YSM 98.2

Yale Scientific

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

MAY 2025

VOL. 98 NO. 2 • $6.99

22

FROM CRYO TO CURE

ZONED OUT 12

SCRATCHING THE SURFACE 14

NO STOPPING NOW 16

AXIONS AND AXIOMS 19

TABLE OF

VOL. 98 ISSUE NO. 2

COVER

22

A R T

I C L E

From Cryo to Cure

Crystal Liu

Animal models of neurodegenerative disease face key challenges, including short lifespans and

rapid disease progression that diverge from human pathology. Discover how induced human

neuronal cell lines are helping researchers build more accurate models—and uncover new insights

into disease mechanisms.

12 Zoned Out

Michael Sarullo

Researchers in the cloud forests of Mexico upend traditional ideas about wildlife conservation by

uncovering surprising changes in carnivore behavior near human communities.

14 Scratching the Surface

Risha Chakraborty

Biofilms, intricate three-dimensional structures formed by bacteria, can be found anywhere from

the sides of glaciers and the bottoms of geyser pools to inside the human body. Now, scientists

are closing in on the molecular mechanisms that control how biofilms assemble and disperse,

unlocking new tools for medicine and beyond.

16 No Stopping Now

Kenny Cheng

Yale biologists have reengineered life’s genetic blueprint, recoding the function of stop codons and

unlocking new possibilities in synthetic biology, biocontainment, and bio-based materials.

19 Axions and Axioms

Diya Naik and Max Watzky

Axions may be our last, best hope for solving some of the most fundamental questions in modern

physics. But what are these elusive particles, and what steps are Yale scientists taking to search for

them?

2 Yale Scientific Magazine May 2025 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

Brain-Computer Interfaces • Matei Coldea

Cloud Seeding • Alondra Moreno Santana

RNA on the Move • Vicky Tan

Sea the Future • Helen Shanefield

Fat’s Double Life • Tiffany Zhou

The Ras-ter Plan• Gabriel Escobedo

Iodine’s Ozone Odyssey • Leah Mock

Fight or Fizzle • Aiden Zhou

Stuck in a Sticky State of Mind • Kenna Morgan

AI Meets MRI • Rishabh Garg

Nose Knows Wine • Justin Zhang

Long B Remembered • Abigail Jolteus

The Fight Against the Flood • Victor Gonzalez

Ordered Chaos • Max Watzky

The Vesicle Express • Michelle Cheon

Folding Fortune • Lynn Dai

Undergraduate Profile: Molly Hill (YC '25) • Michelle So

Alumni Profile: Josie Jayworth (GSAS ’22) • Makena Senzon

Science in the Spotlight: Air-Borne • Annie Cui

Science in the Spotlight: The Deadly Rise of Anti-Science• Estella Wittstruck

Counterpoint: The Cancer Gap • Hien Tran

Science on Trial: An Erasure of Identity • Edis Mesic

www.yalescientific.org

May 2025 Yale Scientific Magazine 3

BRAIN-COMPUTER

INTERFACES: HOW FAR

SHOULD WE GO?

&

CLOUD SEEDING:

CLIMATE SOLUTION OR

DANGEROUS GAMBLE?

By Alondra Moreno Santana

Summoning rain at will may sound like science fiction, yet

many countries already do it through a technique known as

cloud seeding. By releasing substances like silver iodide or

calcium chloride into clouds, they can trigger rainfall.

Cloud seeding has already been used to address water scarcity

challenges across the world, including relieving droughts in China,

helping with air pollution in India, and even producing more snow

in ski resorts in the US. With the development of newer, cheaper,

and more flexible methods, like drones, cloud seeding can now

bring even quicker and more effective results to these challenges.

But like most things that sound too good to be true, cloud seeding

has its limitations. Its effectiveness depends heavily on environmental

factors. For example, if clouds don’t contain enough moisture to

begin with, cloud seeding won’t generate rain. Wind patterns,

temperature, and terrain also play a role, affecting how particles

spread through the atmosphere. Under the wrong conditions, even

the most advanced seeding techniques can fall flat.

While releasing chemicals into the sky might raise some

environmental red flags, current research suggests that cloud

seeding is safe. In fact, compared to alternatives like large-scale

water diversion, cloud seeding may offer a more environmentally

sustainable way to bring much-needed water to the regions that

need it most. ■

By Matei Coldea

Brain-Computer Interfaces (BCIs) are unlocking mindblowing

possibilities—hopefully only in the figurative

sense. By directly linking neural pathways to computers,

these devices are already helping paralyzed individuals

communicate and may one day be used to boost cognitive

performance. With such great power comes great responsibility.

Descartes once wrote, “I think, therefore I am,” but what happens

when our thoughts can be read, written, or shared by a machine?

BCIs blur the line between mind and machine, raising a modern

Ship of Theseus dilemma: at what point does an enhanced mind

stop being you?

Throughout history, inventions have expanded human

potential—from stone tools to smartphones. BCIs may be the

next great leap forward. This moment demands maturity: to

build with caution, not just curiosity. Some researchers advocate

beginning with simulations and read-only BCIs, which allow us

to observe brain activity without altering it. These tools could

enable scientists to explore the mind without interfering with

the self.

Yet, responsible development requires more than technical

restraint. It requires ethical clarity. BCIs must enhance cognition,

not replace it. Cross that line, and we risk what philosopher

Hannah Arendt called the “banality” of artificial thinking:

efficient, yet devoid of the messy brilliance that defines human

thought. While blockchain and quantum encryption may protect

neural data, the greatest challenge is foreseeing unintended

consequences. We only get one shot at preserving cognitive

sovereignty. Let’s get it right. ■


The Editor-in-Chief Speaks

SCIENCE FOR SOCIETY

The beauty and the nuisance of modern science is that the number of questions we

can pose stands far in excess of the number we have the resources to answer. Now,

as federal agencies curtail research initiatives and university budgets tighten, the

challenge of allocating resources is all the more severe. A scientist writing a grant proposal in

the hopes of funding a new scientific endeavor must contend with questions that are equal

parts philosophical and economic—chief among them: Why does this project matter?

One perspective suggests that a scientific project is worthwhile if it will improve

people’s lives. In this issue’s cover story, “From Cryo to Cure” (p. 22), researchers explore

a neuron-transplant therapy that could restore brain function and enable longer, healthier

lives for patients with neurodegenerative diseases. In the winning article from the Yale

Scientific’s recent national essay contest, “The Fight Against the Flood” (p. 27), high school

student Victor Gonzalez paints vignettes of climate resilience as Houston’s engineers and

environmental scientists respond to a changing climate. From medicine to engineering,

the utility of science is apparent: As a systematized expression of human curiosity, science

grapples with the unruly phenomena of the natural world to yield useful solutions.

At the same time, though, science is not merely a process of problem-solving. The

scientific method stems from intuition and observation, and in the end it seeks to broaden

the scope of humanity’s knowledge. “Axions and Axioms” (p. 19) chronicles Yale scientists’

search for an elusive particle that lies at the heart of foundational questions in theoretical

physics and astrophysics. The reward for such fundamental work is often oblique, but it is

no less valuable. Advances in fundamental science give humanity a glimpse into the inner

workings of nature. We broaden our knowledge as we learn to speak fluently the language

of the universe.

In this way, science serves a role similar to that of the arts, extending the possibilities

for what can be known through its fragmentary innovations. In this issue’s undergraduate

profile (p. 34), we meet field ecologist and writer Molly Hill (YC ’25), whose studies on the

intricacies of bird behavior intertwine with artistic expression in her creative projects and

advocacy. Research like Hill’s is imperative for the gradual accumulation of knowledge that

marks the advancement of society—like art, its value lies in its chronicling of the minutiae

that make up life, nature, and the world. In the end, it is part of a great symphony shared

by all.

The team behind this issue of the Yale Scientific Magazine hopes that we play a role, too,

in the positive force that is scientific practice. Thank you to the Yale Science & Engineering

Association and to our subscribers from around the world who make it possible for us to

tell the stories contained in these pages. The Yale Scientific remains eyewitness to centuries

of science at Yale.

About the Art

William Archacki, Editor-in-Chief

I made the cover art with inspiration from the

article “From Cryo to Cure” (p. 22), a look into

the fundamental science behind advancements

in medication. The cover features a mouth and an

array of pills built in transparent layers, conveying

the thin boundary between our bodies and the

ever-expanding improvements to our health. I hope

this issue prompts readers to consider the impacts

of research on human understanding, and the

implications for our own futures.

