repeat several times throughout

the genome, which occurs often. Farren Isaacs, Associate Professor

of Molecular, Cellular, and Developmental Biology at Yale

University, and his colleagues have discovered a powerful method

to uniquely alter the genetic address of repeated genetic sequences.

This method of “filtered editing” allows CRISPR to identify and

edit specific sites of repeated sections of DNA.

For Felix Radford, a graduate student at Yale and first author of a

recently published Nature Communications article on filtered editing,

this discovery has been a long time coming. “As an undergrad

taking molecular biology, I started to think more about biology as a

technology,” Radford said. “Previously, I was thinking about biology as

various processes in life, in the human body, but these very complicated

systems started to remind me more of how computers work.”

Radford’s view of biology as a tool to facilitate creative engineering

was foundational to his interest in synthetic biology and ultimately

led him to the Isaacs Lab as a graduate student. “When I first joined

the Isaacs Lab, my initial project was to engineer the ribosome, a

molecular machine central to the function of all living organisms that

are responsible for the synthesis of proteins or protein biomaterials,”

Radford said. But he quickly ran into an issue—even in bacteria,

which generally have much less repetitive genomes than humans,

their genomes contained seven repeated copies of the ribosomal DNA,

genetic material serving as a template for the production of ribosomes.

CRISPR/Cas9 was unable to distinguish the repeated sites of ribosomal

DNA, preventing Radford from making the edits he wanted.

“It’s like on the computer—you find a string that you want to edit

in a sequence. How do you search for that and find it?” Radford

said. “It’s like Ctrl-F in the genome, but we have these repeated

sequences that will lead you astray.”

PHOTO COURTESY OF NORVIN WEST

Yale Ph.D. candidate Felix Radford picking bacterial colonies for genome editing.

Radford needed a solution. So he turned to self-splicing

introns. These are RNA sequences that do not code for proteins

and can excise themselves from exons (segments of RNA that

do code for proteins). “You can put them into an RNA, and they

will cut themselves out, leaving only the sequence that you want

to edit remaining,” Radford said.

DNA segments encoding self-splicing introns can be inserted

into the genome to distinguish one repetitive site from another,

providing a unique genetic address for CRISPR to recognize and

target. When the DNA is transcribed into RNA, the self-splicing

introns cut themselves out of the RNA strand and stitch together

the gap. This solution was incredibly exciting to the Isaacs Lab

since it would allow them to edit these repetitive sequences

which had previously been exceptionally difficult to target.

After the initial discovery, Issacs posed an interesting

question to Radford: what if he expanded this method

to modify many sites at once instead of just one site in the

ribosome? “To do that, I needed to have different types of

introns that could work in parallel,” Radford said. “We ended

up combining two different introns into one, and it worked in

the same way as the original intron.” This only widened the

door to applications of this technology.

“One application of this is that these repetitive genetic elements

are found in many different organisms,” Radford said. Repetitive

genetic elements comprise over 50 percent of the human genome.

The ability to specifically edit these repetitive sequences offers

great potential for studying and combatting genetic diseases.

Another application that the Isaacs Lab is readily exploring is

the use of filtered editing to alter ribosomes and translation factors

in the cell, repurposing cells to manufacture new sequencedefined

polymers, proteins, and biomaterials. “This can be very

important in utilizing biology as a means to evolve new materials

and medicines,” Radford said.

As for Radford’s future, he is interested in applying this technique

to new problems. “In science, when you have new techniques,

they open up a lot of possibilities that were not possible before,”

Radford said. “I’m curious to see where this goes, to see what new

capabilities are available now that we can do this.” ■


Neuroscience

NEWS

DELVING INTO

DOPAMINE

Environmental factors

could affect our brain

chemistry

IMAGE COURTESY OF ISTOCK PHOTOS

BY VICTORIA VERA

Dopamine, a chemical that acts as a neurotransmitter, is

responsible for sending thousands of tiny “messages”

that ultimately help generate several of our thoughts and

actions. It has a myriad of functions within the body and brain,

but it is best known for allowing us to feel pleasure, satisfaction,

and motivation. With this in mind, it is no surprise that it is a

major point of focus when discussing addiction and reward. Social

factors are also known to heavily influence the human brain and

psychiatric outcomes, although there is scarce research proving a

biological connection. Because of that, leading researchers at Yale

have set out to explore these connections.

In this project, Katina Calakos and Aleksandra Rusowicz, research

assistants at the Yale University School of Medicine, used Positron

Emission Tomography (PET scans) to image dopamine receptor

(D 2/3

R) availability. This data was obtained from previous studies

and then correlated to population and socio-economic measures

obtained from the Social Explorer Analyses of the 2014-2018 Census.

The results were surprising. For one, they found that higher

D 2/3

R availability was significantly associated with a higher total

population in residential ZIP codes. Similarly, in zip codes where a

lower percentage of the population possessed a bachelor’s degree or

higher, there was a higher dopamine D 2/3

R availability. Functionally,

this could mean that environment does have a significant impact

on our brain chemistry.

Dopamine in and of itself is extremely useful and, as previously

mentioned, necessary for normal bodily functions. However,

issues can arise when there is too much or little of it. For example,

excessive dopamine activity has been linked to anxiety, insomnia,

and mania. On the other end of the spectrum, low dopamine

activity can cause problems like muscular issues, cognitive

impairment, and attention deficits. Considering this background

and the findings from this research, one could assume that the

environment does impact the way your brain works.

David Matuskey, Associate Professor of Radiology and

Biomedical Imaging and Medical Director of the Yale (PET) Center,

and Aleksandra Rusowicz, PhD, discussed both the inspiration

and the implications of this research, in addition to what it could

mean going forward. This project was driven by prior animal

studies focusing on how dopamine availability was affected by

the animal’s position within its “society” and how that could later

predispose them to develop drug dependency. Initially, this team

asked questions focused on how green spaces could affect brain

chemistry, as environmental surroundings have been shown to

affect brain activation. All those contexts came together to produce

this more recent research.

Their findings represent one small step in filling this gap that is

all too common for health research. Most of the evidence comes

from epidemiological or longitudinal studies focusing on certain

aspects of a population—living conditions, education, health,

and correlations. However, the biological data to back-up these

findings is simply scarce and a relatively new area of focus. This

is why research like this could help inform future findings that

focus even more closely on the type of social factors that impact

social development. The investigators also expressed their hope

that research like this could potentially have policy implications,

providing a biological backbone to diversity and education

initiatives in communities that are often neglected.

While Matuskey described the use of census data as

“advantageous” because they could focus on surroundings and

environments, their research had some limitations. Despite how

useful it was in gaining insight into these communities, it was

fairly broad and could be considered outdated when we take into

account the changes brought about by newer factors such as the

COVID-19 pandemic. It is likely that if this team had had access to

more specific data, they would have been able to discern even more

detailed patterns about how location and social circumstances

impact the brain developments in question.

Social factors have been correlated to health for years, but thus

far, we have lacked the biological data to support this claim.

Thanks to work like this, we now have biological data that can

support the existing studies. As this type of science gains more

traction, we will see more and more detailed results. Maybe one

day, we can use those findings to push for policy change that

ameliorates the roots of these problems. ■



NEWS

Molecular / Cellular Biology

HALTING AND

REVVING THE ENGINES

OF SPERM CELLS

Exploring sperm cell motility

as a potential avenue for

male birth control

BY CHRISTOPHER ESNEAULT

IMAGE COURTESY OF TBIT

It may seem like women will forever be plagued with the

unfair burden of popping pills to decrease the odds of an

unwanted pregnancy. However, researchers at the Yale

School of Medicine are currently looking into the molecular

processes that could either rev or halt the engines involved in

sperm motility and how those mechanisms could be altered to

potentially create a method of birth control for men.

Jae Yeon Hwang, associate research scientist from Dr. Jean-

Ju Chung’s lab at the Yale School of Medicine, is currently

carrying out research regarding male germ cells. “In a birth

process, the major two factors which can achieve new life are

the sperm and egg,” he said. “After the female reproductive

tract is inseminated with sperm cells, sperm simply migrate to

meet the egg and penetrate it.”

However, there is more to the story. After insemination, sperm

cells begin their journey to the egg and are met with diverse

female reproductive tract environmental factors. During this

journey, sperm cells obtain fertilizing abilities—a process

referred to as capacitation. This biological process triggers these

cells to develop a unique motility pattern called hyperactivated

motility, characterized by the beating of the flagellum, the tail

on the end of the sperm, at high amplitudes. “Hyperactivated

motility is triggered by an calcium influx,” Hwang said.

While researchers knew that calcium was essential for the

development of hyperactivated motility, they did not know

how the CatSper channel, a cation channel specific to sperm, is

expressed in the sperm tail. It was the work of this lab that built

upon knowledge of the previously discovered CatSper channel

to understand how it is arranged on the sperm tail. When

functional, CatSper allows for crucial calcium influx into

sperm cells, which results in hyperactivated motility. However,

if the CatSper channel is deficient, calcium cannot enter sperm

cells, which means that hyperactivated motility cannot be

triggered. This phenomenon results in male infertility.

Hwang’s work comes into play because the goal of his study

was to understand how the CatSper channel is linearly arranged

along the sperm tail. Without CatSperτ, a protein found on

the membrane of sperm cells, Hwang found that the linear

arrangement of the CatSper channel fails to occur, thus impairing

sperm hyperactivated motility and resulting in male infertility.

With the accomplishment of valuable research comes great

moments of pride. Hwang mentioned that while learning that

Cell Reports was going to publish his work was enough to

make him incredibly proud, what made him even happier was

reading the peer reviewers’ comments on his paper describing

how much they enjoyed reading his study. Realizing other

experts in his field valued the work he was doing, Hwang felt a

sense of pure fulfillment.

At the end of the day, this work has important implications.

Hwang said that a new method of male contraception could

theoretically be possible if they could block the CatSper channel

and associated proteins. Conversely, he also added that if someone

is having problems with fertility, the problem can be approached

using knowledge of the CatSperτ-CatSper relationship.

Looking into the future, with the help of the scientific

progress made by Hwang and his colleagues, we are getting

closer and closer to tremendous possibilities regarding the

manipulation of male germ cells. ■


Physics

NEWS

HELLO

HALOSCOPES

A new detection method

for dark photons

IMAGE COURTESY OF PIXABAY

BY ISABEL TRINDADE

Dark matter is known to permeate our universe, but its exact

nature has long remained a mystery. Now, new research

from the Wright Laboratory at Yale sheds light on the

presence of dark photons, a candidate for dark matter. The team,

led by Sumita Ghosh, a graduate student in the Department of

Applied Physics at the Wright Laboratory, developed new methods

of analyzing existing data sets from devices known as haloscopes,

which have previously been used to detect particles known as

axions. This new method of detecting dark photons could help

answer long-standing questions about dark matter.

Ghosh says that she had previously read about dark photons but

had not studied them in her research before. Her greatest motivation,

she says, coincided with the pandemic. “I couldn’t do my regularly

scheduled work anymore,” Ghosh said. Thus, she decided to focus

on this project combining algebra, probability, and coding, all

of which she could do at home. Ghosh was inspired by previous

research on dark photons, including two studies in particular: one

by Arias et al. on WISPy Dark Matter, and another by Caputo et

al., “Dark photons: a cookbook.” “[The Caputo paper] is absolutely

brilliant,” said Ghosh, “and inspired me to do a more rigorous job

on one of the experiments [she analyzed], the CAPP haloscope.”

This research is part of an ongoing scientific investigation into

the nature of dark matter. Previous astrophysical observations

indicate that around eighty-five percent of the matter in the

universe is dark matter, the nature of which is still, for the most

part, unknown. However, most of the previous research in dark

matter has pointed to certain characteristics of dark matter: it is

massive, stable, and manifests primarily through interactions with

the observable universe, particularly gravitational interactions.

One candidate for the basic, or elementary, dark matter particle is

the axion, which is identified using detectors known as haloscopes. A

haloscope is a device made of a strong magnetic field in a microwave

cavity, within which we search for signals matching the range of axion

frequencies. Haloscopes can also detect the presence of dark photons,

which are another dark matter candidate. Not much is yet known about

dark photons, but according to Ghosh, they are a possible “flavor” of the

photon and the mediator of a “dark electromagnetic force.”

“All particles in particle physics have parameters, including

mass, charge, and other properties with a numeric value,” said

Ghosh. Particles such as axions and dark photons, which we know

less about, have is a range of possible values for each property.

The combination of these ranges in vector form is known as the

parameter space. This study describes a procedure to convert

haloscope data from axion parameter space into dark photon

parameter space, thus allowing for more potential detection of

dark photons using haloscopes.

Dark photon fields can be uniformly or non-uniformly polarized,

both of which are considered in this study. “The method outlined

in this work for using a single cavity haloscope as a dark photon

detector may be applicable to any haloscope that employs a similar

analysis procedure,” Ghosh said. Regarding the viability of the dark

photon as a dark matter candidate, they have several mechanisms

that allow them to naturally produce relic abundance—the amount

of a particle that is still around after the Big Bang—of dark matter.

However, Ghosh said, “the motivation for dark photons is not

contingent on their comprising all of dark matter.”

This research is significant because there are many materials

that dark matter could consist of, each of which has a large

parameter space. “It’s important to try to narrow that down

faster than we’re currently able to,” said Ghosh. “Each

experiment built is so expensive, and it would be amazing if we

could make them all more productive by being able to interpret

the same data in many different ways.” Ghosh also noted

that, since the publication of her research, other researchers

have contacted her about ways to extend the results of their

experiments, paving the way for further exploration of other

particles beyond standard-model photons.

Future research in the direction of this study may include

potential improvements in the signal strength detected by the

haloscopes. In addition, the dark photon limits in the polarized

case may be enhanced by tailoring the method of conversion to

each haloscope experiment’s analysis method. “This technique will

be greatly enhanced by single photon detection, similarly to axion

detection,” Ghosh said. ■



FOCUS

Environment / Climate Change

HAZARDS OF THE

HIMALAYAS

CLASH WITH TODAY'S

URBANIZATION

PROCESS

using maximum

entropy modeling

to combine multiple

hazards into a

single framework

BY DANIEL MA

The Himalayan region—Nepal, Bhutan,

and the India Himalaya—hosts not

only intrepid mountaineers but also

seventy-four million regular inhabitants.

Thirty-six million of them live in areas

susceptible to multiple natural hazards.