Malina Reber, Cover Artist

MASTHEAD

May 2025 VOL. 98 NO. 2

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STAFF

Luna Aguilar

Ebru Ayyorgun

Hannah Barsouk

Ryan Bose-Roy

Andre Botero

Sophia Burick

Risha Chakraborty

Yuvan Chali

Kelly Chen

Neo Chen

Yuanyu Chen

Kenny Cheng

Camille Chiu

Cara Chong

Rayyan Darji

Sara de Ángel

Josefina De La Riva

Pempem Dorji

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Molly Hill

Elisa Howard

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Abigail Jolteus

Patricia Joseph

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Dahlia Kordit

Paul Alexander Lejas

Ximena Leyva Peralta

Crystal Liu

Samantha Liu

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Faith Pena

Toler Poole

Yusuf Rasheed

Jake Robbins

William Archacki

Mia Gawith

Evelyn Jiang

Max Watzky

Michael Sarullo

Asuka Koda

Sarah Li

Patrick Wahlig

Aiden Zhou

Makena Senzon

Michelle So

Brandon Quach

Jordan Thomas

Lawrence Zhao

Matthew Blair

Madeleine Popofsky

Lynn Dai

Melody Jiang

Ryder Lariviere

Alondra Moreno Santana

Emily Poag

Malina Reber

Matthew Blair

Claire Zhong

Nikolai Stephens-Zumbaum

Edis Mesic

Ethan Powell

Gabriela Berger

Mia Cooper

Mahitha Ramachandran

Joelle Kim

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Sammy Feingold

Sunny Vuong

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Ignacio Ruiz-Sanchez

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Fareed Salmon

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Helen Shanefield

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Nikolai Stephens-

Zumbaum

Kara Tao

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Hien Tran

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Helen Zhang

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NEWS

Cellular Biology / Environmental Engineering

RNA ON THE

MOVE

THE HIDDEN ENGINE OF CELL

MIGRATION

SEA THE

FUTURE

TURNING OCEAN CARBON INTO

CLEAN FUEL

BY VICKY TAN

BY HELEN SHANEFIELD

IMAGE COURTESY OF WIKIMEDIA COMMONS

IMAGE COURTESY OF FLICKR

Just like how we have to physically move to get to and

from work, cells have to physically move to accomplish

routine tasks. Researchers in the Nicoli Lab of Yale’s

Department of Genetics recently observed an interesting

connection between RNA, a crucial molecule for making

proteins and regulating genes, and this cellular mobility

phenomenon. Associate research scientist Liana Boraas

noticed RNA localization to a cell’s focal adhesions (FAs),

which are macromolecular protein complexes that act as the

cell’s hands and feet.

FA complexes help cells hold on and travel to surrounding

molecules and cells. RNA was found to interact with

FA proteins using the protein G3BP1, forming a

ribonucleoprotein, a complex of RNA and protein involved

in RNA processing and regulation. The researchers studied

endothelial and fibroblast cells, highly migratory cells that

line body surfaces and help with tissue structure. They

discovered that G3BP1 and RNA complexes at FAs can

modulate the appendages, or “limbs,” of the cell, ultimately

dictating cell migration and cell speed.

With this new discovery, Boraas is hopeful this finding

can be applied in wound repair and cancer treatments by

increasing or decreasing cell migration as needed. For

example, scientists would want to accelerate cell migration in

wound repair but inhibit the migration of cancer cells. With

current work underway to engineer specific RNA fragments

for specific cell types, the team is looking to use mouse

models to test this wound repair theory. “I think that if we

can understand [how to manipulate RNA], that’s the future

of medicine,” Boraas said. ■

Oceans are some of the largest carbon sinks on Earth,

storing up to thirty-one percent of total carbon dioxide

(CO 2 ) emissions. As atmospheric CO 2 levels increase,

seawater carbon also increases, causing ocean acidification. This

is harmful to many marine organisms, especially those that build

structures out of calcium carbonate. Researchers in the Hu Lab at

Yale’s Department of Chemical and Environmental Engineering

recently developed a new mechanism for turning inorganic

seawater carbon into fuel, effectively reducing the amount of

dissolved carbon in the oceans.

The team tested a new system designed to improve the efficiency

of photoelectrochemical (PEC) CO 2 reduction devices. These

solar-powered devices float on the ocean, utilizing electrodes

to extract bicarbonate ions from seawater. The anodic electrode

oxidizes water to collect protons, which are transported to the

cathodic side. Protons combine with bicarbonate ions along the

way, enabling fuel production. Though water oxidation sounds

elegant, current PEC devices are often expensive and inefficient,

so the Hu Lab’s research is a crucial improvement.

In the study, the team took multiple pairs of photo-electrodes

arranged in parallel and placed them into an array, allowing

the electrodes to “talk to each other” while the light absorption

remained unaffected. This created a seamless carbon conversion

cascade, greatly boosting efficiency. “That chemical reactor

design allows the electrode itself to behave beyond what a simple,

standalone pair could do,” said Shu Hu, a principal investigator

on the study. By eventually taking their improved PEC device to

the open ocean, the team hopes to mitigate ocean acidification

while producing a carbon-neutral fuel alternative, protecting our

oceans for future generations. ■


Medicine / Biochemistry

NEWS

FAT’S DOUBLE

LIFE

FIGHTING SCARS FROM THE

INSIDE OUT

THE RAS-TER

PLAN

UNLOCKING A HIDDEN BOOST

IN CELL SIGNALING

BY TIFFANY ZHOU

BY GABRIEL ESCOBEDO


IMAGE COURTESY OF THE BOGGON LAB

H

idden beneath your skin, fat cells lead a secret double

life. Researchers in the Horsley Lab at the Yale School of

Medicine have uncovered the complex role that fat cells

play beyond storing energy in tissues. Fat cells aid in wound healing

and protect the skin from fibrosis—an excessive accumulation of

fibrous connective tissue resulting in thickened, hardened skin.

Adipocytes, or fat cells, store fats in a large specialized

compartment known as a lipid droplet. There, fats stored

as triglycerides undergo a critical process known as

lipolysis, which breaks them down into fatty acids. The

fatty acids can trigger an array of cellular responses, from

metabolic processes that generate energy to the activation of

inflammatory responses.

Adipocytes in skin tissue are sparse. However, preliminary

research conducted in the Horsley Lab unveiled promising

insights on how fatty acids from our skin’s adipocytes affect

the development of skin fibrosis. Researchers observed that

fat cells in regions with stimulated fibrosis lost their lipid

droplets as early as five days into fibrosis development.

Surprisingly, when researchers inhibited the enzyme that

regulates lipid breakdown, the development of fibrosis

worsened. This finding suggests that the release of fatty acids

may play a protective role in mitigating fibrosis development.

“Fibrosis causes significant morbidity and mortality, and

while some treatments can slow its progression, no cure is

currently known,” said Maria Fernanda Forni, an associate

researcher in the Horsley Lab. Uncovering the role of

lipids derived from skin adipocytes provides potential

therapeutic targets for future skin fibrosis treatments for

future generations. ■

The Ras family of proteins facilitates cell-to-cell signaling

essential for complex organisms. This communication

process relies on ten GTPase-activating proteins (GAPs).

The first of these proteins discovered, RasGAP, has been known

for nearly forty years. Despite its long history, scientists are still

uncovering how it works.

Most GAPs, including RasGAP, contain two key protein

regions: a GAP domain that chemically interacts with Ras

proteins during signaling, and a C2 domain traditionally known

only for binding calcium in cell membranes. However, a Yale

study from the Boggon Lab in the Department of Pharmacology

has revealed that the C2 domain plays a more active role than

previously thought, directly mediating interactions between Ras

and RasGAP.

“Clues to RasGAP’s complexity emerged when we found

vascular malformations linked to mutations in the C2 domain,”

said Max Paul, PhD student and lead author on the recent paper.

The team discovered that single nucleotide changes at position

R707 were responsible for these effects, even though such

mutations are typically less severe than others in the protein.

After documenting reduced RasGAP performance in R707

mutations, the researchers analyzed protein structures across

the GAP family using both crystal structures and computational

predictions. They found that all C2 domains shared the same

orientation and conserved surfaces (including the R707 position)

across species, suggesting that R707 facilitates GAP interactions

with Ras. Computational modeling of RasGAP-Ras interactions

further supports this expanded understanding of the C2 domain’s

role. Ongoing research will continue to illuminate how these

signaling proteins function in both healthy cells and in diseases. ■



FOCUS

Planetary Science

IODINE’S OZONE

ODYSSEY

The Long Wait for

Life on Land

BY LEAH MOCK


Though Earth is over four billion years old, complex

life only emerged on land about five hundred million

years ago. For much of our planet’s history, the most

developed forms of life were aquatic bacteria, with only a sliver

of the intricacy of the animal kingdom that now dominates the

Earth. So, why did complex life take so long to develop and

emerge from its aquatic origins onto land?

The oldest life on Earth was bacteria, which appeared about

three billion years ago. But prior to the Great Oxidation Event

around two and a half billion years ago, when cyanobacteria

began producing large amounts of oxygen, the planet was

largely devoid of free oxygen. Without free oxygen, there was

no protective ozone layer to cover Earth’s surface. The ozone

layer is a region of Earth’s stratosphere that shields Earth

from UV radiation, which can harm cells. Solar UV radiation

can damage mitochondria, chloroplasts, and DNA, causing

genetic mutations and preventing cells from producing energy.

Without an ozone layer for protection, life remained confined

to the UV-protected waters of Earth’s oceans.

Scientists previously assumed that before the ozone layer

was established, there simply was not enough free oxygen to

form a protective layer. However, new research conducted by

a team of scientists led by Jingjun Liu (GSAS ʼ26) at Yale’s

Department of Earth and Planetary Sciences sought to

understand exactly how the ozone layer affected the timeline

for the development of land-based life. “This very long delay

was caused by a delayed stabilization in the Earth’s ozone

layer,” Liu said. The team found the iodine cycle’s effect on

the ozone is a more central component in the development of

complex life on Earth than previously understood.

The iodine cycle is a biogeochemical cycle that moves

iodine through Earth’s crust, mantle, bodies of water, and

atmosphere. It occurs on Earth now as it did billions of years

ago, though in different forms. Through naturally occurring

processes, inorganic iodine gases discharge from the ocean

to the atmosphere over time. When this iodine reacts in

the stratosphere, it degrades ozone. In the present, iodine is

responsible for about four percent of the ozone loss over the

Antarctic ozone hole, the thinning of the ozone layer over

Antarctica. In the Proterozoic era, from 2.5 billion to 540 million

years ago, iodine was about 180 times more concentrated in

the oceans than it is today. Liu’s team constructed an oceanatmosphere

model to reconstruct the iodine-ozone dynamics

for the early Earth to understand the ozone depletion during

the Proterozoic. They found this heightened level of iodine

massively depleted the ozone layer, preventing the emergence

of complex life on land by disrupting Earth’s protective shield.

Even as oxygen levels rose due to the Great Oxidation Event, the

constant breakdown of ozone by iodine delayed the formation

of a consistent ozone layer. Over time, however, enough ozone

did build up in the atmosphere to form the ozone layer—it

only took two billion more years.

The stabilization of the ozone layer five hundred million years

ago coincided with another event: the Cambrian explosion.

During this period, multitudes of life forms like cnidarians

(a group of organisms including modern jellyfish and coral),

trilobites, and crustaceans appeared on Earth. Fossils of these

creatures can be found in deposits like the Burgess Shale in

British Columbia, Canada. The reason for complex life’s rapid

appearance after billions of years has been debated for decades.

“Of course, we have the Burgess Shale, but it doesn’t address

this fundamental question of why there is no visible life before

the Cambrian explosion. So, in that context, I think the ozone

layer was something that people take for granted,” Liu said.

This diversification of aquatic life eventually allowed for the

emergence of life on land, once the ozone layer stabilized.

While a new understanding of the stabilization of the ozone

layer improves our understanding of Earth’s prehistory, there’s

still more to uncover—for example, we do not yet understand

how the ozone layer fluctuated. As researchers like Liu’s team

continue to unravel the complex dynamics between Earth’s

atmosphere and the evolution of life, the story of how complex

life developed reminds us that even the smallest molecules—

like iodine and ozone—can shape our planet’s future. ■


Immunology

FOCUS

FIGHT OR FIZZLE

How KLF2 Stops

T Cell Burnout

BY AIDEN ZHOU

IMAGE COURTESY OF THE NATIONAL INSTITUTES OF HEALTH

CD8 T cells—a specialized type of white blood cell—

play a central role in resisting viral infection. The body

responds to various disorders by producing highly

functional “flavors” of T cells. Effectors are short-lived, but

actively destroy infected and cancerous cells. On the contrary,

memory T cells endure long after an infection is cured, enabling a

rapid response to that pathogen in the future. Vaccines function

precisely by triggering the creation of these T cells, along with B

cell-derived antibodies.

And yet, as in any prolonged battle, the “frontline soldiers” of

our body’s defenses can get worn out. In cases of acute infection

that are quickly resolved, T cells develop predictably and linearly

into functional states. But in chronic cases, they develop into

dysfunctional states, enabling the infection or cancer to persist.

A paper by the Joshi Lab at Yale’s Department of Immunobiology

explores the factors behind this phenomenon of T cell exhaustion.

They discovered that KLF2—a type of protein that regulates DNA-

RNA transcription, and is therefore referred to as a transcription

factor—plays a crucial role in modulating the developmental

trajectory of effector T cells, and stifling divergence toward

exhausted states. Moreover, they observed that KLF2 acts as a

“master” regulator; it enables other transcription factors to

function correctly.

The study’s first step involved infecting mice models with either

acute or chronic strains of lymphocytic choriomeningitis. Then,

to evaluate the relative role of thirty-nine transcription factors

and epigenetic modifiers (molecules altering gene expression),

the scientists utilized Perturb-SEQ: a technique that integrates

gene-editing technology with single-cell RNA sequencing. By

cutting out specific sections of T cells’ DNA with a technology

known as CRISPR, they observed, first-hand, the consequences

of “knocking out” each gene. “There are fifty thousand cells here,

and each cell has a unique knockout,” said Eric Fagerberg (GSAS

’25), a doctoral student and the study’s lead author. “And so we

get a ton of info for each gene.”

However, when studing such a heterogeneous population,

the researchers had to record this data incredibly precisely to

distinguish individual variation at a cellular level. That’s where

the second part of Perturb-SEQ came into play. “Biologists look

at RNA as a surrogate for the protein,” Fagerberg said. Hence,


RNA sequencing is a popular way to study what a group of cells

expresses. “But single-cell RNA enables us to do that on a cell-bycell

basis, and capture the heterogeneity of a population in any

given context.”

Given this data, the scientists were able to map the trajectory

of each gene-edited T cell. This revealed the crucial role of one

specific protein. “If we knock out KLF2, we observe that they

enrich, quite strongly, in the dysfunctional part of the map

unique to chronic infection,” Fagerberg said. If KLF2 is removed,

an acute infection takes on features of a chronic one. The linear

trajectory that typifies the body’s response to acute infection is

disrupted, as T cells enter unexpected, dysfunctional states.

This surprising discovery has a dual explanation. Firstly,

KLF2 suppresses TOX, the transcription factor that drives T cell

exhaustion. To give evidence for this hypothesis, the team overexpressed

KLF2 in T cells with and without KLF2 knocked out

that were responding to acute infection. T cells without KLF2

started with a disproportionately high level of TOX. Yet, when

the scientists over-expressed KLF2, the TOX gene was reduced to

its natural state. They also observed a similar reduction in TOX

in the context of chronic infection.

KLF2 also supports the function of TBET, a transcription

factor crucial to the production of effector T cells. The

researchers tested this by overexpressing TBET in T cells

with and without KLF2 knocked out. Although effector

differentiation markers were heightened in the cells with

KLF2, there was no significant change in those with KLF2

deactivated. “KLF2 likely regulates the epigenetic state—how

‘open’ or ‘closed’ the DNA is—and it may regulate openings

where TBET exerts function,” Fagerberg said.

Hence, KLF2 enables T cells to develop along functional

trajectories and guards against undesirable states of exhaustion.

This discovery opens a door for future exploration about the

relationships between KLF2 and other transcription factors, such

as TBET, that are dependent on KLF2. Moreover, investigating

other cells in immune response pathways (such as CD4 helper

cells to CD8 T cells) may reveal further dependencies and ways to

enhance the body’s defenses. Fagerberg’s research, by identifying

a key factor for safeguarding T cell function, is likely to inspire

advances in cancer care, immunotherapy, and more. ■


FOCUS

Neuroscience

STUCK IN A

STICKY STATE

A New Link Between

Neural Flexibility and

Opioid Use Disorder

BY KENNA MORGAN

IMAGE COURTESY OF PIXABAY

The widespread use of opioids (such as heroin, morphine,

fentanyl, and oxycodone) has proved to be a complex and

persistent predicament for millions of people around the

world. Globally, sixteen million people meet the criteria for

opioid use disorder (OUD), which is characterized by sustained

opioid use that causes clinically salient distress or impairment.

In the United States, where OUD contributes to more than

forty-seven thousand deaths each year, concerns surrounding

addiction and overdose have fueled widespread fears of an

“opioid epidemic.” Amidst this backdrop, where insight into the

mechanisms underlying substance use disorders seems more

critical than ever, researchers at the Yale School of Medicine

have identified neural flexibility as a key factor that may be tied

to the cognitive impairments commonly observed in individuals

with OUD.

The way that different regions of the brain interact with each

other is incredibly complicated, but there are certain activation

patterns that your brain recurrently engages in. In a study

published in JAMA Network Open, neuroscience graduate student

Jean Ye identifies these patterns as discrete “brain states.” To

various degrees, these states are activated during periods of rest,

movie-watching, and exposure to opioid-related stimuli (for

example, a needle or a bottle of pills). Using functional magnetic

resonance imaging, researchers compared brain activity between

people with and without OUD during these different conditions in

order to measure how participants engaged with several recurring

brain states over time. From there, researchers calculated a metric

called state engagement variability, which assesses participants’

neural flexibility during these same conditions. In other words,

researchers sought to measure how flexibly participants’ brains

could adjust their engagement in different brain activation patterns.

Participants were also asked to complete a specific task intended to

measure cognitive control, which is one’s ability to direct attention

and adjust focus accordingly for different tasks.

Through statistical analysis accounting for many different

variables, researchers could investigate potential associations

between cognitive control and neural flexibility in individuals with

OUD. Their analysis showed that–compared to healthy individuals–

those with OUD consistently experienced lower variability in their

engagement of the recurring brain states investigated, suggesting

that it is harder for their brains to adjust accordingly in the face of

changing situational demands. According to Ye, this has very real

implications, even beyond a clinical research setting, for those who

struggle with substance use.

“Individuals with opioid use disorder may have more difficulty

disengaging from information related to opioids once they are

presented with that information,” Ye said. For example, after

observing a bottle of pills on the counter as they brushed their

teeth, a person with OUD may find it especially challenging to

get the thought of opioids out of their head, even once they have

left the bathroom. In turn, this image of opioids “stuck in their

brain” would likely make it extremely difficult to resist their

craving to use these drugs.