Yale researcher Jack Rusk, a graduate student

at the Yale School of the Environment

and the Yale School of Architecture who

works at the Karen Seto lab, led a project

whose machine learning model produced

that last statistic. When considering wildfires,

floods, and landslides as “hazards,”

forty-nine percent of people in the Himalayas

live in areas susceptible to more than

one of them—despite those areas only encompassing

thirty-one percent of the region’s

land. The model produced by Rusk

and his colleagues provides data on the susceptibility

of the Himalayas and allows geographers

to consider hazard management

in a new way, treating different hazards not

individually but all at once.

Achievements of the Model

Rusk’s study is a part of the Urban Himalaya

project, a NASA-sponsored

collaboration between Yale,

the University of British

Columbia, Kumaun

University in India,

and the International

Centre for Integrated

Mountain

Development

(ICIMOD), an

intergovernmental

agency

for the Himalayan

region.

The project

seeks to understand bidirectional connections

between Himalayan urbanization and

natural hazards: how natural hazards affect

urbanization and how urbanization processes

can induce or prevent further hazards.

Rusk’s model attempted to answer the

first half of that issue.

It took three years of adjustments to get

the final model, which considers the risks of

floods, wildfires, and landslides. Using historical

records of the hazards and known

environmental characteristics, the model

would produce a map of hazard susceptibility

for each variable, then combine those into

a single map for overall multi-hazard risk.

An initial difficulty for Rusk was that the

three hazards were tracked with different parameters.

For example, he had to compare

hazard intensity data in forms as different as

flood depth at a particular location and the

total volume of a landslide. There was also the

issue of non-reported data. If a hazard happens

in a less populated area, it is less likely

to be reported, skew- ing the

distribution to favor

more populated areas.

Additionally,

not all the factors

had data for the

same number

of years.

Furthermore, to have a single model incorporating

different hazards, one would

have to consider the same environmental

factors for each variable. The final paper

used ten environmental variables, some of

the more important ones being elevation, distance

to permanent water, type of land cover,

precipitation, slope, and soil type. Certain

variables may be correlated for some hazards

but not others, and not all of these would be

relevant for every hazard. For example, slope

has little to do with wildfires but is more associated

with landslides.

Hence, a multiple-hazard informed model

seemed implausible at first. Yet, these

considerations are necessary to understand

and improve life in the Himalayas, where

multi-hazard risk is present over the long

term and in the short term. Floods, wildfires,

landslides, and earthquakes commonly

cause each other, so hazard mitigation

teams need to be prepared to handle these

hazards simultaneously.

“You need to develop a framework for

hazard mitigation that describes the overlaps

and interactions between hazards,”

Rusk said. “Practices that are good for

managing the risk of one hazard might exacerbate

the risk of another.” For example,

clear-cutting land is a common hazard prevention

method for

wildfires—creating

a fire break. But

since trees stabilize

soil with

their roots,

denuding

a

piece of

land also

makes

it more


IMAGE COURTESY OF JACK RUSK

Map of multi-hazard risk in the Himalayas.

prone to landsliding, potentially

leading to disastrous outcomes.

Understanding the Results

IMAGE COURTESY OF JACK RUSK AND MEREDITH REBA VIA JENNY WONG

Priyankar Chand (center touching the tablet), and

Karen Seto (behind Chand) working with people in a

workshop.


Rusk ultimately found that maximum entropy

modeling would be the best for his data.

Maximum entropy modeling works by finding

the most uniform hazard distribution for

the entire region while accounting for the environmental

variables. This methodology has

several advantages. For one, it works without

knowing where hazards did not happen,

which negated the issue of inconsistent reporting.

Additionally, it can handle both categorical

and continuous environmental factors—for

example, specific types of soil and

total precipitation are both variables in the final

model. It also does not lose accuracy when

fed irrelevant or correlated factors, allowing

for a consistent set of factors to be used for

all three hazards. Finally, it outputs a single

probability for each hazard at each location.

This simple output allowed Rusk’s team to use

a consistent methodology for defining “risk”

for all three hazards, allowing them to combine

the three hazard maps into one. When

the model was constructed using a subset of

the historical data, it was able to predict patterns

in the rest, an early indication of success.

Rusk’s results must be placed in the

context of Himalayan urbanization patterns

to make sense. Himalayan urbanization

often occurs as micro-urbanization,

a term coined by Seto to describe

the growth of settlements that are small,

scattered, and removed from existing cities.

Tzu-Hsin Karen Chen, a postdoctoral

fellow at the Seto lab who collaborated

on Rusk’s study, attributes micro-urbanization

in the Himalayas to a feedback

loop initiated by road construction. “Villages

[near a road] will have a lot of

new products that are transported to

the market in the urban area, and

therefore they have more capital

to expand,” Chen said. Thus, people

flock to settlements in

thin, fertile valleys

that are

convenient

places

for expanding existing

cities and optimal places to lay

roads leading to them.

However, these valleys are also the most hazardous

parts of the Himalayas. Their moist,

fertile soils take less water to saturate in a flood.

Their steep hillsides and low elevation make

them prone to landsliding, especially as settlement

on the valley bottoms forces people

to move up the hills and cut terraces for arable

land. These valleys also have hotter temperatures

than higher elevations do, making them

more prone to wildfires during droughts.

And yet, millions still inhabit these hazardous

areas. “There are reasons to be near

these urban agglomerations that aren’t related

directly to the presence of hazards—

access to education, access to healthcare,

access to the money economy,” Rusk said.

People choose these opportunities for socioeconomic

mobility, despite the hazards, in

the hopes of connecting with a wider world.

Where Do We Go From Here?

Rusk is the first to admit that his work

would have been impossible without his

fellow researchers physically located in the

Himalayas. “I’ve been humbled by the opportunity

to work with such an amazing

group of collaborators,” he said. Truly understanding

the impacts of hazards requires

talking to people where they happen; machine

learning models can only go so far

since they don’t explain why hazards happen

in certain patterns or how

they affect people.

“In all of this work,

you just have to

shuttle between largescale

patterns and everyday life

on the ground,” Rusk said.

The Yale team’s next project will zero in

on how urbanization changes the landscape

locally and affects hazards—the second

part of the Urban Himalaya project’s

overall goal. “We have one map that assesses

overall hazard patterns across the past

three decades,” Chen said, referring to the

output of the current model. “But now we

want to have a map for every year, from

1992 to the present.” These maps will allow

the researchers to see both hazards and urbanization

change together.

And humans are not only changing the

environment on a local scale but also on

a global scale. As climate change increases

extreme precipitation and lengthens

droughts, existing hazards will also grow

in frequency and destructiveness.

Managing multi-hazard risks requires

the coordination of normally independent

national governments, local agencies

managing separate hazards, and individuals

alike. Rusk’s group has helped illustrate

what progress can be made with an integrated,

multi-talented team looking at the

big picture. Now it is time to do the same

back on the ground. ■

ART BY DANIELLE DE HAERNE

ABOUT THE AUTHOR

Environment / Climate Change

DANIEL MA

DANIEL MA is a junior History and Ecology & Evolutionary Biology double major in Franklin College.

In addition to writing for YSM, he plays for Yale’s quiz bowl team and is an executive editor of the Yale

Historical Review. He is also a historical geography research assistant at the Digital Tokugawa Lab under

Dr. Fabian Drixler.

THE AUTHOR WOULD LIKE TO THANK Jack Rusk and Dr. Tzu-Hsin Karen Chen for the time they

offered to be interviewed and their general enthusiasm about their research.

FURTHER READING

Rusk, J., Maharjan, A., Tiwari, P., Chen, T.-H. K., Shneiderman, S., Turin, M., & Seto, K. C. (2022). Multi-hazard

susceptibility and exposure assessment of the Hindu Kush Himalaya. Science of The Total Environment,

804, 150039. https://doi.org/10.1016/j.scitotenv.2021.150039

Grainger, C., Tiwari, P. C., Joshi, B., Reba, M., & Seto, K. C. (2021). Who is vulnerable and where do they

live? Case study of three districts in the Uttarakhand region of India Himalaya. Mountain Research and

Development, 41(2). https://doi.org/10.1659/mrd-journal-d-19-00041.1

FOCUS


FOCUS

Linguistics / Social Neuroscience

MODELING MINDS

The "theory of mind" in linguistic communication

BY KATRINA

Consider a Thanksgiving dinner

where your mother asks you to set

the table. She tells you to put out the

square plates, the nice water glasses, and

the large napkins. But when you go into

the kitchen, you find that there are multiple

square plates, you have forgotten which

glasses your mom likes, and the napkins are

all the same size. You guess which ones she

wants and bring them all out. Unfortunately,

all your guesses were wrong. You’ve let your

mother down. And now Thanksgiving is off

to a highly traditional start—all because of

an issue in communication.

Communication is fundamental to the

functioning of our society, but too many of us

often fail to use it effectively in our interpersonal

interactions. Researchers in psychology like

Yale University’s Julian Jara-Ettinger and the

University of Oslo’s Paula Rubio-Fernandez

are deep in the weeds trying to understand

what underlies this miscommunication. Most

recently, they have focused on studying how

our minds use linguistic communication to

reference objects. Through their research, they

hope to learn how we come to know what is in

another person’s mind.

STARBIRD

The Experiment

In a series of three experiments, Jara-

Ettinger and Rubio-Fernandez presented

participants with a virtual trackpad that

has four quadrants, each containing an

object. For the first two experiments,

this object is a simple shape. Its size and

color vary from quadrant to quadrant.

Participants also see a line of text that

refers to one of these objects—for instance,

“the rectangle”—and are expected to

click on that object. The participants

are informed that these directions are

written by someone who cannot see the

contents of one of the four quadrants (‘the

director’). The participants’ mission is to

deduce where the blindspot is. Variations

in the words used to indicate the target

object may give clues.

Consider a situation in which there

are two rectangles of different colors on

the screen, but one of them lies within

the director’s blindspot. The director will

indicate “the rectangle” rather than “the

blue rectangle” because it does not know

it needs to distinguish between colors,

only between shapes. This principle

of not giving more information than

necessary is known as a Gricean maxim

of communication.

Each time after selecting the target

object, participants also identify the

quadrant they believe constitutes

the blindspot. They indicate their

confidence about both choices by

clicking closer or further away from

the center of the screen, which would

indicate complete uncertainty.

Rubio-Fernandez explained that

the research team wanted to create an

experiment that would ask people to

work through linguistic ambiguity in the

same manner that they would encounter

ambiguity in the world. “They use what

the other person knows, which objects

they know about, and take into account

whether or not the other person uses

adjectives contrastively or not,” Rubio-

Fernandez said. “These three factors

should allow someone with good social

cognition to figure it out.”

In the first experiment, the directions

describe the target objects with adjectives

regarding their shape and color. These are

considered absolute adjectives because

they have a fixed meaning—a “red cup”

looks red regardless of what color the

cups around them might be. The second

experiment repeated the process of

the first but used size adjectives with a

relative meaning. For example, when

told to retrieve a “small cup,” one would

return with different cups depending on

how big the surrounding cups are.

The second trial had an additional layer

of uncertainty. The directions in this trial

had some unknown propensity to use

adjectives even though they would not be

helpful in distinguishing between possible

targets. For example, the director may ask

for “the small triangle” even when there

is a display of all different shapes. This

conditions the participant to believe that

the director uses adjectives like “small”

where it is not necessary. Therefore, if the

display later shows a new arrangement of

shapes and asks for “the small rectangle,”


Linguistics / Social Neuroscience

FOCUS

the participant cannot know whether the

word “small” is being used to contrast one

rectangle from a second, thus making it

harder to pinpoint the blindspot.

The third experiment replicated this

experimental paradigm with real world

objects rather than simple colored shapes.

Models of the Mind

To understand how participants used

language to identify the blindspot, the

experimenters created two probabilitybased

computer models that would go

through the same trials as the human

participants. They based these models on

two different theories of how a person

might try to approach the task.

The first model was based on a concept

in psychology known as the “Theory of

Mind”. Jara-Ettinger explained the model in

terms of our interview conversation. “You’re

representing what's happening in my mind,”

he said. “When you're talking with me, you

realize that I'm not just some regular object

like a glass of water on a table. You have a

very strong sense that there's a mental life

inside of me. It’s not just a curiosity; it's what

you use to make sense of my behavior.”

“Theory of Mind” is the process of

internally modeling the mental life of

another. “It's a huge space of possible

things that range from you knowing

nothing to you knowing everything to

you knowing some parts of things," Jara-

Ettinger said. "Then I can figure out, 'okay,

so under which states of knowledge would

your words make sense?’”

The first model, then, included three

parameters: the random chance that

the target object would be in the chosen

quadrant (a one in four probability), the

increased random chance that it would

be in one of the quadrants visible to the

director (a one in three probability), and

the probability that the director was using

as few adjectives as possible. The model

calculated the last parameter based on the

director’s word choice in each experiment.

This last probability factor allows it to

consider the likelihood that the director

is using adjectives unnecessarily, thus

presenting a model of the director’s mind.

The second model, or the “deductive”

model, is much simpler. It used only basic

logic like “the blindspot cannot be one

of the indicated squares” to identify the

blindspot. Because this model lacks the

final probability factor from the “Theory

of Mind” model, it can only reverse

engineer the director’s intent. It does not

imagine the set of possible beliefs that the

director could have. Rather, it identifies

which quadrants the director can see to

guess which quadrant is out of their sight.

Our Minds

Jara-Ettinger and Rubio-Fernandez

found that the “Theory of Mind” model

was a great fit for the data derived from

human trials across all three experiments,

while the “deductive” model was not. Both

the “Theory of Mind” model and human

participants were relatively successful at

locating the director’s blindspot. The high

correlation between “Theory of Mind” and

data from human trials suggests that it is

likely that people use “Theory of Mind” in

their everyday lives.

ABOUT THE AUTHOR

IMAGE COURTESY OF JULIAN JARA-ETTINGER AND PAULA RUBIO-FERNANDEZ

Participants identified a single object indicated by the prompt (here: “The triangle”). On the third grid, (L)

represents where participants tapped for the first prompt, (R) represents where participants tapped for the

second prompt, and (B) represents where they believed the director’s blindspot was located.

ART BY NOORA SAID

Jara-Ettinger said the results give us

reason to marvel at the power of our

minds. “If we designed the model to

make the best possible inferences it can

and participants are giving you identical

answers, it seems that on average,

participants are also giving you the best

possible inferences,” he said.

But what does this mean for daily

communication? If people are, in

fact, relatively good at determining

another’s blindspots, why is it that we

miscommunicate so many times each day?