The study also revealed that lower neural flexibility during

rest periods (following exposure to opioid-associated stimuli)

was related to worse cognitive control. This finding suggests an

association between reduced neural variability and difficulties in

mental functioning and behavior. While limitations are inherent

in any sort of research, the results suggest that improving the

brain’s ability to switch between different activation patterns

may be an important goal to focus on in treating the cognitive

effects of OUD.

These new findings are especially important considering their

specificity to opioid use disorder. “With this population, there isn’t

much work done looking into [brain] dynamics and flexibility,”

Ye said. Although past research had investigated the relationship

between cognitive effects and neural flexibility in those with

depression and anxiety, little work has questioned this link in those

with substance use disorders. However, as opioid use continues to

devastate communities across the US and around the world, new

research in this field offers an encouraging step forward—bringing

renewed hope at a time when it’s needed most. ■


Medicine

FOCUS

AI MEETS MRI

Revolutionizing

Tumor Tracking

BY RISHABH GARG

IMAGE COURTESY OF FLICKR

A

cancer patient lies patiently in the narrow tube of an MRI

machine, the room humming with magnetic pulses. For many

patients, the scariest part is not the scan itself, but the long wait

that follows. Has the treatment been working? Is the tumor getting

smaller? Somewhere down the hospital corridor, a radiologist sits in a

dim room, eyes locked onto a glowing monitor, meticulously tracing the

outline of a tumor on dozens—sometimes hundreds—of MRI slices.

“It can take up to four hours,” said Noemi Jester, postgraduate

research fellow and lead author on a new study out of the Yale

Department of Orthopaedics & Rehabilitation 3D Tumor Lab.

The process, known as manual segmentation, is the standard

for accurately measuring tumor volume from an MRI. It involves

measuring and summing the area of tumor in each MRI slice to calculate

the volume of the tumor. But it’s time-intensive and unsustainable for

widespread clinical use. Prior methods tried to shortcut this process

using linear measurements—estimating tumor shape as an ellipsoid

based on its longest diameter. While faster, linear volumetric analysis

tends to be very inaccurate. That inaccuracy is particularly problematic

for a type of tumor called vestibular schwannoma, a typically benign

growth on the trigeminal nerve connecting the ear to the brain. The

tumors present themselves quite differently from the spherical growths

one may usually think of. The schwannomas are shaped similar to

ice cream cones, with a wide base but a narrow tip, leading to linear

approximations grossly overestimating the size.

The issue with overestimation is that it introduces blind spots. For

irregularly shaped tumors like vestibular schwannomas, the linear

method tends to overestimate total volume, especially in the wider

regions. When growth occurs in the narrower, underestimated areas

of the tumor, it often goes undetected. In other words, real changes

in the tumor’s shape or size can be masked within the noise of an

imprecise approximation. Physicians heavily rely on tumor volume

to determine the tumor’s growth rate, and inaccurate or delayed

volumetric analysis creates a pressing clinical challenge. For patients,

the absence of accurate volume data can reduce their confidence in

treatment and understanding of their condition.

To move away from linear measurements and to make the precision

of manual volumetric analysis more accessible, the researchers have

turned to artificial intelligence.

Working with radiologists and computer scientists, Jester and her

team trained a neural network to segment vestibular schwannomas


automatically, comparing its output with the time-consuming

manual segmentations.

“Vestibular schwannomas are a very characteristic type of brain

tumor, growing along the same nerve within the auditory canal,”

Jester said. To train the neural network, Jester and her team leveraged

this specificity. The network uses pattern recognition to identify the

general location of the tumor. MRI images are made up of varying

densities based on fat and fluid content, and tumors have a distinct

density compared to surrounding tissues. By detecting these density

differences, the neural network can effectively segment the tumor

from the non-tumor areas in each MRI slice. The training process

involved optimizing the network using over a hundred MRI scans.

The result? A remarkable match. There was a high level of similarity

between the AI’s measurements and those done by hand—and each

measurement took only about two minutes, over one hundred times

faster than the current process.

Automating the manual volumetric analysis process doesn’t just

save time—it reshapes the doctor-patient experience. “Right now,

radiologists spend more time segmenting than analyzing,” Jester said.

With AI handling the segmentation, radiologists and the rest of the

patient’s physician team can focus on the bigger picture: how the

tumor is behaving, whether treatment is working, and how best to

plan the next steps.

Even more exciting, the AI generates 3D images of the tumor

following segmentation, which can help patients visualize their

tumor—something traditionally buried in complex radiology reports.

“The model creates a beautiful, intuitive rendering,” Jester said. “It

helps patients understand where the tumor is and how it’s changing

over time.” By observing the tumor structures in 3D, patients may gain

a sense of empowerment and control, seeing more clearly what they

are fighting against, which could positively impact their approach to

treatment and their overall sense of agency.

Now, imagine a patient walks out of the MRI room and instead of

waiting in uncertainty for forty-eight hours for an incomprehensible

report and a week for an appointment with a physician to explain the

situation, they are led directly into a physician’s office, where a 3D

model of the tumor is already on the screen. With this innovation,

the days of anticipation could soon be replaced by informed,

empowered choices, creating a more efficient, patient-centered

healthcare system. ■


FOCUS

Ecology

In the biodiverse foothills and cloud

forests of Chiapas, Mexico, a story

of adaptations to human influence is

unfolding—not just among

wildlife, but also in

how conservationists

approach their work. In

a recent study, Germar

González (YSE ’24), in

collaboration with Nyeema

Harris at the Yale School of

Environment, uncovered

fascinating patterns in how

carnivores adjust their behavior

based human influence, even within

protected zones. The study illuminates the

complicated nature of carnivore-human

interaction and how our human influences

can dramatically alter the daily activity

patterns of nearby carnivore populations.

Conserving Coexistence

ZONED OUT

HOW HUMAN ACTIVITY MAY

CHANGE CARNIVORE BEHAVIOR

BY MICHAEL SARULLO

ART BY DAHLIA KORDIT

For González, the idea of conservation

extends beyond solely ecological data. “I

had studied conservation in college, but it

was a very science‐focused curriculum that

sometimes left out the social perspective,”

González said. His keen interest in

the social implications of ecology led

González to the Applied Wildlife Ecology

Lab at Yale, where his research with Harris

embraced both ecological and societal

dimensions of conservation.

The research group’s approach focuses

on addressing the increasingly

prominent issue

of human-wildlife

coexistence. For

González and his

team, this isn’t just

about managing

occasional wildlife

encounters in urban areas; it’s about

rethinking how humans and wildlife can

live together in shared spaces. As cities

grow, as humans develop land, and as

climate change reshapes ecosystems, the

boundaries between human and wildlife

habitats are becoming increasingly

porous—and in some cases, they seem to

overlap entirely.

In places like the montane cloud forests

of El Triunfo Biosphere Reserve in Chiapas,

Mexico, these overlaps are shaped by

different land-use designations. These mark

clear gradients of human activity, each

presenting unique implications for wildlife.

Researchers in the Applied Wildlife Ecology

Lab recognize that most ecosystems today

are already influenced by people, and that

traditional conservation models—focused

on isolating nature from human use—

aren’t always sufficient. By studying how

animals shift their behavior in response

to varied levels of human presence, the

team hopes to understand how we can

better manage these shared landscapes in

the long-term. “There’s going to be more

humans coming into natural landscapes

and vice versa […] we’re going to have

wildlife coming into people’s landscapes,”

González said. “So, the question becomes

how we can achieve coexistence?”

Blurred Boundaries

El Triunfo Biosphere Reserve is

categorized into three distinct zones: core

areas with little to no human activity, buffer

zones where human use is allowed but

regulated, and adjacent private lands often

used for small-scale farming. Each zone

represents a distinct level of human activity,

enabling researchers to observe how wildlife

behavior varies in response to the type of

landscape and the degree of human presence.

“Our research was designed to measure how

different management zones affect carnivore

behavior,” González explained.

To explore these dynamics, the researchers

set up thirty-three motion-activated

camera traps throughout the reserve. These

cameras operated continuously for several

weeks, capturing thousands of images

whenever animals passed by. This allowed

the team to monitor fourteen unique

carnivore species within the reserve, noting

differential behavior patterns based on

their presence in zones, changes in activity

overlap relative to known predators and

prey, and competition between species.

The results were surprising: researchers

witnessed the greatest changes in carnivore

activity not in the areas with the highest

human activity, the private land, but

rather in the intermediate buffer zones.

Margays—a medium-sized wild cat

species—shifted from their normal activity

patterns to nocturnal behavior in buffer

zones. Gray foxes showed similarly marked

differences in their activity across different

management zones. Such findings appear to

challenge what is commonly known as the

“human shield hypothesis,” which posits

that human presence may protect smaller

predators from larger ones by deterring

the latter. “It seems that

even in human-dominated

buffer areas, these smaller

mesocarnivores are forced

to adjust their activity,”

González said.


Conducting research in remote cloud

forests came with considerable difficulties.

According to González, planning camera

placements from maps was often unreliable

due to unpredictable on-the-ground

conditions such as steep terrain and dense

vegetation. To resolve these issues, the

team decided to group cameras in circular

clusters to best capture the the landscape,

rather than simply placing cameras in

a line. The researchers also used several

statistical methods—including kernel

density estimation and permutation-based

analyses—to more accurately assess shifts

in carnivore activity patterns and measure

temporal overlap, which refers to the degree

to which different species are active during

the same periods of the day.

This approach enabled the researchers

to not just detect behavioral changes in

single animals, but also observe changes

in the broader web of interactions among

species. “The apparent overlap of activity

in the buffer zones was very high for our

established predator-prey pairs, which we

thought was really unexpected and points

to more complex interactions caused by

human influences,” González said.

Community Connections

For González, successfully engaging

local communities wasn’t an afterthought,

but rather an essential component of the

research process. “We presented at various

town halls and went to villages to explain

our work. We even printed flyers in Spanish

to let people know what we were doing," he

said. This outreach helped build trust with

local residents whose daily lives are directly

involved with the studied wildlife, and

reflected González's belief that effective

conservation must incorporate community

perspectives from the very beginning.

González also offered advice to aspiring

ecologists, encouraging a holistic approach

to education. “Ecology is a very huge field.

I would recommend being ready to learn

more about other fields like social sciences,

politics, and even economics,” he said.

Essentially, conservation in our modern era

requires interdisciplinary skills paired with

versatility in unknown circumstances. “It’s

not just about knowing the animals. It’s about

understanding why conflicts happen and

how we can collaborate with communities

to resolve them,” González said.

The study doesn’t just add to academic

discourse—it upends long-held beliefs about

how we define, design, and manage protected

areas. González cautioned that zoning labels

like “buffer zones” can give a false sense of

protection, as the team’s findings showed high

levels of human impact in these areas despite

their intended purpose. Such a disconnect

between how conservation zones are planned

and on-the-ground reality suggests that

traditional management strategies may need

to be reconsidered.

As Mexico and other nations have agreed

to enhance conservation efforts—like

the international 30x30 initiative, which

aims to protect thirty percent of land and

ocean by 2030—González’s data is integral

for ecologists and policymakers alike in

navigating the delicate nature of wildlife

conservation. “Our findings emphasize that

how we devise preservation management

must be flexible and include the voices of

local communities,” González said.

Future Directions

While the current research provides

valuable insights, González acknowledges

the necessity of more detailed research.

Future research would benefit from a finerscale

study with more cameras monitored

Ecology

FOCUS

over a longer time

frame, incorporating

additional variables

such as direct

measures of human

activity, vegetation

cover, and prey availability. Such research

could clarify the causal factors behind the

observed behavioral shifts, and it might

also provide practical guidance for those

who manage human-wildlife interactions in

shared landscapes.

As González explained, “Our findings

can aid in assessing protected area efficacy

and understanding carnivore response to

anthropogenic pressures in shared landscapes.”

But the researchers’ data

is worth much more

than just journal

articles—it serves as

a crucial link between

academic research and

the real-world challenges

of conservation.

As the boundaries

between natural habitats

and human settlements

grow increasingly blurred, the

team’s approach incorporating both

biological and societal context proves

promising for genuine coexistence. By

combining stringent scientific methods

with meaningful engagement

with communities, the team’s work

demonstrates that conservation can

honor both ecological imperatives and

human needs—a balance that will be

essential for protecting biodiversity in

quite the dynamic world. ■

ABOUT THE AUTHOR MICHAEL SARULLO

MICHAEL SARULLO is a sophomore in Branford College from Royal Palm Beach, Florida

majoring in Molecular Biophysics and Biochemistry and Statistics and Data Science.

Michael serves as the Features Editor for YSM in addition to teaching and previously

acting as the Director of Events for Synapse. Outside of YSM, Michael engages in

computational approaches to synthetic biology for Yale iGEM and conducts research

in the Lemmon lab.

THE AUTHOR WOULD LIKE TO THANK Germar González for his aid in compiling

this article.

FURTHER READING

González, G., Gámez, S., & Harris, N. C. (2025). Carnivore activity across landuse gradients

in a Mexican biosphere reserve. Scientific Reports, 15(1). https://doi.org/10.1038/

s41598-025-87850-7



FOCUS

Cellular Biology

SCRATCHING THE

SURFACE

THE DYNAMICS

OF CELL-BIOFILM

INTERACTIONS

BY RISHA

CHAKRABORTY

ART BY ALONDRA

MORENO SANTANA

Surprisingly, the strongest organisms in the

world are made up of only one cell. These

are bacteria. While they can’t do much on

their own, they are powerful in numbers. Bacterial

communities with enough members are capable

of forming vast three-dimensional structures

called biofilms. These biofilms can be found in

every environment on Earth, from frozen arctic

glaciers to the scalding hot waters of geysers.

They even form naturally within the human

body, helping us digest food and supporting

the development of babies’ immune systems.

However, other bacterial biofilms are less

friendly. Strep throat, urinary tract infections,

cholera, tuberculosis, and a slew of other

diseases are caused by foreign bacteria forming

biofilms within the body, disrupting our

natural physiology with consequences that

range from inconvenient to deadly. But these

biofilms may have fatal flaws—potential selfdestruct

mechanisms that regulate how the

bacteria assemble and disperse. Currently, a

team led by Yale researchers is investigating

these powerful bacterial on-off switches,

gaining new insights into biofilm behavior and

opening the door to potential treatments for a

wide range of bacterial diseases.

Getting to this point has not been easy. The study

of biofilms formed by harmful, foreign bacteria

has long lagged behind research into their

friendly counterparts, especially in understanding

how these structures form and break apart. One

of the biggest challenges lies in understanding

the material that holds these biofilms together.

The structural glue is made up of complex

sugars—or more formally, polysaccharides—

that bacteria secrete into their environment to

form a sticky, protective matrix. While human

cells are also supported by a network of secreted

proteins and sugars called the extracellular

matrix (ECM), there is no homology, or one-toone

correspondence, between the components

of the human ECM and bacterial biofilms. The

problem is compounded by the huge diversity of

sugars in bacterial biofilms, including some that do

not have equivalents created by the human body.

Despite these obstacles, Jing Yan, an assistant

professor of molecular, cellular, and developmental

biology at Yale University, and his postdoctoral

associate Alexis Moreau were undeterred.

Together with their team, they used an ingenious

workaround to study the formation and dispersal

of bacterial biofilms, offering new insights into

these complex microbial communities.

Seeing what Sticks

Yan and Moreau chose to study the biofilms

formed by Vibrio cholerae (Vc) as their model

organism. As its name implies, Vc is responsible

for cholera, a highly virulent disease that spreads

through contaminated water and kills tens of

thousands of individuals each year. “Vc is a

very important pathogen. Whenever there is a

disruption in the purified water, in the access

to the purified water purification system, then

there could be a potential outbreak. [You] never

know what will happen next,” Yan said. But

Vc is not just interesting because of its lethal

consequences—it is also easy to manipulate

genetically. Yan and Moreau were able to take

advantage of this fact, suppressing or “knocking

out” certain Vc genes in order to see their effects

on the biofilm.

The first culprit the team investigated was

Vibrio polysaccharide (VPS), the main sugar

in the biofilms formed by Vc. VPS is the

primary structural component of Vc biofilms,

serving as a scaffold for a number of proteins

that are integral to the adhesion of the biofilm.

For decades, scientists had thought VPS itself

acted like an adhesive, attracting nearby cells

in the biofilm and promoting a process called

bridging aggregation, where cells stick together

in loose, disorganized clumps. The theory was

that the more sugar was added, the stronger

the attraction the cells would feel, creating even

larger aggregates. In order to investigate this

hypothesis, the team took a strain of Vc and

knocked out the genes responsible for all of its

major matrix proteins, controlling for all their

effects, and placed the bacteria into different

kinds of media. When they tried VPS, they


Cellular Biology

FOCUS

saw that the cells did not clump in disorganized

groups as predicted. Rather, they assembled

into a tight, parallel arrangement, which filled

the space extremely efficiently.

So, if Vc biofilms aren’t held together by

bridging, what keeps them from falling apart?

It turns out that the structures that the Vc cells

formed in Yan and Moreau’s experiment, called

parallel linear aggregates, are the telltale signs of

another adhesion mechanism called depletionattraction.

Unlike gravity or the electrostatic

interaction between positive and negative

charges, depletion-attraction is not a direct force.

Rather, it emerges from the principle that systems

tend towards maximum disorder,

or entropy. Imagine a few Vc cells

suspended in a sea of small VPS

particles. When two cells come

close enough together, the VPS

particles can no longer enter the gap

between them, creating a “depletion

zone.” This exclusion actually increases the order

of the system by restricting where the particles

can go. To restore disorder, the system responds

by pushing the cells together, eliminating the

depletion zone and freeing up the VPS particles

to traverse a larger area.

Attraction and Depletion

But does depletion-attraction account for

the behavior of the biofilm throughout the

entire growth process? To test this question, the

researchers examined aggregates at different points

of their growth. They found that early in biofilm

development, cells secreted VPS and also were

coated with VPS, enabling cells to be anchored to

the ECM via sugar-sugar interactions. However,

after a sufficient cell density had been reached,

cells were no longer coated with VPS, unmasking

repulsive cell surface-VPS interactions and

triggering depletion-attraction. This process was

accelerated by treating the cells with the RbmB, a

protein that cleaves sugars off protein anchors by

causing surface modeling and creating cells with

VPS-free coats.

On the other hand, treating VPS-coated cells

with the cell-matrix adhesion proteins Bap1

and RbmC accelerates bridging aggregation.