“It’s very surprising because it seems

that one of the most salient things for

us is that in conversation, we get each

other wrong,” Jara-Ettinger admitted.

But he then reoriented the question:

“Yes, we do get things wrong, but we also

just take for granted how often we get

things right. We’re just so used to getting

inferences very quickly that we just kind

of ignore those.” ■

KATRINA STARBIRD

KATRINA STARBIRD is a junior in Timothy Dwight College majoring in Earth and Planetary

Science. She studies natural resource science and policy, is a research assistant for Professor Justin

Farrell, and is a member of the Independent Party of the Yale Political Union.

THE AUTHOR WOULD LIKE TO THANK both Julian Jara-Ettinger and Paula Rubio-Fernandez for

their time in explaining their research and for their sparkling conversations.

FURTHER READING

Jara-Ettinger, J., & Rubio-Fernandez, P. (2021). Quantitative mental state attributions in language

understanding. Science Advances, 7(47). https://doi.org/10.1126/sciadv.abj0970

Keysar, B., Lin, S., & Barr, D. J. (2003). Limits on theory of mind use in adults. Cognition, 89(1), 25-41.



FOCUS

Immunobiology

ART BY SOPHIA ZHAO

Amid the COVID-19 pandemic, a figure crawls from the darkness. Born

from the collaborative efforts of investigators at the Yale School of Medicine,

he represents a crucial scientific weapon for COVID-19 researchers—a

bridge between understanding the disease and effectively treating it. He is

a hero that wears no cape, and his name…is Mr. G.

Okay, his full name is MISTRG6.

And he is a mouse.


Immunobiology

FOCUS

Who is Mr. G?

Mr. G is a genetically engineered mouse

with a human-like immune response to

COVID-19: through him (and mice like

him), researchers may be able to better

test both existing and new potential treatments

against the virus. Mouse models

like Mr. G can be crucial to answering key

questions about how the virus works and

how we can combat it.

Over four hundred million cumulative

cases of COVID-19 have been recorded

in the past six months. Roughly eighty

percent of them have been classified as

“mild”. The remaining twenty percent of

cases are “severe,” with symptoms including

respiratory failure, blood clotting, and

multi-organ dysfunction.

Why do some people experience only

mild cases while others face life-threatening

ones? Through Mr. G, Yale School of Medicine

Sterling Professor of Immunobiology

Richard Flavell and Esen Sefik, a post-doctoral

fellow in his lab, aimed to find out.

“Some [COVID-19 treatments] worked

in a subset of patients, but not all of them,”

Sefik said. “There were a lot of unknowns

at the time, and we thought that if we had a

model, we could help.”

The Challenges of an Animal Model

Scientists have traditionally relied on

animal models to evaluate the safety and

efficacy of vaccines and antiviral candidates.

However, while a plethora of animals

– ranging from rabbits to primates – have

been studied for their immune response to

SARS-CoV-2, no standard laboratory animals

have developed the severe respiratory

failure, organ failure, or cytokine storms,

which are intense inflammatory processes,

seen in severe human cases. Some animals

barely show any symptoms.

But the lack of symptom overlap with

humans does not mean that these animal

models lack usefulness as a starting

point for study. Animals are affected by

SARS-CoV-2; the difference merely lies

in how they respond. With this in mind,

if researchers could alter the response of a

COVID-infectable species to match the human

immune response, they could create a

suitable animal model to study the disease.

Of the animal species that do get infected,

mice stand out as the most promising

for this type of study. Mice have

been used in biomedical research for

nearly a century, and, as a result, scientists

understand their physiology with

near genomic-level precision. We also

share about ninety-five percent of our

DNA with mice, so our biological responses

to disease are typically similar

enough for findings to be translatable to

humans. In addition, practically speaking,

mice are small, easy to transport, and

have a fast reproduction time with an accelerated

lifespan, making them incredibly

cost-effective and efficient for studying

infectious disease processes.

However, the differences in the immune

response to COVID-19 between

humans and mice still represent a major

obstacle for researchers. In humans, inhaled

SARS-CoV-2 travels to the alveoli

in the lungs, where the exchange of carbon

dioxide for fresh oxygen in the blood

occurs. There, the virus hooks onto a

protein called the angiotensin-converting

enzyme type 2 receptor (ACE2), which

provides an entry point into the alveolar

cell lining. Once taken in, the virus

breaks the cell apart, releasing millions

of new viral particles and inflammatory

cytokines. These cytokines cause plasma

and immune cells in the blood to leak

into the alveoli, blocking gas exchange

and causing fluid buildup in the lungs.

However, unlike humans, standard laboratory

mice infected with SARS-CoV-2

do not show major signs of infection.

This is partly because the ACE2 receptor

in mice is structurally different from the

ACE2 receptor in humans, enough so that

SARS-CoV-2 generally cannot effectively

bind to the mouse receptor, enter alveolar

cells, and cause chronic infection. To

address this difference, Flavell and Sefik

turned to Akiko Iwasaki, the Waldemar

Von Zedtwitz Professor in the Department

of Immunology at Yale, who found

a way to use gene therapy to induce mice

to transiently express the human version

of ACE2. By delivering the human-ACE2

gene through a mild adeno-associated virus

(AAV) injected into the trachea, her

team successfully transferred the gene

into cells into the lung tissue of mice.

“Humanizing” a Mouse

While mice with just the human-ACE2

gene get sick, they do not necessarily exhibit

severe COVID-19 symptoms. The

immune systems of mice and humans are

just different enough that “humanized

mice,” or mice adapted to have a human

immune system, have become crucial

HUMANIZING MOUSE

MODELS By Ryan Bose-Roy



FOCUS

Immunobiology

tools in studying the clinical applications

of anticancer and anti-HIV drugs. Thus,

Flavell and Sefik teamed up with Iwasaki

to develop a mouse with both the human

receptor to SARS-CoV-2 and the human

immune cells for disease response.

“Humanizing” the mouse immune system

occurs by taking progenitors of human

immune cells and injecting them into

a mouse. This technology is decades-old,

and Flavell, along with Markus Manz and

Regeneron Pharmaceuticals, have been

pioneering work in this field for years. To

create Mr. G, Flavell’s lab took a variety

of human hematopoietic stem cells from

fetal liver, cord blood, and adult blood and

injected them into the liver of an immunocompromised

baby mouse. Once the

mouse was eight weeks old, the stem cells

had differentiated to yield a system of human

immune cells.

Ordinarily, the mouse’s immune system

would recognize these human stem

cells as ‘foreign’ and reject them. To preemptively

address this issue, the researchers

first genetically modified the mice

when they were still clumps of embryonic

stem cells: several mouse genes were replaced

with human genes coding for proteins

that would support humanization.

The names of these ‘humanization’ proteins—M-CSF,

IL3, SIRPα, THPO, RAG2,

and IL2Rγ—can be combined to form the

acronym MISTRG, or, more concisely,

the name of our hero, Mr. G.

Once the human immune cells were

grafted, the human-ACE2 gene was

injected into Mr. G’s neck so that his

lungs would respond appropriately to

COVID-19. And after 14 additional days

of waiting, Mr. G’s “humanization” process

was finally complete.

These responses are virtually unobserved

in normal mouse models.

“As we learned more about

[COVID-19] and the patient data kept

coming, macrophages and monocytes

seemed to be at the center of pathology,”

Sefik said. “If you look at other humanized

animal models, unfortunately, most

of them lack these cells.”

Why does replacing mouse immune

cells with human ones produce such adverse

outcomes? Sefik hypothesized that

human cells contribute in a unique way.

“The way that human immune cells respond

to the virus and produce antibodies

results in delayed viral clearance, and so the

virus also stays longer,” she said. In standard

laboratory mice, COVID-19 infection

peaks in two days and goes away after four.

In Mr. G, the infection lasts over a month,

making it a chronic infection.

To test the effectiveness of different

vaccines and antiviral therapeutic agents,

Flavell and Sefik treated Mr. G with human

monoclonal antibodies collected

from patients by Michel Nussenzweig, an

immunologist at Rockefeller University.

They found that administering human antibodies

to Mr. G eight hours before infection

blocked his excessive weight loss and

reduced the amount of infectious SARS-

CoV-2 to undetectable levels. However,

when these anti-COVID-19 antibodies

were administered after infection as a therapeutic

practice, the effect was much less

pronounced, and the mice still exhibited

some, albeit milder, symptoms.

Finally, Flavell and Sefik tested the

ABOUT THE AUTHOR

effect of dexamethasone, a potent immunosuppressive

steroid currently used to

treat patients with severe COVID-19 infection.

They found that dexamethasone

administration for mice like Mr. G, as in

humans, worked best if delivered during

a specific window of time when the immune

system was activated for long

enough to fight infection but not too long

to cause infection.

Mr. G: More than a Mouse

Flavell and Sefik’s research, done in collaboration

with Iwasaki and several other

researchers in and outside of Yale, is crucial

in developing means to better understand

and treat SARS-CoV-2 infection. Nevertheless,

much work remains to be done. Mr.

G’s effectiveness as a model organism is still

limited. “We have a good representation

of monocytes and macrophages [immune

cells], which is great, but we don’t have all

the cell types in place,” Sefik said. “We are

not going to see all the pathologies that we

need.” For instance, Mr. G does not exhibit

blood clotting, a common symptom found

in patients with severe COVID-19.

Regardless, Mr. G does bear many of

the same viral and therapeutic responses

to different COVID-19 variants as humans.

His creation represents a major

milestone for researchers aiming to understand

and treat the virus. Mr. G will scurry

down the path of SARS-CoV-2 infection,

sniffing out vaccines and antiviral drugs to

save human lives. ■

RYAN BOSE-ROY

Mr. G on the Battleground

While the concentration of infectious

SARS-CoV-2 in normal mice is quite low,

the viral concentrations in Mr. G are comparable

with the high levels found in severe

human cases. “It’s a good model to

start with, and it is already telling us a lot

about how we can go about treating the

disease,” Sefik said. Physiologically, Mr. G

exhibits the same COVID-19 symptoms as

severely ill humans: fibrosis, weight loss,

and a heightened, persistent inflammatory

immune response that damages tissues.

RYAN BOSE-ROY is a sophomore in Trumbull majoring in “Something we’ll figure it out.” In

addition to writing for YSM, Ryan works the Trumbull buttery shift on Sunday nights, where he

delights in making quesadillas and regaling customers with stand-up bits while taking their orders.

THE AUTHOR WOULD LIKE TO THANK Dr. Esen Sefik for her wonderful insights on developing

humanized mouse models to study COVID-19, as well as for her time and enthusiasm about

her research. The author would also like to thank, both upon Dr. Sefik’s request and of his own

accord, Dr. Richard A. Flavell, Dr. Akiko Iwasaki, Dr. Michel Nussenzweig, Dr. Haris Mirza, and

the other authors of the paper. Dr. Sefik requested acknowledgement from Yale EHS for their

extensive assistance in providing space, resources, and training during difficult circumstances.

FURTHER READING

Rongvaux, A., Willinger, T., Martinek, J., Strowig, T., Gearty, S. V., Teichmann, L. L., Saito, Y.,

Marches, F., Halene, S., Palucka, A. K., Manz, M. G., & Flavell, R. A. (2014). Development and

function of human innate immune cells in a humanized mouse model. Nature biotechnology,

32(4), 364–372. https://doi.org/10.1038/nbt.2858


Ecology / Environment FOCUS

THE META GUT

Conservational clues provided by hippo poop

As it turns out, hippo excrements contain multitudes. In fact, the organisms that live in

feces may be powerful enough to influence an entire ecosystem.

BY HANNAH SHI AND RISHA CHAKRABORTY

Conservation ecology is on

everyone’s mind today and with

good reason. With global warming

and imminent extinctions making daily

news, the preservation of ecological

biodiversity has never felt more urgent.

To this end, conservation ecologists have

made an effort to identify the key players

in the most ecologically diverse ecosystems

in the world, hoping to find clues about

the relationships between organisms

and nonliving factors that make such

ecosystems high-functioning.

Kenya’s Mara River Valley is a prime

example. The fish, birds, and hippos in the

Kenyan Masai Mara are interdependent

for survival, but recent evidence suggests

researchers have overlooked the key players:

microbiota. The ecological stability of the

Masai Mara is characterized by the relationship

between these two biotic spheres, described by

community coalescence

theory. The

basis of this relationship, as it turns out, can be

found in hippo poop.

The Meta-Gut

Thousands of hippos in Kenya’s Mara

River Valley excrete an estimated 9.3 tons

of feces each day. This waste contains gut

microbiomes with trillions of bacteria and

archaea, which may even function outside

the animal itself. Christopher Dutton

GRD ‘19, a postdoctoral associate in the

Department of Ecology and Evolutionary

biology at Yale, and collaborators such

as Amanda Subalusky GRD ‘16, who

is also a postdoctoral associate in the

same department, have found that the

microbiome of hippos may play an

unanticipated role in regulating biological

and chemical processes within their larger

ecosystem. “Is it possible

that these pools

could actually,

in a way, be functioning like an extension

of the hippo gut?” Dutton said. “It’s kind of

crazy to think that gut microbiota can be

driving what’s happening in this whole river.”

This continual exchange of organic matter

between hippos and their environment has

led to the proposition of a novel conceptual

framework known as the “meta-gut.”

Hippo Pools: What Makes Them Special?

All animals carry specialized

microorganisms in their digestive tract,

which help facilitate biologically essential

processes such as the metabolism of

carbohydrates and the synthesis of amino

acids, fatty acids, and vitamins. As hippos

wallow in the Mara River, they unload their

gut microbiota through the excretion of

waste, introducing

nutrients and microbes

into the river. The metagut

suggests that this

continual loading

of organic matter

results in an

environmental

patch within an

ecosystem that

shares similar

characteristics

to the gut

environment of

the host animal.

In other words, the

river ecosystem inherits

characteristics of the

hippo gut.


ART BY LUNA AGUILAR


FOCUS

Ecology / Environment

A small-sized photo of hippos fighting.

Even without expensive genomic

technologies, Dutton and his colleagues had

deduced that the constitution of the pools

that had high hippo density – high-subsidy

hippo pools – differed from pools further

upstream. High-subsidy hippo pools were

anoxic, or oxygen-depleted, with higher

concentrations of methane, hydrogen

sulfide, and minerals such as magnesium

and calcium, as well as lower concentrations

of oxygen and nitrates (compared to the

oxic conditions of low-subsidy hippo

pools and the Mara River itself). Genomic

technology allowed the researchers to

correlate these findings with the microbial

communities found in both the hippo gut

and high-subsidy hippo pools and

identify the key

PHOTO COURTESY OF CHRISTOPHER DUTTON VIA JENNY WONG

microbes causing these biochemical

differences in the pools.