Although previous studies have shown that Bap1

is necessary for helping biofilms adhere to other

surfaces, such as the inner lining of the gut, they

have never elucidated how the protein interacts

with ECM sugars like VPS to mediate this

adherence. “The biofilm is made together because

you have this complex matrix, the combined

matrix of polysaccharide[s] and proteins that are

not independent. They interact with each other.


This interaction is what we're really

interested in seeing,” Yan said.

The team found that treating

VPS-coated cells with Bap1 in the

early growth phase, without the

presence of additional secreted VPS,

created loose, disorganized aggregate

patterns characteristic of the bridging

aggregation model. Moreover,

when extracellular VPS was present

alongside Bap1, the cells strongly

adhered to the ECM, indicating a

cooperative interaction between the

protein and the polysaccharide in

driving biofilm assembly.

The Aggregation Switch

Yan and Moreau developed a model of

biofilm growth that explained how bacterial

communities switch between different modes

of aggregation. In early growth phases, when

there are abundant nutrients for all the bacterial

cells in a community, the cells are coated with

VPS. During this stage, the presence of Bap1

and RbmC facilitates bridging aggregation,

allowing cells to connect through shared

interactions with the ECM. As nutrients run

low, however, the system shifts: RbmB activity

cleaves the VPS coats off cells, and the cellmatrix

interaction switches from attractive

to repulsive, triggering a transition to

dispersion aggregation. Interestingly,

the model switch requires nearly all

the VPS coats to disappear, meaning the

bridging aggregation mechanism usually

dominates over the dispersion mechanism

throughout most of biofilm development. This

likely explains why biofilms tend to grow steadily

until a critical point, after which cells begin

dispersing from the community.

In this model, the aggregation mode switch

seems to underlie the activation of biofilm

ABOUT THE AUTHOR

PHOTOGRAPHY BY MICHELLE SO

Alexis Moreau (background) and Jing Yan (foreground) examine

a petri dish containing a cell culture.

dispersal. In fact, in the absence of a VPS coat,

dispersion-aggregated cells are no longer held

within the matrix and slough off the biofilm.

Therefore, surface remodeling catalyzed by

RbmB, or simply by depleting VPS sugar levels,

causes the cell-matrix interaction to become

repulsive, the linchpin for biofilm dispersal. “If

you just apply a small flow [of RbmB] right on

those aggregates, those bacterial cells aggregated

to each other are just simply eliminated by the

flow. There are some implications [that this] could

be a potentially useful strategy,” Moreau said.

This research opens exciting

possibilities for controlling harmful

bacterial biofilms by manipulating

how cells interact with their matrix.

By targeting the switch from

attraction to repulsion, one can

imagine the development of therapies

that trigger biofilm dispersal on

demand. This approach holds promise

not only for treating persistent infections but also

for manipulating biofilms to treat disruptions

in bacterial communities underlying disease.

Understanding and harnessing these cellular

dynamics could mark a major shift in how we

manage bacterial communities in both medicine

and beyond. ■

RISHA CHAKRABORTY

RISHA CHAKRABORTY is a senior neuroscience and chemistry major in Saybrook College. In

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

Orquesta Tertulia, volunteers at YNHH, and researches Parkinson’s disease at the Chandra Lab in

the Yale School of Medicine. She enjoys cracking jokes, having “philosophical” discussions with

her friends, and spilling tea at duty with her FroKids.

THE AUTHOR WOULD LIKE TO THANK Jing Yan and Alexis Moreau for their time and

enthusiasm in sharing their expertise.

FURTHER READING:

Donlan R. M. (2002). Biofilms: Microbial life on surfaces. Emerging infectious diseases, 8(9), 881–

890. https://doi.org/10.3201/eid0809.020063 immuni.2024.01.005


FOCUS

Biochemistry

No Stopping Now

Biologists Re-Write the Amino Acid Code

By Kenny Cheng

Art by Melody Jiang


Biochemistry

FOCUS

Proteins are the molecular machines of life,

driving everything from the formation of

memories to the division of cells. Each

protein is assembled from a chain of building

blocks called amino acids, strung together in a

specific order dictated by a language shared by

all living things: the genetic code.

Inscribed in DNA and translated through

RNA, the genetic code is read in three-letter

segments called codons, each composed

of nucleotides—the basic units of genetic

information. With just four kinds of nucleotide

bases, the code yields sixty-four possible

codons: sixty-one that specify the twenty

standard amino acids and three that serve as

stop codons, marking the ends of the protein

chain. Long thought of as a standardized

lexicon, the genetic code is now being

reimagined. In a landmark study published in

Nature, Yale researchers have fundamentally

altered the genetic code by changing the

function of two stop codons, in what they call a

genomically “recoded” organism.

“The genetic code, long thought of as

a fixed system, actually exhibits natural

deviations,” said Farren Isaacs, a professor

in Yale’s Department of Molecular, Cellular,

and Developmental Biology and principal

investigator of the study. “By engineering

translation machinery, we can rewrite this

fundamental language of life, expanding the

biochemical capabilities of cells to produce

novel proteins and synthetic chemistries.”

The Codon Connection

The genetic code is degenerate, meaning

multiple codons can encode the same amino

acid. This built-in redundancy adds a layer

of protection against mutations—if one

nucleotide changes, the codon might still code

for the same amino acid, leaving the resulting

protein unaffected. But this feature also offers

an opportunity: because some codons are

functionally interchangeable—either encoding

the same amino acid or serving as stop

signals—not all of them are strictly necessary.

By reassigning these synonymous codons,

researchers can incorporate new synthetic

amino acids, expanding the genetic code and

unlocking an endless library of novel proteins.

“The way I think about it is this: ribosomes

are like protein printers, mRNAs are the recipes,

and codons are the words. By changing what

the words mean, we’re rewriting the language,”

said Mike Grome (GSAS ’19), a postdoctoral

researcher at Yale and the study’s first author.

Engineering the Impossible

There are three natural stop codons in the

genetic code, written as UAA, UAG, and UGA

to designate the codons they each contain. These

short sequences act like punctuation marks,

signaling the cell’s protein-making machinery

to stop building a protein. Previous work by

Isaacs tackled a crucial hurdle: systematically

recoding 321 UAG codons to UAA and deleting

Release Factor 1 (RF1)—the protein responsible

for recognizing both UAG and UAA stop

codons and ends protein synthesis by triggering

the release of the finished protein. Removing

RF1 was a necessary step to detach UAG from

its original function so it could be repurposed

within the genetic code.

In their latest study, the Isaacs Lab, in

collaboration with the lab of Jesse Rinehart (GSAS

’04), associate professor in Yale’s Department of

Cellular and Molecular Physiology, took this

effort a step further by replacing 1,195 UGA

codons with UAA. Together, these changes left

UAA as the only functioning stop codon in a

strain of Escherichia

coli they dubbed

“Ochre,” effectively

freeing UAG and UGA

for reassignment.

This was more than

a symbolic genomeediting

feat—it was a

foundational advance

toward expanding

the genetic code and

reprogramming the cell’s

translational machinery.

To accomplish this

genome-wide recoding,

the researchers used a

two-phase engineering

strategy: Multiplex

Automated Genome Engineering (MAGE) and

Conjugative Assembly Genome Engineering

(CAGE). MAGE is a high-throughput

technique for introducing many small, targeted

edits to DNA while it is being copied, enabling

broad codon replacement across the genome.

CAGE complements this by leveraging bacterial

conjugation—a natural process in which

bacteria transfer genetic material through

direct contact—to combine these edited DNA

segments. One strain carrying an edited region

transfers it to another through a pilus, allowing

engineered parts to be combined in a stepwise

fashion so different edited regions from separate

strains are gradually merged into one. Through

successive rounds, the team assembled a

complete strain in which all native UGA (and

previously UAG) codons had been replaced

with UAA. The genetic code could still say

“stop” with UAA, but now UGA and UAG were

freed for new biological roles.

But codon replacement was only half the

battle. “It’s not just about replacing a codon and

expecting everything to fall into place,” Isaacs

said. “The translation machinery is highly

interconnected, and once you start modifying

key elements, there are all these secondary effects.

We had to account for those to make this work.”

tRNA Tinkering

A critical challenge was reengineering

the molecular machinery that terminates

translation. With all UAG codons removed,

RF1 could be deleted without consequence—

eliminating its recognition of UAG and UAA.

This left only Release Factor 2 (RF2), which

recognizes both UGA and UAA. In order to free

up UGA for reassignment, the researchers had

Postdoctoral associate Mike Grome holds a cell culture.

PHOTOGRAPHY BY EMILY POAG

to reengineer RF2 so it would recognize only

UAA, not UGA.

However, removing RF2’s recognition of

UGA created an unexpected issue. A tRNA

molecule responsible for inserting the amino acid

tryptophan—which normally reads the codon

UGG—began to misread for UGA as well. As

a result, tryptophan was inserted at unintended

sites, leading to errors in the resulting proteins. To

prevent this, the team redesigned the tryptophan

tRNA to restrict its recognition exclusively to

UGG, eliminating unintended UGA decoding.

This step was vital for safely converting UGA—a

former stop signal—into a functional codon

capable of encoding a new amino acid.



FOCUS

With UAG and UGA successfully reassigned,

the team was able to incorporate noncanonical

amino acids—synthetic or rare amino acids not

typically found in nature. They achieved this by

introducing orthogonal tRNA/synthetase pairs:

custom molecular tools

that operate independently

from the cell’s native machinery.

These orthogonal pairs specifically recognize

the reassigned codons and install designer

amino acids at defined locations, greatly

expanding the chemical diversity of proteins

beyond natural limits.

This two-tiered strategy—comprising

genome-wide codon replacement and release

factor/tRNA engineering—was essential to

creating a genomically recoded organism. But it

wasn’t plug-and-play: the team had to carefully

adjust how codons were used, how different

tRNAs competed for them, and how release

factors responded to stop signals. Thanks to

the team’s methodical approach, the final E. coli

strain, “Ochre,” demonstrated robust growth

and maintained accurate protein synthesis. This

work builds on earlier efforts, including a project

by the Isaacs Lab and the Church Lab at Harvard

Medical School in which a UAG-lacking E. coli

strain was engineered with increased resistance

to a virus.

Beyond Stopping

Biochemistry

The implications of the Ochre strain are

profound. Freed codons can now encode

noncanonical amino acids, allowing scientists

to design biomolecules with properties

beyond what is found in nature. Recoding also

underpins genetic biocontainment strategies: by

engineering organisms to depend on synthetic

amino acids, they become incompatible with

wild-type systems, reducing the chances of

their surviving outside the lab and thereby

minimizing ecological risks. Moreover, recoded

organisms can be outfitted to resist viral

infections, as many viruses rely on standard

translation mechanisms.

Looking ahead, the project is advancing

along several exciting paths. One major focus

is on further engineering the recoded strain

to more efficiently incorporate two distinct

noncanonical amino acid chemistries into

proteins. The team is actively refining both

the cellular and translational machinery

to improve yield and purity—key

parameters for making this platform

widely adoptable and impactful.

Beyond technical optimization, the

Isaacs Lab is exploring how this new

approach to protein synthesis—using

two synthetic amino acids—can drive the

design of entirely new biomaterials.

Previous work has demonstrated

the potential of incorporating

a single noncanonical amino

acid to build protein-based nanowires and

programmable biologics—engineered proteins

designed to carry out specific tasks in the body.

With the new ability to “multifunctionalize”

proteins, the lab is now investigating how

to create programmable nanostructures—

tiny, customizable shapes made of protein in

two or three dimensions. By using different

ABOUT THE AUTHOR

chemical groups at specific positions, they can

control exactly how and where proteins link

together. This could open doors to a new class

of advanced biomaterials, including engineered

hydrogels and other structural assemblies with

tunable properties.

Another exciting direction involves extending

these recoding technologies into new microbial

and eukaryotic hosts to enhance genetic

isolation. These efforts could create

organisms resistant to viral infection

and horizontal gene transfer, offering

powerful tools for bio-applicationsin

industrial, environmental, and

therapeutic settings.

Together, these developments

point toward a future where

genomically recoded organisms

serve as versatile platforms for

both synthetic biology and safe,

functional biotechnologies

across multiple domains.

“Once you start opening

up the genetic code,” Grome

said. "The possibilities

become endless—from

novel therapeutics

to entirely new

biochemical pathways

that don’t exist

in nature.” ■

KENNY CHENG

KENNY CHENG is a sophomore majoring in molecular, cellular, and developmental biology. Outside of

YSM, Kenny carries out research in the Breaker Lab and is a venture lab associate at Yale Ventures.

THE AUTHORS WOULD LIKE TO THANK Farren Isaacs and Michael Grome for their time and

enthusiasm about their research.

FURTHER READING:

Isaacs, F. J., Carr, P. A., Wang, H. H., Lajoie, M. J., Sterling, B., Kraal, L., Tolonen, A. C., Gianoulis, T. A.,

Goodman, D. B., Reppas, N. B., Emig, C. J., Bang, D., Hwang, S. J., Jewett, M. C., Jacobson, J. M., & Church,

G. M. (2011). Precise manipulation of chromosomes in vivo enables genome-wide codon replacement.

Science (New York, N.Y.), 333(6040), 348–353. https://doi.org/10.1126/science.1205822

Lajoie, M. J., Rovner, A. J., Goodman, D. B., Aerni, H.-R., Haimovich, A. D., Kuznetsov, G., Mercer, J. A.,

Wang, H. H., Carr, P. A., Mosberg, J. A., Rohland, N., Schultz, P. G., Jacobson, J. M., Rinehart, J., Church, G.

M., & Isaacs, F. J. (2013). Genomically recoded organisms expand biological functions.. Science, 342(6156),

357–360. https://doi.org/10.1126/science.1241459

Napolitano, M. G., Landon, M., Gregg, C. J., Lajoie, M. J., Govindarajan, L., Mosberg, J. A., Kuznetsov, G.,

Goodman, D. B., Vargas-Rodriguez, O., Isaacs, F. J., Söll, D., & Church, G. M. (2016). Emergent rules for

codon choice elucidated by editing rare arginine codons in Escherichia coli. Proceedings of the National

Academy of Sciences of the United States of America, 113(38), E5588-5597. https://doi.org/10.1073/

pnas.1605856113


Astrophysics

FOCUS

Axions and

Axioms

The Hunt for Dark Matter at Yale

By Diya Naik and Max Watzky

Art by Lynn Dai



FOCUS

Astrophysics

Deep within the winding corridors of

Yale’s Wright Laboratory, a machine

converses with the universe.

Through the soft murmur of circuitry, the

gentle hum of coolers, and the low drone of

spinning motors, the machine calls out to

the cosmos, waiting for a faint reply. It has

repeated this routine daily for almost twelve

years, shutting down only when a hurricane

threatens its power source or when a part

needs replacing. The machine does not mind

the long wait—it stands resolute, working

patiently and meticulously, and will keep

searching for decades more if it must. Tune,

scan, wait. Repeat.

This is the HAYSTAC experiment. At

first glance, its day-to-day operations might

seem like monotonous work. But for the

Yale scientists who tend this machine, its

work could not be more exciting. Without

exaggeration, HAYSTAC is looking for one

of the most important kinds of matter in the

universe—a tiny, elusive particle called the

axion. Although it was hypothesized nearly

fifty years ago, the axion has recently enjoyed

a resurgence of attention and research.

Indeed, it may be scientists’ last, best hope to

solve some of the most pressing problems in

modern physics.

Now, HAYSTAC, which stands for the

Haloscope at Yale Sensitive to Axion

Dark Matter, is just one part of a massive

institutional search for the axion at Wright

Laboratory. Yale’s Axion Dark Matter group

is enormous, spearheaded by six professors

and comprising dozens of staff scientists,

postdoctoral researchers, PhD students, and

undergraduates—and that’s to say nothing

of their many assistants and collaborators

around the globe. Aside from HAYSTAC, the

group is making rapid progress on two new

initiatives, called ALPHA and RAY. ALPHA,

which stands for the Axion Longitudinal

Plasma Haloscope, is a new experiment to

search for axions with greater speed, and

RAY, which stands for Rydberg Atoms at

Yale, is a technological effort to improve the

efficiency of the axion-detecting instruments

that underlie HAYSTAC and ALPHA.

Symmetry and Conservation

The story of the axion, like many other

stories in fundamental physics, is one

of symmetry. We all feel intuitively how

beautiful symmetry can be, like the perfectly

mirrored wings of a butterfly. But in

physics, symmetries are beautiful for a

different reason: they reveal something

profound about the fabric of reality. When

a system exhibits some kind of symmetry,

it indicates that some physical quantity

must be conserved. Imagine a hockey puck

sliding across an ice rink. Now, imagine

the rink magically shifts ten feet to the

right. Nothing about the ice has changed—

it still looks the same in every direction, a

quality called translational symmetry, so

something must be conserved. In this case,

the symmetry of the space implies that the

puck’s momentum remains constant. Even

though the ice has moved, the puck keeps

sliding along at the same speed and in the

same direction as before.

But what happens when we see

conservation without symmetry

to match? This was exactly the

problem facing particle

theorists Roberto Peccei

and Helen Quinn

in the 1970s. They

were exploring a

symmetry called

charge conjugation

parity (CP) and its corresponding

conservation law: specifically, if a particle’s

charge and location in space are flipped, it

should obey the laws of physics identically

as before. Peccei and Quinn noticed that

the existing theory actually broke this

symmetry, but experiment after experiment

repeatedly showed that the conservation

law was preserved!

So how did Peccei and Quinn solve this

discrepancy? They proposed the existence

of a new particle that would dynamically

cancel out the CP asymmetry. “This axion

particle was added to the standard model

to explain why there’s no CP violation. In

the long history of physics, many particles

have been introduced successfully based

on observed symmetries and conservation

laws,” said Steve Lamoreaux, the principal

investigator of HAYSTAC.

A Dark Twist

At the same time Peccei and Quinn

proposed their resolution to the CP problem,

another problem was brewing in fundamental

physics—the problem of dark matter. Stars

and galaxies in space move according to the

PHOTOGRAPHY BY MAX WATZKY

RAY’s experimental setup, featuring a device to detect

the influence of photons on Rydberg atoms.

gravitational pull they exert on one another,

which is proportional to their masses. But

astronomers noticed that the motion of

these objects was completely inconsistent

with the masses

they could see.

“Basically,

visible matter

does not

explain how these galaxies

move. There seems to be some

missing matter that has some

gravitational effect, and this matter

was called dark matter,” said Karsten

Heeger, Director of Wright Laboratory.