Specifically, Dutton and his colleagues

used 16S rRNA sequencing technology to

compare RNA genomes across samples

from areas in the Mara River with high

and low hippo population density. 16S

rRNA sequencing confers two benefits over

other sequencing technologies. First, each

organism has 16S rRNA specific to its species,

making the 16S rRNA a highly-identifiable

label. Second, since rRNA itself is a relatively

short-lived biological molecule like RNA,

researchers were able to characterize which

members of the microbial communities

in hippo feces actually play active roles in

shaping the ecosystems the hippos inhabit.

Hippo Gut Influences on the

Biogeochemical Cycles of the Mara

The idea of the meta-gut may

revolutionize our understanding

of the abiotic and biotic

components in an

ecosystem. Within highsubsidy

hippo pools,

certain biochemical

differences were clear. For

one, active microbial

communities common

to the hippo gut and

hippo pools were

strongly associated

with higher concentrations

of biochemical oxygen demand,

methane, nitrous oxide, and

hydrogen sulfite, suggesting that

hippo gut microbes may be driving these

chemical changes in the river. Secondly, as

tons of hippo feces sink into the water, the

river environment becomes anoxic. This

chemical change may allow for the successful

transfer of hippo microbiota into the river,

and survival after, as microbes from within the

gut are adapted to anaerobic environments

present in the digestive tract of animals.

As this organic unloading occurs, the

microbial communities from the hippo gut

can colonize the digestive tracts of other

animals, including fish and insects, in the

Mara River Valley. Multiple species of fish

in tropical rivers consume hippo feces and,

in doing so, may participate in the larger

meta-gut. “If some of the hippo microbiota

is colonizing the guts of fish and insects,

you have to start asking yourself questions

like, ‘Is it possible that the fish that are living

with hippos and consuming their feces are

somehow gaining some type of physiological

advantage from the gut microbiota that they’re

taking?’” Dutton asked. If such processes are

possible, migrating gut microbiota from

one species to another can confer important

biological advantages for adaptation.

Hippo Pools Over Time and Space

These biological advantages and the

meta-gut itself are not constant over time.

Characterizing the hippo pool microbiome

before and after flushing flows (large

torrents of water that essentially recycle

the water of the hippo pools) showed that

the hippo pool’s microbiome best matched

the hippo gut’s microbiome in the intervals

between flushing. Evidently, it takes time for

the meta-gut to be established. Moreover,

the flushing flow experiment also provided

clues to how the hippo pools impacted

upstream parts of the river. Directly after

flushing, the hippo pools most resembled

the upstream river regions, indicating that

there are some innate free-living microbial

communities that are common in all parts

of the river. However, the microbes that

most contributed to the biochemical and

ecological stability of the high-subsidy

pools were directly derived from hippo

feces and were largely contained to the

hippo pools.

The Hippo Gut and Ecological Stability

Thus, there’s more to the Masai Mara hippos

than meets the eye. When hippos and their


Ecology / Environment

FOCUS

Subalusky Picnic Rock Hippo Pool.

neighbors swim around in feces, not only

are the animals propagating their own gut

microbiota but that of an entire ecosystem.

Our current understanding of ecosystems, and

the organisms that comprise the biodiversity

of the ecosystem, are largely limited to what

we can see and touch. However, the team’s

work with the hippos’ gut microbiota, and

consequently, the river ecosystem microbiota,

point to the importance and ubiquity of

microorganisms. Without them, the entire

river ecosystem could collapse. “When species

cohabitate, I think it’s really important that we

acknowledge that every organism living in

the Masai Mara is sharing their microbes,”

Dutton said. “The more diversity you have

on the landscape, the more of a chance that

you’re going to get the correct colonization in

your gut that helps you survive.”

But even if the hippo meta-gut is crucial

to the river ecosystem, why should this

matter to us? If the ecosystem functions,

as far as the planet-conscious person is

concerned, there isn’t much harm. And yet,

the preservation of biodiversity, beyond

just the preservation of ecosystems, is one

of the central goals of ecology. Dutton

explained the difference between a partially

functioning ecosystem and an effectively

functioning ecosystem. “Biodiversity is

so important, specifically [when we’re]

looking at the effective functioning of

ecosystems,” Dutton said. “When we throw

ecosystems out of whack, that’s when we

start to get these problems of excess carbon

in the atmosphere from CO2, methane,

PHOTO COURTESY OF CHRISTOPHER DUTTON VIA JENNY WONG

and nitrous oxide.” Thus, the preservation

of the gut microbiome of the larger species,

like hippos and beavers, in the Masai Mara

is just as important to the functioning of

geochemical systems as the preservation of

the observable species themselves.

Future Steps

Next, Dutton wants to specifically identify

the taxa of the hippos’ gut microbiota

involved in nitrogen and carbon recycling

that ultimately contribute to the growth

and survival of plants, animals, and our

planet. He will work with the hippos at an

ABOUT THE

AUTHORS

experimental stream facility at Disney and

do detailed sampling of the biochemistry in

microbial communities. Specifically, Dutton

is excited about using metatranscriptomics,

a technique that sequences the active

genetic code in a cell to indicate what

functions the cell is carrying out in realtime.

Identifying the communities of

microbiota that are functioning will enable

the team to distinguish between the species

that are present in the feces and those that

play significant roles in the functioning of

the meta-gut ecosystem.

Ultimately, the hippo meta-gut is a

microcosm of all ecosystems, where

the role of the microbiota has been

largely underestimated. The respective

focuses of ecologists and microbiologists

studying this have been largely divergent

until the concept of meta-guts was shown

to be critical to the geochemical cycles

that improve the welfare of the entire

ecosystem and, ultimately, the entire

planet. Thus, as we focus on the warming

of the planet and the accumulation of

carbon in the atmosphere, we must

consider the preservation of biodiversity,

from the smallest species to the largest.

Though it might seem unexpected to

think that part of the solution to climate

change and ecological preservation

is lodged in hippo poop, a better

appreciation of the interspecies relations

in an ecosystem and the roles

they play will fill a critical

gap in our understanding

of life on our planet. ■

HANNAH SHI &

RISHA CHAKRABORTY

HANNAH SHI is a junior majoring in Molecular, Cellular and Developmental Biology and the

History of Science, Public Health, and Medicine. In her free time, Hannah enjoys dancing and

growing houseplants in her dorm room.

RISHA CHAKRABORTY is a first-year Neuroscience major prospect in Saybrook College.

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

and Undergraduate Jazz Collective, volunteers for HAPPY (Hypertension Awareness and

Prevention Program at Yale) and researches Parkinson’s Disease at Chandra Lab in the School

of Medicine. She enjoys cracking jokes and having philosophical discussions with her friends

and taking Choco Pies from her PL Jenny at the Asian American Cultural Center.

THE AUTHORS WOULD LIKE TO THANK Christopher Dutton for his time and enthusiasm

about his research.

FURTHER READING

Castledine, Meaghan, et al. “Community Coalescence: An Eco-Evolutionary Perspective.”

Philosophical Transactions of the Royal Society B: Biological Sciences, vol. 375, no. 1798, 23 Mar.

2020, p. 20190252, 10.1098/rstb.2019.0252. Accessed 27 May 2021.



FOCUS

Molecular Biology

ART BY ANN-MARIE

ABUNYEWA

How does soil organic matter help crop growth?

BY SHUDIPTO WAHED AND HANNAH BARSOUK

Water, sunlight, and a spoonful

of sugar: a simple recipe that

sustains much of life on Earth.

Plants and other organisms famously use

photosynthesis to convert light into the

chemical energy that drives their lives.

Central to this process is a protein complex

called photosystem II (PSII), an enzyme that

captures photons of light and breaks down

water to release oxygen and protons.

Scientists have been interested in PSII

since its discovery in the 1960s. Its relevance

stems from the applicability of principles

learned from biological solar fuel production

to many fields, including synthetic

photocatalysis, crop optimization, as well

as evolutionary biology. Professor of Chemistry

and Director of the Energy Sciences

Institute Gary Brudvig has been studying

photosynthesis for well over forty years. “His

group has in many ways pioneered a lot of

our most basic understanding of photosystem

II,” said Christopher Gisriel, a current

postdoctoral associate at the Brudvig lab. By

the 1980s, researchers had identified a photosynthetic

cyanobacterium that they could

easily genetically modify. Studying this species,

Synechocystis sp. PCC 6803 (Syn.6803),

provided useful insights into PSII’s photosynthetic

mechanism, such as the specifics

of water oxidation and electron transfer.

What scientists could not do, however,

was solve the molecular structure of this

species’ PSII protein. For biological proteins

and enzymes, function is considerably affected

by three-dimensional structure, like

how a house-key works because of the proper

arrangement of its grooves and how they fit

within the lock. Because water oxidation is

highly complicated, the lack of high-resolution

structures to guide functional investigation

has meant that many aspects of it remain

unclear. “So basically, we’ve been going in

somewhat blind,” Brudvig explained. “If you

try to do structure-function studies with no

structure, you’re kind of on thin ice.”

In an effort to fill in this gap, at the beginning

of 2022, Gisriel and Brudvig’s team published

a Proceedings of the National Academy of

Sciences (PNAS) study reporting the first cryo-

EM structure of PSII from Syn. 6803. To the

authors’ surprise, there were a number of differences

in the PSII structure compared to its

previously presumed architecture, underscoring

the need to re-examine previous data using

this new structural blueprint. Not only do

their findings challenge several time-honored

notions about PSII’s mechanism of action, but

the reported structure also provides a basis for

introducing tiny changes in the protein to unlock

the mysteries of biological photocatalysis.

The Troubled Heart of Photosynthesis

Much of our knowledge of PSII can be

attributed to site-directed mutagenesis


Molecular Biology

FOCUS

VISUALIZING

THE HEART OF

PHOTOSYNTHESIS

Using photosystem II, a photosynthetic enzyme, to help

solve the mysteries of solar fuel production

experiments – in which targeted changes

are made to DNA – conducted in the last

fifty years. In these specific experiments,

scientists introduced mutations in the

PSII gene to assess the role of individual

amino acids, which comprise proteins, in

the enzyme’s function. These studies have

almost entirely been performed using Syn.

6803 cyanobacteria, which can survive

with altered PSII if supplemented with

glucose. This makes it an ideal model organism

for mutagenesis because in many

other species, mutations in PSII often led

to cell death, leaving researchers unable to

investigate function further.

However, the molecular structure of

PSII in Syn. 6803 had remained unsolved

because the organism is sensitive to the

harsh conditions required for techniques

like X-ray crystallography, which is used to

elucidate molecular structures. To this day,

the only reported structures for PSII have

come from thermophilic cyanobacteria, organisms

that thrive in high temperatures.

However, they are poor model organisms

for mutagenesis experiments due to their

intolerance of growing with altered PSII.

“All this work has been going on in parallel–mutagenesis

in organisms with no

known structures, and structural determination

in thermophiles that could not

be mutated,” Brudvig said. “People just assumed

that they were all the same and that

they could use the thermophile as a basis

for structure.” Scientists have therefore been

forced to proceed with this assumption to

interpret their functional data.


But this approach may not be truly justified.

Firstly, there are obvious differences in

the DNA sequences of the PSII genes from

mesophilic and thermophilic organisms,

which implies diverging structure and function.

Moreover, membrane proteins from

mesophilic and thermophilic organisms are

generally known to have different molecular

characteristics. Thus, the study of PSII

function is greatly limited by the lack of a

high-resolution structure for the model organism

from which most biophysical data

comes: Syn. 6803.

A Structural Blueprint

Large, often unstable, protein structures

like PSII from Syn. 6803 are difficult, if not

downright impossible, to crystallize for use

in X-ray crystallography experiments. But

there is now an alternative technique to

visualize this three-dimensional structure:

cryo-EM. Single-particle cryo-EM bombards

a thin sheet of a protein solution with

electrons, using a camera to detect how

electron waves interact with the sample. A

computer then reconstructs a 3D model of

the protein from hundreds of thousands of

2D images in different orientations. “I like

to think of myself as a very, very high-resolution

photographer,” Gisriel said.

The Brudvig lab reported the structure

of PSII from Syn. 6803 with single-particle

cryo-EM at a resolution of 1.93 Angstroms

(Å). For reference, the average resolution

for published cryo-EM membrane protein

structures is ~5Å. At this unprecedented

resolution level, the Brudvig group could

even see the presence of some individual

protons within the complex.

PSII is biologically found in a dimeric

state, with two identical monomers, each containing

twenty one subunits. The core consists

of four subunits, with thirteen peripheral subunits

embedded in the membrane and four

“extrinsic” subunits found on the inner surface

of the membrane. With their novel structure

in hand, the Brudvig group could now

identify any major differences between the

thermophilic and Syn. 6803 PSII enzymes.

Cofactors are non-proteinous molecules

within an enzyme that promote its

catalytic activity. Most cofactors are indeed

conserved between the two species, except

for a pigment called BCR101, which helps

absorb light energy. Previous studies had

suggested that BCR101 was important to

allow PSII to dimerize, where two identical

PSII proteins chemically associate. However,

even without BCR101, Syn. 6803 still

retains a dimeric configuration, implying

that BCR101 is not as crucial for this role.

Interestingly, some peripheral and extrinsic

subunits, namely PsbO, PsbU, and PsbV,

are quite dissimilar between PSII from

the different species. This was unexpected

because these subunits surround the intricately

controlled “active site” of PSII, where

the enzyme’s catalytic activity occurs and

performs key functions in water oxidation.

The last remaining extrinsic subunit,

PsbQ, is found in both thermophilic and Syn.

6803 PSII. Notably, however, PsbQ had never

before been observed bound in complex with


FOCUS

Molecular Biology

Whichever the case, this remarkable

difference between the Syn. 6803 PSII and

thermophilic PSII enzymes highlights the

importance of the authors’ reported structure.

Without structural data from the

model organism used for studying PSII,

it is difficult to accurately interpret functional

data, which could lead to assigning

function in a manner inconsistent with true

biophysical constraints.

Significance and Future Directions

the PSII protein. Its analysis revealed that its

binding in Syn. 6803 is primarily driven by

unique electrostatic interactions that are not

present in the thermophilic cyanobacteria.

PsbQ-binding does not induce any conformational

changes in the PSII complex, so the

authors believe that it mainly serves to provide

additional protection for the active site.

Water Channels

The authors were surprised to observe poor

conservation of PsbO, PsbU, and PsbV between

Syn. 6803 and thermophilic PSII structures.

For decades, these extrinsic subunits

have been thought to form channels into the

active site to provide it with water to oxidize

and routes for the protons and oxygen byproducts

to exit. The striking differences observed

in extrinsic subunit structures suggest that differences

in these water channel functions are

central to PSII’s enzymatic activity.

Scientists had previously identified what

they considered to be three main water channels:

the large, broad, and narrow channels.

Although the broad and narrow channel

structures are relatively well conserved between

Syn. 6803 and thermophilic PSII, the

most notable differences were observed in

the large channel. Analysis of thermophilic

structures had suggested that the large channel

may play an important role in transporting

water and protons to and from the active

site. However, the authors found that, in Syn.

6803, the large channel is completely blocked

by extension of the PsbV subunit.

PHOTO COURTESY OF CHRISTOPHER GISRIEL VIA JENNY WONG

A far, horizontal vantage point of Dr. Christopher Gisriel (front) pipetting. A graduate student (back) is

working in the background.

Blockage of the large channel suggests

that it may not actually be as crucial to PSII

function as researchers had previously suggested.

In fact, it is not much of a channel at

all if one end appears to be closed off. These

findings suggest that the narrow and broad

channels may be the only ones that matter

for water oxidation, which is supported by

both their conservation in all known PSII

structures and previous mutagenesis studies.

Another plausible explanation is that

PsbV may be involved in a sort of gating

mechanism that selectively opens/closes

the large channel.

ABOUT THE

AUTHORS

Photosynthesis fuels the life of many

organisms, from trees in the Arctic to hot

springs cyanobacteria, to the grass outside

Sterling Memorial Library. PSII is considered

the only global solar fuel catalyst shared between

all photosynthetic organisms and the

central water oxidation enzyme. With this

in mind, this research can help create a new

generation of synthetic fuel catalysts, which

could artificially reproduce this process of

water-splitting to generate energy.

The structural differences in PSII from

Syn. 6803 and thermophilic cyanobacteria

have important implications in understanding

the mechanism of water oxidation, suggesting

that many of the field’s prior findings

may now require re-examination.

With cryo-EM, researchers can observe

the structure of the mutated enzyme.

This work holds vast promise in

unlocking the mysteries that persist in

understanding the biomolecular mechanisms

of photosynthesis. ■

SHUDIPTO WAHED is a sophomore in Benjamin Franklin from Pittsburgh, Pennsylvania, interested in

studying Molecular Biophysics & Biochemistry. Shudipto conducts research on protein engineering in

the Ring Lab at Yale’s School of Medicine. Outside of YSM, Shudipto is a senator for the Yale College

Council and an analyst in the Yale Student Investment Group.

HANNAH BARSOUK is a first-year at Morse from Pittsburgh, Pennsylvania, interested in studying

Molecular Biophysics & Biochemistry. She is a Synapse Outreach Coordinator, senior staff writer, and

photographer for YSM. In her free time, she enjoys messing around with riboswitches at the Breaker lab,

making a ruckus with the Yale Undergraduate Skateboarding Union, and scrolling on biochem TikTok.

THE AUTHORS WOULD LIKE TO THANK Professor Gary Brudvig and Dr. Chris Gisriel for their time

and enthusiasm about their research.

FURTHER READINNG

SHUDIPTO WAHED &

HANNAH BARSOUK

Hussein, R., Ibrahim, M., Bhowmick, A., Simon, P. S., Chatterjee, R., Lassalle, L., Doyle, M., Bogacz, I., Kim,

I. S., Cheah, M. H., Gul, S., de Lichtenberg, C., Chernev, P., Pham, C. C., Young, I. D., Carbajo, S., Fuller, F. D.,

Alonso-Mori, R., Batyuk, A., . . . Yano, J. (2021). Structural dynamics in the water and proton channels of

photosystem II during the S2 to S3 transition. Nature Communications, 12(1). https://doi.org/10.1038/

s41467-021-26781-z


Biomedical Engineering

FEATURE

BOMB-SNIFFING INSECTS

DECODING ODOR-EVOKED NEURAL RESPONSES IN LOCUSTS

BY ELISA HOWARD

Have you ever considered hijacking an insect? While this

may seem like an absurd idea, the notion of exploiting

an organism for its biological attributes is not all that

foreign. Take, for instance, the use of canaries in coal mines

during the 1900s. The canary acquires oxygen both when it

inhales and exhales, and this double dose of air results in the

bird’s increased vulnerability to carbon monoxide and other

poisonous gases. Thus, the health of the canary provided a means

for coal miners to understand the safety of their environment.

Professor of Biomedical Engineering Baranidharan Raman

and colleagues at the Washington University in St. Louis aim

to harness nature’s incredible biology for a different purpose:

hijacking the locust olfactory system to engineer

bomb-sniffing insects. “Through evolutionary

processes, biology has come up with these

amazing small-molecule detectors

that are present in your nose, my

nose, as well as locusts,” Raman

said. In locusts, the approximately

fifty thousand olfactory receptor

neurons (ORNs) of each antenna

convert odorants into neural signals

that funnel into the antennal lobe. “Why

not use the insect as a sensor, tap into the

neural signals while the insect is interacting

with the environment, and use those neural

signals to understand whether chemical A or

chemical B is present?” Raman asked.

In previous work, the researchers implanted electrodes to

record neural signals in the antennal lobe. They demonstrated

that those neural responses provide a fingerprint to discern

between explosive and non-explosive vapors in addition to

different types of explosive vapors. In a recent study published

in Proceedings of the National Academy of Sciences, Raman

and his team investigated how locusts recognize a particular

odorant regardless of stimulus history, dynamics, and

context. “You can smell coffee in a coffee shop, grocery shop,

or restaurant. It smells the same whether you are on the coast

or in the driest of the Sahara Desert,” Raman said. The same

is true for locusts, but how?

In the presence of an odorant, neural signals from

ORNs of the antenna drive the activity of cholinergic

projection neurons (PNs) and GABAergic local

neurons (LNs) of the antennal lobe. PNs and LNs

reformat the signal, resulting in intricate spiking patterns

among PN ensembles. Those PN patterns encode

odor intensity and identity. To test the locust’s

invariant stimulus recognition ability, the


researchers conditioned the insects through methods

resembling that of Russian physiologist Ivan Pavlov. In the

presence of a food reward, locusts automatically open

their sensory maxillary palps. After the presentation of

an odorant followed by a food reward in six training

trials, the locusts learned to open their maxillary palps

in response to the odorant alone.

Raman and colleagues examined changes in palp

opening—an indicator of odorant recognition—in

response to perturbations, including varied stimulus dynamics,

altered stimulus history, the existence of competing cues, and

differences in ambient conditions. The results support the

hypothesis that locusts detect an odor regardless of such

perturbations. “Now we know the behavior is stable.

How stable are the neural responses?” Raman

questioned. The researchers recorded the

activity of antennal lobe PNs and found much

variability in odor-evoked firing for singleneurons

and cell ensembles. “There was

no single feature that was reliable and

robust that allowed this perception of an

odor to remain constant independent of

all these perturbations,” Raman said.

To decode the neural responses,

Raman and colleagues used a linear

classifier. The classifier assigns a weight to each

neuron and successfully predicts the presence

of an odor if the sum of weighted neurons

exceeds a threshold value. In investigating how the classifier

works, they discovered two different ensembles of neurons in the

locust olfactory system: ON neurons, active in the presence of the

stimulus, and OFF neurons, active in the absence of the stimulus.

The classifier assigns positive weights to the ON neurons and

negative weights to the OFF neurons. “When you combine the

activity of all the ON neurons while subtracting the activity

of the OFF neurons, if that sum is above a certain threshold

value, the odor is present. Simple as that,” Raman said. In fact,

a classification scheme using only ternary weights—positive one

for ON neurons, zero for non-responders, and negative one for

OFF neurons—enables robust odor recognition.

Uncovering more of locust olfaction through the study of

ON and OFF neurons, Raman and his team are one step closer

to exploiting biology’s expertise to hijack the insect olfactory

system. Next time you try to squash a bug, look closer: bombsniffing

insects are an innovation of the near future. ■

ART BY ANASTHASIA SHILOV


FEATURE

Materials Engineering

A STICKY SITUATION...

UNDERWATER

FOCUSED DELIVERY OF ENERGY

INTO DIFFUSIVE SYSTEMS

What do mussels have that we humans don’t? Well,

many things, but among them: the ability to stick to

surfaces underwater.

Strong underwater adhesives have versatile and useful realworld

applications ranging from underwater equipment repair

to surgical glue. Researchers from the Washington University

in St. Louis combined mussel foot proteins and spider silk to

create a hydrogel that can adhere to surfaces underwater. “Nature

already offers a wealth of materials, and some of them even

outperform synthetic materials,” said professor Fuzhong Zhang,

a lead researcher on the study. The mussel foot proteins naturally

secreted by mussels allow them to adhere to a variety of surfaces,

even in the harsh conditions of seawater. “We’re inspired by

natural materials that are very impressive in some aspects. The

first step is trying to reproduce it. Once we are confident that we

can synthesize the material with similar properties, then we can

engineer it to make it perform better,” Zhang said.

And engineer it they did. The new adhesive hydrogel is able

to stick to a wide range of surfaces—ranging from glass to

mammalian tissues—underwater. The researchers began with

the zipper-forming motif of an Aβ amyloid protein, which

conveniently tends to self-assemble into stable nanofibrils.

Then, they added spider silk protein for much-needed material

strength and mussel foot protein for improved surface adhesion.

Engineered microbes produced the final hybrid protein. This

process, which pushes the boundaries of traditional recombinant

DNA technology, presented unique challenges to the researchers.

“The mussel protein contains a special amino acid, DOPA, which

basically offsets tyrosine. It’s not one of the 20 canonical amino

acids. In our case, we have to engineer the bacteria so that it can

incorporate DOPA into the protein with high efficiency,” Zhang

said. The incorporation of non-canonical amino acids is critical

to the function of these tri-hybrid proteins.

This microbial production of useful, naturally-occurring

materials has the advantage of allowing advanced, specific

DNA control of functional groups. “Scientifically, the biggest

challenge is to understand the sequence-property relationship

of protein-based adhesives. With that knowledge, we will be

able to create adhesives with desirable properties,” Zhang said.

The researchers were able to fine-tune the properties of the

hydrogel—structure, strength, cohesion, and adhesion—by

adjusting the different domains and sequences of spider silk and

mussel foot proteins.

BY EUNSOO HYUN

ART BY ALEX DONG

On a

practical

level, this novel

hydrogel provides

several advantages over

pre-existing competitors in

the field. Since the hydrogel is

biocompatible and biodegradable, it is

an attractive, unique candidate for tissue repair

and surgical applications. Another feature is its mechanical

similarity to collagen, a major structural element in the

extracellular matrix. “It is critical for a surgical adhesive to

have similar properties with the natural extracellular matrix

because that can promote more rapid tissue repair and reduce

the chance of failure,” Zhang said. The hydrogel is also proteinbased,

as opposed to other previously developed polymerbased

adhesives. One area in which a protein-based adhesive

is necessary is coral restoration, where the adhesive must work

well underwater in addition to being safe, i.e., not releasing any

potentially toxic materials.

This project is an exciting example of the potential of synthetic

biology. Zhang reminisced on the team’s first, unexpected

encounter with the possibilities of mussel foot protein. “A few

years ago, one of my graduate students, Eugene Kim, who is now

an Assistant Professor at George Mason University, worked on

this project. At that time, the adhesive protein he made looked

the same as any other protein—it was just a powder that would

dissolve in solution,” Zhang said. Kim didn’t test the proteins

underwater—he simply added some protein solution between

two aluminum bars. “The next day, when he tried to pull, it was

so strong he could not pull it apart. And he’s a strong guy!” Even

before officially testing the material, the researchers found that

it was strong enough to lift a full one-liter bottle of water despite

only having a tiny area of adhesion.

Synthetic biology is a rapidly growing field, full of

innovation and growth. “I want people to learn more about

the opportunity that synthetic biology provides to material

science and material engineering. We would like to work

with many researchers who believe in the power of synthetic

biology. We welcome new students to join us and explore this

exciting field together,” Zhang said. ■


SPANISH “PERRO” VS.

HUNGARIAN “KUTYA”

CAN DOGS DISTINGUISH HUMAN LANGUAGES?

BY BREANNA BROWNSON

Just about everyone with a pet has experienced the

phenomenon of talking to an animal without any

expectation of an intelligible response. Even though our

pets don’t understand exactly what we’re saying, many pet

owners claim that they have grown closer to their pets by

talking to them. Have you ever wondered just how much your

pet takes away from these interactions? Laura Cuaya and her

fellow researchers at Eötvös Loránd University’s Department

of Ethology have made great strides in understanding how

dogs process what they hear.

Cuaya was motivated to study speech perception in dogs because

of her personal experience moving from Mexico to Hungary with

her dog, Kun-kun. “Before, I had only talked to him in Spanish. So

I was wondering whether Kun-kun noticed that people in Budapest

spoke a different language, Hungarian,” Cuaya said.

Cuaya noted that dogs are a particularly interesting species

because their evolutionary history starts completely separated

from humans but later switches to paralleling them after dog

domestication. “With dogs, we have a wonderful opportunity to

study the evolution of speech perception. Dogs needed to adapt

their social minds to a human environment. Understanding humans

became important for them,” Cuaya said. Although there

are different biological mechanisms and neuronal pathways in

dog and human brains, both species have developed unique

manners of completing the same task—recognizing human

speech patterns—over the course of their evolutionary history.

Cuaya conducted a study on eighteen family dogs, including

her own dog, Kun-kun, to determine how the canine

brain detects speech and represents language. Her research

focused on determining how dogs react to four main types of

sound: natural speech in a familiar language, natural speech

in an unfamiliar language, scrambled speech in a familiar language,

and scrambled speech in an unfamiliar language. To observe

which parts of the dogs’ brains were active in response to

different types of speech, Cuaya used functional magnetic resonance

imaging (fMRI), a scan that measures small changes in

blood flow to map brain activity. Then they used multivoxel pattern

analysis (MVPA), a technique that correlates neural activity

patterns with different areas of the brain where stimuli are

processed, to analyze the fMRI results.

One of the biggest challenges Cuaya faced was making

sure the dogs stayed still in the fMRI machine. For

fMRI scans to be usable, there can only be up to three millimeters

of movement while the dogs are laying in the scanners.

Dog trainers were brought in to teach the dogs to stay

still for the duration of the scan, and dog owners

stayed nearby throughout the entire

Neuroscience

FEATURE

scans to keep the dogs comfortable and relaxed. The dogs were

free to leave at any time.

Cuaya found that the primary auditory cortex responsible

for processing simple sounds in dog brains showed different

responses to scrambled and normal speech. Furthermore, different

neural activity patterns were seen in the secondary auditory

cortex, the part of the brain that processes more complex

noises, when dogs listened to the language they were most

often exposed to compared to a language they hadn’t heard

before. Even though we don’t teach our dogs the language we

speak, they become familiar with it because of the evolutionary

advantage associated with it. When we speak, our dogs

are actually picking up on the rhythms in our voice and the

sounds of our words. Dogs with the ability to recognize subtle

cues in their owners’ language were more easily domesticated,

and with domestication came the benefit of food and shelter.

Cuaya offered an analogy to help us better understand dog

speech perception by comparing it to an experience many of

us can relate to when traveling. “Maybe you have experienced

this feeling as a tourist in a new place. You think to yourself, ‘I

don’t know what language that is, but I know it’s not English,’”

Cuaya said. Dogs experience the same thing when hearing

people speak in a language they aren’t used to.

The next time you go to vent about your day to your pets, maybe

you’ll think twice about just how much of your speech they’re really

picking up on. They might be paying more

attention than you think, and

you have our mutualistic

evolution with dogs to

thank for that. ■

IMAGE COURTESY OF DR. CUAYA



FEATURE

Medicine / Physiology

HOW PIGS COULD

HELP US PEE

A NEW ERA OF XENOTRANSPLANTATION

BY KAYLA YUP

F

or Jayme Locke, the hardest part

about being a transplant surgeon

is knowing that a gold standard

treatment exists yet being unable to use it.

In the face of end-stage kidney disease, the

biggest barrier to treatment is the ongoing

organ shortage. With demand drastically

exceeding supply, a radical solution is

imperative. That solution oinks, rolls

in mud, and can play video games with

their snouts. Enter the pig: an innovative

solution to the organ supply crisis.

At the University of Alabama at

Birmingham (UAB), Locke was the lead

surgeon in a study that performed the

world’s first transplant of genetically

modified kidneys from a pig into a

human. According to Locke, there are

eight-hundred thousand Americans with

kidney failure, and within that group, sixhundred

thousand are on dialysis. Only

around ten percent of these Americans

make it to the kidney transplant waiting

list, and a measly three percent receive

kidney transplants each year.

“We know kidney transplantation is

the cure for kidney failure. We want to

be able to offer the cure to everyone in

need,” Locke said.

Only about thirty-five percent of

people survive past eight years on

dialysis. Meanwhile, a kidney transplant

offers a success rate of ninety-five percent

(for deceased donor transplants) to

ninety-eight percent (for living donor

transplants). A kidney transplant also

improves a person’s quality of life. Kidney

failure is an end-stage disease—if it is not

ART BY IVA KNEZEVIC

fixed, the patient will die. Therefore, the

prospect of having an organ on the

shelf, waiting for anyone who needs

it, is truly revolutionary.

In their search for a donor source

animal, pigs stood out. In order to

meet the current and projected

demand for kidney transplants,

the research team needed an

animal that could rapidly

reproduce large litters. “The

domestic pig was chosen because

of its ability to ‘scale-up.’ They

also have a lifespan close to thirty

years, which is great when it comes

to kidney longevity,” Locke said.

However, since the pig is still

relatively foreign to the human

immune system, it was crucial to edit

ten genes to make the pig kidney more

“human.” These edits, along with the

standard immunosuppression involved

in human-to-human transplantation,

allowed the human body to tolerate the

pig kidney and for the pig kidney to

sustain the person.

The specific genetic modifications

included the targeted insertion of two

human complement inhibitor genes, two

human anticoagulant genes, and two

immunomodulatory genes, in addition

to the deletion of three pig carbohydrate

antigens and the pig growth hormone

receptor gene. The end result was a

herd of genetically engineered pigs

whose inability to express red blood

cell antigens allowed them to serve as

universal donors.

According to Locke,

one of the greatest challenges

in xenotransplantation is

understanding tissue compatibility

between the porcine donor and the

human recipient. If the tissues do

not match between the donor and the

recipient, the latter will reject the organ

within minutes of establishing blood

flow. To overcome this challenge, the

team reached out to Vera Hauptfeld-

Dolejsek and Julie Houp, co-directors

of the UAB Histocompatibility Lab, who

developed a novel assay specific to pigto-human

transplant.


Medicine / Physiology

FEATURE

The pig donor’s red blood cells were

combined with the human recipient’s

serum in a crossmatch for the assay.

This assay tested whether a kidney from

a pig could tolerate an adult human

environment. The negative control was

pooled human male AB serum, while the

positive control serum contained IgG, an

antibody known to react with porcine cells.

In the study, the human recipient’s blood

was mixed with pig cells to demonstrate a

negative crossmatch, allowing

the transplantation to

proceed. This ability to

predict compatibility

between the pig

xenograft and the

human recipient

would prove

to be very

accurate.

The second

hurdle of this

study was

testing for

hyperacute

rejection

without

harming

a living

person.

Hyperacute

rejection

occurs a few

minutes after

the transplant

due to the antigens

being completely unmatched—the body’s

immune system treats the transplanted

organ as a foreign object and attacks it.

The team’s solution was to create the first

human preclinical model.

The Parsons model was named in

honor of Jim Parsons, a fifty-sevenyear-old

man from Huntsville,

Alabama. Parsons had been a

registered organ donor through

Legacy of Hope, which is

Alabama’s organ procurement

organization. In light of

his sense of adventure and

desire to make a difference, the

Parsons family sought to pay tribute to

his character. After Parsons was declared

brain dead and his organs were deemed

unsuitable for donation, the Parsons

family ultimately consented to him

serving as the first preclinical model for

this groundbreaking study.

While human brain death had already

been used to harvest organs for human

transplantation, it was novel to leverage

brain death as a preclinical human

model. One critical concern to be

tested via the model was the vascular

integrity of pig kidneys. Pigs do not

have the same mean arterial pressure

as an adult human being, so whether

the transplanted kidney would be able

to hold its integrity was unknown.

Another goal of this preclinical model

was to determine whether the genetic

engineering, coupled with a negative

prospective crossmatch, were sufficient

to prevent hyperacute rejection.

During surgery, the two pig kidneys

were positioned in the exact anatomic

locations used for human donor kidney

transplantation and employed the same

attachments to the renal artery, renal

vein, and the ureter.

“In the present study, the crossmatch

was performed prior to transplant—

just as happens in human-to-human

transplantation—and it was negative,

predicting there would not be hyperacute

rejection. The only way to validate this

was to perform the actual transplant and

demonstrate the kidney turned pink and

made urine. We did this leveraging the

Parsons Model, and in so doing, answered

key safety questions without risking the

life of a living person,” Locke said.

To the team’s delight, the pig kidneys

reperfused promptly in the same manner

as human transplants. The kidneys retained

optimal color and turgor, the vascular

connections between donor organ and

recipient stayed intact, and there were no

major bleeding episodes. Within around

twenty minutes, the right kidney started

making urine, later followed by the left. The

ureter had successfully carried urine from

the pig kidney into the human bladder.

There was no sign of hyperacute rejection.

This success proved the accuracy of

their crossmatch and firmly established

brain death as a viable preclinical model

IMAGE COURTESY OF TYLER GREER

A Doppler probe is used to assess blood flow inside

the right pig kidney after transplantation into the

human recipient.

for studying the human condition—where

a treatment’s safety and feasibility may be

tested without doing harm to someone.

Such a model would extend far beyond

xenotransplantation—many diseases that

have yet to be understood, along with new

techniques and devices in need of testing

before use on a living person.

In a pathogen-free facility, a herd of

pigs awaits. These pigs will be the proper

size for adult human transplantation by

June 2022. The team hopes that the FDA

will approve their Investigational New

Drug Application and thereby allow the

launch of a phase I clinical trial in living

persons, a process Locke is hopeful to

begin in 2022.

Particularly in the era of COVID-19,

regulatory agencies will rigorously

assess the transmission of viral diseases

from pigs to humans. In this study, the

team tested the pig pre-procurement

to ensure that the pig did not have any

diseases. Further, the human recipient’s

blood was tested post-transplantation

to prove the absence of pig-derived

infections or diseases.

Locke is hopeful that the pig xenograft

kidney will be available for widespread

use as early as five to ten years from now.

She envisions xenotransplantation and

allotransplantation as complementary;

together, there is the real potential to

completely eliminate the waiting list and

wipe out the organ shortage.

For now, our ability to pee may be

secured, one pig at a time. Who knows

what organ or animal will be next. ■



FEATURE

Artificial Intelligence

THE

PRECISE CHOREOGRAPHY

OF

NATURE'S MASTER WEAVERS

MAPPING THE MINUTE MOVEMENTS OF HACKLED

ORB WEAVERS CONSTRUCTING THEIR WEBS

BY HANNAH HAN

In one act of the famous ballet “Swan

Lake,” fourteen dancers raise their

arms and flutter their hands in

synchrony, while the lead ballerina spins

in a slow pirouette center-stage. As the

ballet progresses, the dancers execute a

series of choreographed motions—jumps,

twirls, and leaps—that are distinctive for

each of the four acts in the performance.

The sequence of a ballerina’s movements

can be applied to the equally elegant and

complex process of spider web-building.

Andrew Gordus, an assistant professor

and behavioral biologist at John

Hopkins University, has studied spider

web construction for over five years. He

explained that spiders, like ballerinas,

build up a repertoire of techniques,

such as leg sweeping, abdomen bending,

and silk pulling, which they use during

specific phases of web-building. When

combined, these movements form the

intricate architecture of their webs.

Gordus’s fascination with web-building

began over five years ago, when he

stumbled upon a stunning web while

walking through Central Park. At the time,

he wondered how such a small organism

could accomplish such a complex feat.

“It’s amazing that an animal with a

brain no bigger than a fly’s built this

web,” Gordus said. “And it’s really

impressive because if you went to a zoo,

and you saw a chimpanzee build this

web, you would think, ’Well, that’s a

really talented chimpanzee.’ But this is

being done by an animal with a really

tiny brain.”

This discovery prompted Gordus

to read all of the existing scientific

literature on web construction and

to email researchers studying spider

It’s amazing that an animal

with a brain no bigger than a

fly’s built this web.

behavior. However, the field was

not well-developed, and some of his

questions remained unanswered.

In his last few months as a postdoc at

Rockefeller University, Gordus’s advisor

allowed him to conduct experiments

on spiders in a separate facility on their

campus in New York City. When Gordus

moved to Johns Hopkins University in 2016

to start his own lab, he continued studying

web-building as a side project. Over time,

ART BY BELLA GUZMAN

more graduate students joined his lab, and

the project gained traction, becoming the

largest undertaking in his laboratory.

Though Gordus is fascinated by the

physical web itself, he is more interested

in the behavioral processes that govern

its construction. In his 2021 study

published in Current Biology, Gordus

studied the movements of hackled orb

weavers, which are found in the western

United States. Orb weavers typically

build spiral-shaped webs using strands

of silk that have the same dry, wooly

texture as cotton candy. Gordus’s love

for these creatures is evident—a red

spider was sewn onto the black jacket he

was wearing during our interview. (His

hat was also emblazoned with a cartoon

worm—the other model organism he

primarily works with in his lab is the

roundworm, C. elegans.)

In his study, Gordus and his team

were interested in inferring the spiders’

internal states by examining the

construction of their webs. He explained

that every animal’s behavior is dictated

by a myriad of internal states, including

hunger, sexual arousal, and emotion,

that manifest in physical actions, such

as grooming or mating rituals. “The

question we wanted to know was: What

are the behaviors that this web is a

record of?” Gordus said. “What are the


Artificial Intelligence

FEATURE

IMAGE COURTESY OF FLICKR

A hackled orb weaver rests on its web. Gordus and his

team used these animals as model organisms to study

the construction of spider webs.

behaviors, the rules, [for each stage of]

web-building?”

In order to study these spiders’

movements, Gordus and his team used

infrared illumination and a high-speed

camera, which captured the minute

motions of each of the spider’s eight

legs. The entire process involved many

attempts, unexpected failures, and an

abundance of perseverance. Gordus

said that they originally tried to study

the spiders under red light, but the orb

weavers refused to build their webs

without complete darkness. The team

then transitioned to infrared light, which

is invisible to both humans and spiders.

To track the orb weavers’ movements,

the scientists placed labels with infrared

dyes on each of the spiders’ legs, a

technique commonly used to examine

fly behavior. However, they were met

with great resistance. “[The spiders]

hated having their limbs labeled, and

they would just spend the whole time

sitting there trying to take it off,” Gordus

said. “And then, they would [sometimes

stop building and would] stick to their

own web, and we would come back, and

they would just be dangling.”

Instead of the labels, the team decided to

use a camera that detected the reflection

of infrared light off of the spiders’ bodies.

They also adopted two recently published

algorithms specifically designed for limb

tracking, called LEAP and DeepLab

Cut. The scientists first trained the

algorithms on several thousand frames of

spider movements, which they manually

tracked. The algorithms were then able to

track millions upon millions of frames,

capturing the minute motions of the

spiders’ legs.

After monitoring six different

orb weavers, the team adopted a

machine learning algorithm, called

the hierarchical hidden Markov model

(HHMM) to deduce patterns in web

construction. The algorithm employed

probability models to predict the spider’s

web-stage based on transitions in its

behavior, without knowing where the

spider was on the web. The researchers

found that the predictions made by

the HHMM mapped onto established

phases of web-building based on the

spider’s position. This solidified the

association between the orb weaver’s

distinct behaviors and specific phases

of construction. Developing the model

involved trial and error—existing

algorithms used to predict fly movements

did not perform as well when applied to

orb weavers, so they had to write their

own code from scratch.

After years of troubleshooting and

diligent work, Gordus’s lab finally

developed a fully-fledged experimental

system. Upon collecting their data and

analyzing the results, the researchers

came to a startling revelation. Contrary

to their expectations, the orb weavers

did not build their webs reflexively,

moving from phase to phase without

pausing. Instead, the spiders revised

their work as they went, returning to

past locations on their webs to rearrange

misplaced strands of silk. Sometimes,

the weavers even repeated entire phases

of web construction before proceeding

again, indicating that they might have

internal models of their webs that they

are attempting to replicate.

“We were surprised [at] how frequently

the spider could go back and try a prior

phase over again,” Gordus said. “[The

spiders are] constantly assessing what

they’re building with this internal goal,

and [they have] a flexible way of trying

to get to that goal.”

Looking ahead, Gordus’s team hopes

to study the effects of certain drugs on

web construction in order to elucidate

the neurological activity associated with

each phase of building. The team is

looking into the effects of two chemicals

in particular: lysergic acid diethylamide

(LSD), a potent psychedelic drug,

and ecdysone, a steroidal hormone in

arthropods that induces molting and

influences decision making.

Already, the researchers have confirmed

that ecdysone causes the orb weavers

to stop building their webs at a certain

stage. They also know that giving the

spiders a microdose of LSD results in the

construction of perfectly symmetrical,

evenly-spaced webs. Gordus said he is

interested in further studying the effects

of LSD on neuromodulatory pathways,

or chemical pathways in the brain that

control internal states.

“If the spiders build really good

webs [after consuming LSD], then we

want to know what changed in their

behavior,” Gordus said. “Are they just

executing the behaviors really well, like

a professional web builder? Or do they

have [obsessive compulsive disorder],

and they’re constantly doing a lot of

error correction? We’d like to know,

what is the behavioral readout?”

By deducing which motor neurons

are activated in the spiders’ brains after

the administration of certain drugs, the

researchers might be able to understand

the effects of these chemicals on human

behavior. For now, though, Gordus

and his team are focused on studying

orb weavers and the graceful, intricate

choreography of their web-building. ■



FEATURE

Behavorial Science

VIDEO GAMES FOR THE WIN

HOW SKIES OF MANAWAK IS IMPROVING LITERACY

BY CRYSTAL LIU ART BY CATHERINE KWON

Marco, a fourth-grader in an

Italian public school, plays

Skies of Manawak, a newly

developed computer game supervised by

his teacher during class time. One zone

in the game, “The Flight,” looks like a

typical action game: he collects objects,

avoids obstacles, and battles enemies to

fulfill a given quest.

Once Marco finishes a level, he is

directed to “The Village”: this zone

exhibits key characteristics of an incentive

world, and where he has to redeem points

earned from “The Flight” to decorate his

village. The village comprises nine minigames,

each designed to train a different

cognitive skill. In one game that trains

working memory, Marco is shown a

series of graphics before being prompted

to select the last three graphs he saw. In

another game designed to cultivate split

attention, he needs to control a person

and a bird simultaneously, weaving

around obstacles by jumping or sliding as

the person and flying higher or lower as

the bird. After accomplishing a few tasks

in The Village, Marco finally discovers

the next quest that leads him back to “The

Flight.” Difficulties of the action segment

and mini-games are adapted based on

Marco’s performance on each task.

Skies of Manawak (SOM) is a childfriendly

action video game created by

European researchers to improve children's

reading skills and help them develop the

ability to pronounce Italian words and

texts fluently and accurately. They recruited

151 students aged eight to twelve without

learning disorders in a public school for

training. Students were randomly assigned

either to the experimental group playing

SOM or the active control group playing

Scratch, an interactive programming game

tailored to kids.

Researchers integrated both Skies of

Manawak and Scratch into the school

curriculum. Students played the games

during class time for one hour twice a

week over the span of six weeks. They

were evaluated three times: before the

training, right after the six-week period,

and six months after the end of training.

The training was simultaneously a social

experience. “For example, the children

that played Scratch learned the basics

but also prepared a Christmas card

all together for their teachers and

parents,” said Angela Pasqualotto,

a postdoctoral researcher at the

University of Geneva and the

University of Trento who

was the first author of

the paper published

in Nature Human

Behaviour.

As expected, the

experimental group

showed significant

improvements in

visuospatial attention

and cognitive planning. The former

was measured with a Bells Test adapted

for children, where participants tried

to find as many bells as possible in a

graphic amid distractors. The Tower of

London test was administered to evaluate

planning. This test involved two boards

with pegs and several beads of different

colors. Examinees tried to move the beads

on one board to match the pattern on the

other in the least number of moves. Both

advantages were maintained at the sixmonth

follow-up.

Researchers also evaluated the

participants’ reading skills, which

were not directly trained in the game.

Besides word lists and meaningful texts,

they developed lists of pseudowords for

students to read aloud. Have you played

the word-guessing game Wordle? How

many times have you put in a word that

reads perfectly fine, only to find out that

it doesn’t exist? Pseudowords are groups

of letters that abide by pronunciation

rules but aren’t part of the vocabulary

in a certain language.

At the end of the six-week training

period, students who played SOM

demonstrated significantly higher reading

speed and accuracy than those who played

Scratch. This difference was maintained

at a follow-up test six months after the

training. This pioneering study shows

an improvement in reading accuracy in

addition to reading speed, both of which

are fundamental for literacy.

Besides reading the text aloud, scientists

also measured reading comprehension

but found no significant improvement.

“Comprehension is a more complex

ability which requires many other

subskills,” Pasqualotto said. However,

she pointed out that comprehension was

only measured right after the training.

Students in the SOM group showed a

small but significant improvement in


their grades twelve and eighteen months

after training—an advantage that grew

over time. This trend may suggest slower

and more modest progress in complicated

skills like comprehension.

Previous studies on non-conventional

training tools have been largely centered

around children with dyslexia, a learning

disorder that involves difficulty with

reading. Affected individuals have a

harder time decoding letters and words

into related speech sounds. This study

extends positive findings in dyslexic

children to a broader population.

It took the experimenters over three

years to complete the study—two years

on game design, followed by recruitment,

training, and follow-up studies for up to

eighteen months. Along the way, they

encountered a variety of challenges. Game

designers recruited over three hundred

children aged eight to fourteen to help

refine the SOM storyline and aesthetics. It

was extremely tricky to get children at this

age to follow instructions and to collect and

analyze their opinions. When the game

was finally ready for testing, researchers

had to coordinate logistics with teachers

and continuously edit their proposals to fit

into the original curriculum.

Usually, in a randomized control trial,

experimenters don’t know whether a

participant is assigned to the experimental

or control group. This process of

“blinding” reduces the researchers’ biases

when evaluating the participant. In this

study, however, it was impractical to blind

every experimenter since at least one of

them had to talk to school representatives

and supervise the training. In the end,

two experimenters were blinded, and the

third, Pasqualotto, became the one who

oversaw the entire program. Researchers

compared the results scored by the blinded

experimenters against combined results

from all three of them and found no

difference between the scores.

Italian is an extremely transparent

language. One can almost always

pronounce a word correctly following

pronunciation rules. In contrast, English

is an opaque language, with numerous

sounds corresponding to one letter and

vice versa. In logographic languages like

Chinese, there is no alphabet, and the

reader needs to remember the sounds of

each character. Pasqualotto and her team

hope to assess the efficacy of SOM in other

languages and compare it to Italian. “My

expectation is that training attentional

control and executive functions,

particularly working memory and

cognitive flexibility, could be beneficial

for all languages,” Pasqualotto said. But

it will be interesting to investigate the

potential differences in the extent of

progress made across different languages.

The researchers carried out the

training before COVID-19 when

social interactions were still largely

unrestricted. However, with the global

pandemic, it is harder not only for these

interactions to happen in the classroom

but also for experimenters to meet with

participants and administer the tests.

The pandemic pushed Pasqualotto and

her team to allow children to play the

game and carry out subsequent testing

at home. While the game was originally

Skies of Manawak Developers.

Behavorial Science

FEATURE

developed on

computers, the

researchers are now coming

up with a version on tablets

since touch-based technology is more

accessible and popular in an average

household. They are also updating

testing protocols so that cognitive tests

can be administered at home without

experimenters. They hope to eventually

develop a product complementary to

school activities that is simultaneously

useful for research purposes.

Despite the many challenges and

obstacles, Pasqualotto has been pleased

with her team's achievements. “Research

should have an impact on our life. This

type of study is certainly demanding in

terms of time and organization, but it also

gives you a bigger reward and sense of

satisfaction in the end,” Pasqualotto said. ■

IMAGE COURTESY OF STUDIO BLIQUO



UNDERGRADUATE PROFILE

KATE PUNDYK

BF ’22

BY CATHERINE ZHENG

Amidst a mess of flour and dough in a small San Francisco

apartment, one can find 2022 Rhodes Scholar Kate Pundyk

baking away, having set stacks of research journals and

books on technology policy aside to try out a new recipe. While

STEM and the humanities often find themselves on opposite ends

of the spectrum, Pundyk found her calling in the intersection of

technology and social policy through a long-winding path with

many different research experiences and universities.

Pundyk first left her home in rural Crowsnest

Pass in Canada at seventeen-years-old to

live in Hong Kong. During her stay, she

witnessed firsthand how the citizens

stood up for their rights during

the Umbrella Revolution. “[I]

realized how powerful activism

can be, even in situations where

it feels like the opponent is a

very large and very powerful

entity,” Pundyk said. This

experience abroad quickly

became a turning point

in her life, motivating her

continued work in social

justice and activism.

Pundyk started her college

education as a political

science student at Wellesley

College following her two-year

stay in Hong Kong. She found

herself traveling to Cambridge each

semester to take classes at MIT. With her

time split between taking more humanitiesoriented

classes at Wellesley and technologyfocused

classes at MIT, the intersection between the two

came about naturally. “It was impossible to go from any of the

foreign policy, world politics courses that I kind of gravitated

to, and then go to my cybersecurity class at MIT and not think

about how those two overlapped,” Pundyk said.

Pundyk became involved in the MIT Little Devices Lab during

her time at Wellesley, which focuses on creating affordable

medical technology for people in disaster or low-resource

settings. As a technology policy researcher and political science

student, she was primarily involved in researching how access

to medical devices depended on financial stability. For example,

she investigated how big pharma’s corporate nature affects

engineering and technology access, preventing low-income

people from getting the medical care they need.

After two years at Wellesley, Pundyk decided to return to Canada

and work in the Office of the Premier in Alberta. With just two years

of undergraduate education under her belt, Pundyk was adamant

about pursuing her interests and creating change in fields that she

believed mattered, taking part in progressive campaigns. Later in

2019, Pundyk transferred to Yale to pursue her interest in technology

policy and its role in human rights abuses and equity.

At Yale, she found herself involved in a host of different

activities and organizations. One of the most notable was

reporting for the Sci-Tech desk at the Yale Daily

News (YDN). Having worked in government,

Pundyk knew that the ability to

communicate technical subjects to

lay audiences was lacking in many

politics-oriented communities,

and this was something she

was hoping to work on at the

YDN. With the COVID-19

pandemic, it was especially

important for her to easily

communicate the newly

discovered science and

engineered technology to a

broader audience.

While the pandemic

didn’t alter the course of

her education too much,

it became clear to Pundyk

that she was following the

right path. “COVID highlighted

the cleavages in our society that

urgently need to be focused [on].

[It] clarified that I’m making the right

choices and going for a career that centers

human rights and tries to build up other voices

that might be left out of the discussion,” she said.

In addition to the YDN, Pundyk started working with the Yale

Genocide Studies Program on a project known as Mass Atrocities

in the Digital Era (MADE). As part of this project, she brought

a technology-oriented angle to the research, focusing on how

technology plays a role in bringing about human rights injustices,

specifically looking into the accountability of human rights abusers,

memorialization of victims, and prevention of future atrocities.

For the upcoming fall semester, Pundyk will continue studying

the intersection of social policy and technology at Oxford during

her Rhodes scholarship, pursuing a Master of Science degree in

social data science and a Master of Philosophy degree in socio-legal

research. She is looking forward to moving home to Canada after

graduating from Oxford. “[It] was less about any individual feat and

more a confluence of a bunch of good things happening in a row and

being surrounded by good people who built me up,” Pundyk said. ■

PHOTO COURTESY OF KATE PUNDYK VIA ALEX DONG


ALUMNI PROFILE

JAMES DIAO

MY ’18

BY YUSUF RASHEED

Growing up next to the biggest medical center in the world,

James Diao YC ’18 was meant to be a doctor. A third-year

medical school student at Harvard Medical School (HMS)

and MIT, Diao was recently awarded the Churchill Scholarship to

do a year of master’s study in science policy at the University of

Cambridge for the 2022-23 academic year. With this scholarship,

he plans to take a deep dive into understanding the regulation of

healthcare technology and the efficacy of clinical algorithms

across diverse populations.

Diao’s initial interest in medicine and research stems back

to his hometown of Sugar Land, Texas, where he shadowed

Rachel Rau, a pediatric oncologist at the Texas Medical Center

in high school. “I learned a lot about science. I learned a lot

about patient care. I thought her job was the coolest job in the

world,” Diao said. At Yale, he continued to shadow clinicians

at Haven Free Clinic and became a Peer Counselor for Yale’s

anonymous and confidential hotline, Walden Peer Counseling.

Now, he’s spending time with patients in his core rotations.

In addition to his clinical experience, Diao has also spent a lot of

time on research. In April of 2020, he started studying the misuse

of race in kidney function tests with Arjun Manrai at the HMS

Department of Biomedical Informatics. Diao’s idea to pursue this

project was a bit spontaneous. “My mentor and I had previously

worked on equity and representation for cardiovascular genetics,

but kidney disease wasn’t on our radar

at all. It wasn’t until I learned about

the issue on Twitter that I began

diving into the literature and

thinking about ways to

contribute,” Diao said.

The “issue” Diao

had stumbled upon

was related to the

glomerular filtration

rate (GFR). GFR

measures how well

a person’s kidneys

can filter substances

from their blood, which

is essential in the early

detection of potential

kidney disease. The current

test to measure someone’s GFR is

an equation that involves several variables,

including age, sex, and race, with higher results indicating

healthy kidney function. “The main issue is [with] the race

and ethnicity component. If you’re Black, your number will

be assigned 16% higher,” Diao said. As a result, Black patients

with higher GFR numbers may have less access to specialist


PHOTO COURTESY OF JAMES DIAO VIA LAUREN CHONG

care, kidney transplants, and coverage by Medicare. Diao’s

research quantified the effect of including and removing

race from the equation, and he found that up to one million

Black Americans may receive unequal

kidney care due to their race.

When the race variable was

eliminated, he found that

access to diagnosis and

specialist care increased

for Black Americans.

Race-free equations could

also achieve the same

performance metrics

as the original ones.

In October of 2021, the

National Kidney Foundation

and the American Society of

Nephrology officially released

national recommendations supporting

a new race-free equation, citing Diao’s research.

During Diao’s first year of medical school, he joined the

machine learning team at tech startup PathAI, where he

worked on deep learning models in pathology. He then

joined Apple’s Motion Health team, where he worked on

studies to predict cardiovascular risk for the Apple Watch

using accelerometer data from consumer wearables. Diao

was named to the 2022 Forbes “30 Under 30” List for his

work and received the prestigious Paul & Daisy Soros

Fellowship in their 2021 cohort.

When he’s not conducting research, Diao is probably

ballroom dancing. This hobby started in college

when he searched for activities to get involved in.

“Ballroom was one cool [club] where they don’t

care if you’re new to it all”, Diao said. “You don’t

need to have any experience, you just show up, and

their whole thing is ‘We’ll teach you!’”

As Diao finishes medical school and approaches

the next step of his career, he hopes to continue

tackling systemic problems in medicine. He wants

to become a professor and investigator, studying

the performance and equity of medical technology

and translating this research to the realms of patient care,

company advising, and clinical trials.

Diao advises undergraduates to remember that they are only

at the very start of their careers. “There will be so much time

to double down on whatever ends up being your life’s work,”

Diao said. “I think there’s a lot of value in exploring early and

exploring all the different paths that are available to you and not

committing so early.” ■

PHOTO COURTESY OF JAMES DIAO VIA LAUREN CHONG


SCIENCE DENIAL: WHY IT HAPPENS

BY SOPHIA DAVID

IN DON'T LOOK UP

SCIENCE

newspapers, scientific research, statistics, and distressing anecdotes, many

IN

IMAGE COURTESY OF THE STORY COLLIDER

The phrase “Live every day like it’s your last” is frequently thrown

around. However, this advice is remarkably difficult to obey, in

part because it is remarkably difficult to believe. In Adam McKay’s

movie Don’t Look Up, people are informed by indisputable science that

an impending comet will destroy the Earth in about six months; however,

much of the world remains disturbingly in denial. People carry on with

their lives, concerning themselves with trivial celebrity relationships and the

presidential reelection.

This film overtly underscores the pervasive denial of scientific

facts. In our society today, plagued by COVID-19 and threatened by climate

change, the movie’s message to trust science is all too relevant. Despite

refuse to get vaccinated, wear a mask, or make environmentally sustainable

life choices. Of course, it is easier to ignore the fact that thousands of people

die daily from COVID-19 or to deny that a comet is descending upon us.

Without belief, there is no need for lifestyle changes, but there is also no

hope for a solution.

What, then, does it take to make people believe? In the film, as the

end of the world looms closer and closer, hordes of Americans rally behind

the “Don’t Look Up” movement, blissfully ignorant of the enormous comet

shining above them. It is not until one man looks up that the crowd follows,

unveiling the truth. Seeing the comet for themselves makes them believe

in its existence While perceiving for oneself is likely more effective than

statistics, it is unfortunately not always possible. In this case, by the time it

became possible, their fate was imminent. Nothing could be done. Believing

no longer mattered.

This raises the more nuanced question: what does it take to make

people believe before it is too late? Perhaps we can take a lesson from

this rallying scene. It was one man, importantly an insider of the “Don’t

Look Up” movement, who catalyzed a whole crowd’s belief. We should not

underestimate the power of convincing just one disbelieving person of a

scientific truth. Not only does each vaccinated, masked, or recycling person

make a difference, but each also has the power to communicate beliefs

from within social networks. Just as one head turning up turns others, one

conversation can lead to many more.

The movie divides people into two groups: believers and deniers.

Yet, among the believers, some strive to solve the problem for the world and

some strive to solve it for themselves. While many scientists work to destroy

the comet to save Earth, others focus their attention on finding personal

escapes from the disaster. Don’t Look Up’s message is more than just to trust

science. Believing alone isn’t enough to prevent the spread of COVID or

global warming, and our conversations cannot stop there. These disasters

affect us all, and just as we do not face them alone, we must use knowledge

of them to protect, not just ourselves, but everyone. ■


REVIEWING THE ANTHROPOCENE

REVIEWED

BY LUCY ZHA

John Green, the author of several best-selling books such as Turtles

All the Way Down, or better known to us college students as the host

of the series CrashCourse which saved our world history grades, has

also been producing a podcast titled The Anthropocene Reviewed. In his

monthly episodes, he shares his epiphanies on the things that have kept

humanity, humanity.

In truth, I see this podcast more like a John Green TM personal journal. He does

not contrive himself as an expert in anthropology; instead, he simply reflects

on specific moments from his personal life. In the episode “Mortification and

Civilization,” John Green explores the evolution of the word “mortification.”

Green defines "mortification" literally as "to cause death." "[Nowadays, the

word means] extreme fear from public embarrassment... a low-level form of

death," Green said. He then gives us an anecdote when he was giving a talk

in 2008, and one student at the end pointed out to him that his fly was open

the entire time. Oops, what a great way to ruin the mood. By sharing his

mundane experiences—the Canadian geese in his backyard, the Dr. Pepper

he drinks every morning, and a few lyrics from his favorite band, “The

Mountain Goats”—Green gives the histories and scientific backgrounds of

commonplace objects in his life.

Green extends the conversation from not only everyday occurrences but

Talso problems Hthat impact the

E

world globally and that are deemed “newsworthy.”

Green admitted that he would give COVID-19 a one-star rating in the

episode “Plague.” “Plague is a one-star phenomenon, but our response needs

not to be,” Green said. He reassures us that the COVID-19 pandemic is by

no means unprecedented. The Black Death in the 14th century decimated at

least one-third of the European population. “Corpses were laid on the streets

of Florence… Father did not dare to visit their souls,” Green said. However,

IMAGE COURTESY OF PIXNIO

in community, there also lies strength. When another round of the pandemic

came around again in Eyam in 1665, the village came up with a plan together

that held church services outdoors, maintained social distancing, and buried a

family’s own dead themselves. Humans had prevailed.

From John Green’s meticulous uncovering of his life’s many intimate

SPOTLIGHT

moments, he has proved to us that the Anthropocene is an era where

happiness, loneliness, life, death, and many other contradicting emotions

coexist because we, humans, are on this earth, together. This podcast

itself is also Green’s way of connecting with his readers in a time where

we are forced to be isolated. It is a miraculous feeling to see the famous

and knowledgeable author, whom I look up to, talk to his listeners as a

part of the ordinary ether. And in this age of quarantining, at least I, John

Green, and other listeners of this podcast, are here together.

Indeed, I would give The Anthropocene Reviewed a rating of five out

of five stars. ■



FOCUS

COUNTERPOINT

Computational Biology

SALAMANDERS SHOULD

NOT BE ALIVE

BY NATHAN WU

IMAGE COURTESY OF UNSPLASH

According to all known laws of evolution, there is no

way that salamanders should be able to exist. At first

glance, these creatures seem like marvels of evolution

with regenerative abilities and other unique adaptations that

protect them from predators. However, upon closer inspection,

their very existence seems to break all rules. Their hearts

are practically hollow, with muscle walls as thin as a single cell.

Their cells are oversized, sometimes hundreds of times larger

than those of humans. Trying to build such a small animal

with such large cells is like trying to make a detailed sketch

with a king-size Sharpie. Rather than being evolutionary marvels,

salamanders seem to be on the verge of death at all times.

Perhaps more surprising, though, is that many salamanders

seem to be barely born. They normally start their lives as

aquatic larvae and later metamorphose into terrestrial adults.

However, several species have lost their ability to metamorphose,

remaining confined to a half-larval state for the entirety

of their lives, never losing their gills or developing strong

limbs. Their bones never fully harden, remaining soft cartilage

instead. Even their brains are embryonic, with less cell differentiation

than their amphibious relatives.

So how are they still around?

The secret to this anatomical curiosity lies where most biological

secrets lie–within the genome. However, its peculiar

phenotypes may not come from specific genes. Instead, they

are a product of the quantity of DNA present.

Salamanders contain some of the largest genomes of any animal,

with some species carrying 38 times as much DNA as

humans. Their slow development can be explained by the fact

that all their “extra” DNA drastically increases the time it takes

to transcribe DNA to RNA. The size of the salamanders’ genome

goes against the common notion that larger, more complex

animals, like humans or primates, should carry larger

genomes than simpler ones, like salamanders. So why are salamander

genomes so large?

Scientists discovered that salamander genomes are riddled

with sections of DNA called “selfish genetic elements.” These

elements consist of short DNA segments, called transposons,

which contain various genes that code for their own replication.

Once copies of these transposons are produced, they

insert themselves into different parts of the genome. Transposons

can also affect the function of native genes, activating

or deactivating them, potentially harming the host.

Transposons are found in most living things, including humans,

but their density in salamanders is extremely unusual.

Usually, transposons are deleted over time through random

mutations, but it is believed that salamanders parse their genomes

at a rate much slower than humans or other organisms,

resulting in the accumulation of genetic material.

These rogue, selfish genetic elements appear to be a wrinkle

in the laws of evolution that we are familiar with. Scientists are

beginning to look at the genome itself as an ecosystem, with

transposons acting as species within it to better understand

their role. Under such a model, transposons adapt and change

to maximize their prevalence in the genome. If a transposon’s

location has a positive or neutral effect on the host, it will likely

persist there, being passed down to future generations.

Usually, if the accumulation of transposons begins to have detrimental

effects on a species, natural selection will pare down the

genome. The persistence of the salamander’s large genome suggests

that the downsides associated with it do not significantly

affect them. As a result, this genetic process created a feedback

loop where salamanders’ slowly growing genomes pushed them

into the evolutionary niche that they occupy today.

Our knowledge of salamanders and transposons is altering

our understanding of evolution. Not all changes to phenotypes

are driven by evolutionary pressure or are beneficial to the organism.

Rather than viewing DNA and organisms as inseparable,

scientists are beginning to consider DNA as something

that attempts to replicate itself through whatever means, without

consideration for the overall well-being of its host.

Salamanders’ bloated genomes seem to have pushed it to the

brink of extinction. Its mangled bones, flimsy heart, and underdeveloped

body don’t make any sense.

The salamander, of course, lives anyways. Because salamanders

don’t care what humans think is impossible. ■


BY DHRUV PATEL

HIDDEN

HISTORIES

THE SHREWD FAMILY

BUSINESS THAT SOLD TIME

ART BY MALIA KUO

In the first four decades of the twentieth century, Ruth

Belville—alongside her modest pocket-watch—sold time as

part of her family’s business. But to truly understand her story,

we must understand why she sold time. Prior to the nineteenth

century, people kept time by referencing the position of the sun:

the sun’s peak meant it was noon, and midnight was when the

peak was furthest away. When mechanical clocks were invented,

towns and cities began keeping a local time, meaning that noon

would be exactly twenty-four hours after the previous noon.

Time zones were also adopted in the mid-nineteenth century

to standardize time across vast regions. Such standardization

allowed for synchrony across cities and states in proximity to

each other, a phenomenon that frequent travelers and railroad

companies especially appreciated. Unsurprisingly, most people

began using mechanical clocks. Though these clocks were more

reliable than others, they were still not entirely accurate. For

example, such clocks would slowly deviate from the local mean

time (determined by the time zone). It is in this context that the

story of the Belville family arises.

In London, the Royal Observatory in Greenwich was

responsible for keeping the time. To signal the time to the public,

the Observatory would raise a balloon above the building at

precisely 1 p.m. every day. Later, the Observatory installed a large

clock on its gate so that anyone could see the accurate time at any

moment rather than waiting for a signal. However, to view this

clock, people had to physically make a trip from their homes and

offices across London to the Observatory, which of course, was

inconvenient. Moreover, calibrating watches and clocks in the

nineteenth and early twentieth centuries was more complicated

than it is today, requiring some level of expertise. Seeing this as

an opportunity to profit, John Belville, an assistant at the Royal

Observatory, began visiting a network of two hundred clients

around London once a week, calibrating their watches and

clocks with his own pocket watch, which he calibrated with the

Greenwich mean time daily. This business passed to his wife

when John died, and then to his daughter Ruth.

As with any business, the Belville family service faced

competition, particularly when Ruth took over after her

parents’ deaths. Telegraphs were capable of signaling time,

and different firms would compete to sell their telegraph

time service. Nevertheless, Ruth had an advantage: electric

telegraphs were not as accurate nor as reliable as her stateof-the-art

pocket watch, which was accurate to the tenth of a

second. Moreover, the firms selling telegraph time had trouble

keeping their services in order and received many complaints.

Ruth, however, was reliably consistent and professional.

Indeed, the watch’s accuracy and familiarity with the Belville

family business made it an easy decision for clients to remain

subscribed to this service.

Ruth Belville carried that pocket watch—which she fondly

called “Arnold”—around London every week for forty-eight

years. Each day, she would visit up to ten customers across

London, from the outskirt docklands to the central Mayfair.

Over these forty-eight years, radio became a prominent

method of communication (including communication about

time), and the electric telegraph also became more accurate

and reliable. However, there was still a market for Ruth’s

service—the new technologies did not simply replace the older

ones. Instead, they co-existed for quite some time.

Eventually, however, modern technologies outpaced Ruth’s

pocket watch. The invention of the telephone speaking clock,

which gave the precise time on the third stroke, signaled to

Ruth that her pocket watch could no longer compete with more

efficient and accessible modes of communication provided by

modern technologies. She finally retired at the age of eighty-six.

In all, the Belville family business spanned 104 years, from 1836

to 1940. Before Ruth passed in 1943, she donated Arnold to the

Clockmakers’ Company Museum.

Today, we are all accustomed to seeing the time on our phones

and digital watches. The Belville family business story is a tale

of the industrializing world, a world filled with the clashing of

the old and the new. ■



Interested in getting involved with

Yale Scientific

for writing, production, web,

business or outreach?

Learn more at

yalescientific.org/get-involved

AD_Yale_Congrats_half_Winter_2_22_draft_1..qxp_8 2/6/18 10:02 AM Page 1

Congratulations Class of 2022!

The Yale Science and Engineering

Association is here for you.

Founded in 1914, the YSEA is one of the oldest university student/alumni

organizations in the world with a focus on STEM.

Whether near or far from New Haven, we help our members realize their

goals and to connect in ways that strengthen the Yale science and

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YSM Issue 95.1

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