Today, most physicists agree that dark

matter is composed of tiny yet-undiscovered

particles, perhaps many times smaller than

protons, neutrons, or electrons. Dark matter

must also interact very weakly with regular

matter or light, since we cannot see or touch

it. As our understanding of dark matter has

grown over the decades, the list of viable

particle candidates has shrunk precipitously,

leaving few options on the table. What

particle might actually fit the bill?

“The axion is the perfect particle, because

it’s tiny and barely interacts with anything,”

Lamoreaux said. The axion could not be

a better candidate: it had the potential to

resolve both the CP asymmetry problem

and the paradox of dark matter, killing two

birds with one stone. There was just one

small problem: the same things that make

the axion the perfect candidate for dark

matter, its minute size and refusal to interact

with other matter, also make it a nightmare

to measure.

Today, physicists know of only one viable

mechanism to observe the axion. In the

presence of a strong magnetic field, an axion

can convert into a photon, a tiny packet of

light. But this process is incredibly rare,


Astrophysics

FOCUS

making the photon signal extremely hard to

detect. “To get a sense for how much power

we’d get, if you lit a match on the surface of

the Earth […] that would be the energy rate

for photons on the pupil of your eye if you’re

on the surface of the Moon,” Lamoreaux said.

To complicate matters, physicists aren’t

sure what frequency of light the axion would

convert into. “There’s a huge parameter

space, from ten microelectronvolts up to

one hundred electronvolts,” Lamoreaux said.

That’s a span of eight orders of magnitude—if

the axion is real, actually finding the signal it

emits would require an immense amount of

grit and ingenuity. That’s where HAYSTAC,

ALPHA, and RAY come in.

Loud and Clear?

HAYSTAC and ALPHA are effectively

ultra-sensitive radios, searching through

each possible axion frequency through a

process of tuning. The radio receiver is a

metal cavity exposed to an extremely strong

magnet. The magnetic field converts axions

into photons, but these photons are too dim

to be observed directly. Instead, they must be

amplified through resonance with the cavity.

Think of plucking the strings on a violin: the

shorter the string, the higher the pitch of

the note. Similarly, adjusting the length of

the cavity changes the frequency of light it

amplifies—if the cavity is small, it resonates

at a higher frequency, and if the cavity is

large, it resonates at a lower frequency.

But even with this technique, searching

over such a vast array of frequencies with

only one device would take many, many

years. “We can do a couple [frequencies]

in a day, but it will take months to scan

Rather than mark the end

of an era, the detection of

the axion would mean a

beautiful beginning for a

brand new era of questions

and discovery.

over a given frequency range,” said Claire

Laffan (YC ’21), a PhD student working

on ALPHA. And for higher frequencies,

the scanning process runs even slower. “To

resonantly enhance a very high frequency

photon, you need a small cavity. However,

the smaller the volume of the cavity,

the fewer axions go in and out of it, and

therefore there’s a lower probability you’ll

detect anything,” Laffan said.

Today, the Yale axion team is focused on

accelerating the search. The ALPHA team

is experimenting with special synthetic

materials in order to tune the resonant cavity

more efficiently. “The cool thing about our

new resonator is that its frequency range

is not dependent on its volume, so we can

make an arbitrarily large volume cavity while

still being sensitive to these really high mass

axions,” Laffan said. Meanwhile, the RAY

team is engineering new, more sensitive

detectors to measure the light from axion

conversion. Their technology takes advantage

of Rydberg atoms, a special class of matter

that is extremely sensitive to photons.

By measuring how the electrons in a

Rydberg atom become energized

when exposed to light, the RAY

team can measure the effect of a

single photon at a time. “Right now,

we’re testing to see if our atoms

are being transitioned to some

other Rydberg state via the axion

interaction,” said Tyler Johnson, a

postdoctoral researcher working on RAY.

ABOUT THE

AUTHORS

The Axion Alliance

However, despite their trailblazing

innovations, the Yale team knows they can’t

do it alone. They see their mission as aiding

the worldwide scientific community. “One

experiment is not going to do it in anybody’s

lifetime. We need to have a harmonized

effort with people working on different

frequencies and all sharing technologies,”

Lamoreaux said. “If we can demonstrate this

proof of concept, it would change the way

that other experiments work, and we could

all scan the parameter space faster and look

for axions in places that we haven’t before,”

Laffan said.

And what if we actually find the axion? It

would be a revolution in physics, potentially

resolving the now age-old mysteries of CP

symmetry and dark matter. “I never get

my hopes up that it’s going to be there—

it could be the WiFi signal, or someone

walking in the laboratory,” Laffan said. But

rather than mark the end of an era, the

detection of the axion would mean

a beautiful beginning for a brand

new era of questions and discovery.

“I think that it is one of the most

human things we can do, to ask

questions and try to find answers

regardless of what those answers

might tangibly give us […] I think

building these experiments is a

beautiful expression of our curiosity,”

Laffan said. ■

DIYA NAIK

MAX WATZKY

DIYA NAIK is a sophomore in Pierson College majoring in physics. Diya works at the Yale Quantum

Institute on quantum computing research. She’s often found frantically emailing people as the

co-president of the Society of Physics Students, wrangling scheduling as a project lead in the Yale

Undergraduate Quantum Computing Club, and reconnecting with the humanities through poetry

and art.

MAX WATZKY is a sophomore in Benjamin Franklin College majoring in physics and statistics and

data science. Max currently works in a biophysics lab at Yale’s School of Medicine, investigating how

neurons grow and develop. He also serves as editor of YSM’s full-lengths section and co-president of

Yale’s Society of Physics Students. You can often find him running, reading, or extending his legendary

Duolingo streak.

THE AUTHORS WOULD LIKE TO THANK Steve Lamoreaux, Karsten Heeger, Tyler Johnson, Claire

Laffan, and Eleanor Graham for their invaluable help with this article.

FURTHER READING

Graham, E., Ghosh, S., Zhu, Y., Bai, X., Cahn, S. B., Durcan, E., Jewell, M. J., Speller, D. H., Zacarias, S. M.,

Zhou, L. T., & Maruyama, R. H. (2024). Rydberg-atom-based single-photon detection for haloscope

axion searches. Physical Review D, 109(3), 032009. https://doi.org/10.1103/PhysRevD.109.032009

Wilczek, F. (1978). Problem of strong P and T invariance in the presence of instantons. Physical Review

Letters, 40(5), 279–282. https://doi.org/10.1103/PhysRevLett.40.279



FOCUS

Neuroscience

Computational Biology

FROM CRYO

TO CURE

What Transplanted

Neurons Tell Us About

Neurodegenerative Disease

By Crystal Liu

Art by Melody Jiang


Neuroscience

FOCUS

Neurodegenerative disease is the

ultimate scourge—it steals our loved

ones away by eroding both their

minds and bodies. As the global population

grows older, complex age-related disorders like

neurodegenerative disease are becoming more

prevalent, posing a formidable challenge to

modern medicine. For most of human history, a

diagnosis like Alzheimer’s or Parkinson’s disease

was a death sentence; by the time an individual

began exhibiting symptoms, it was often too

late for meaningful intervention. Today, while

a handful of treatments can ease symptoms or

moderately slow progression, none can halt the

disease at its root—at least not yet.

In a recent study published in Biology, a team

based at Yale and UC Davis has developed a

new platform that allows researchers to study

potential treatments with greater biological

accuracy and precision than ever before. By

transplanting human neurons into the brains

of rodents and nonhuman primates, they

established a living model of Huntington’s

disease that can examine how emerging

treatments interact with diseased neurons in

real time.

At the cellular level, neurodegenerative

diseases are characterized by the progressive

loss of neurons, specialized cells responsible for

processing and transmitting information in the

brain. The most common form, Alzheimer’s

disease, damages neurons in the hippocampus,

the brain’s memory hub, and the cerebral

cortex, which governs language, reasoning,

and other higher-order cognitive functions.

As the damage spreads, the brain physically

deteriorates, leading to memory loss, cognitive

decline, and, ultimately, death.

Huntington’s disease is a rare, inherited

neurodegenerative disease that affects about five

to ten out of every hundred thousand people in

the United States. It is caused by a mutation in

the huntingtin gene, which produces a misfolded

protein, mutant huntingtin (mHTT). In turn,

this misfolded protein causes further problems

in protein synthesis and neuronal function in

the striatum of the basal ganglia, a brain region

primarily responsible for movement control.

As the disease progresses, patients develop

involuntary jerking or writhing movements

known as chorea. Symptoms typically appear

in a person’s thirties or forties, but patients don’t

typically live more than fifteen years after the

initial onset. The disease currently has no cure.

Huntington’s disease eventually kills cells

that produce a chemical called gammaaminobutyric

acid (GABA) in the basal ganglia.

Ordinarily, GABA prevents neurons from firing

out of control. This helps control the brain’s

signals to the rest of the body, like those that

force muscles to contract and relax. But as these

GABA-producing cells die, neuronal signaling

becomes erratic.

Hunting for Treatments

One emerging treatment for

neurodegenerative diseases like Huntington’s

is neuronal cell replacement therapy. This

approach replaces the neurons lost to disease

with healthy ones by tapping into advances in

stem cell biology. Since it is impossible to harvest

neurons from donors and directly transplant

them into patients, clinicians instead harvest

non-neuronal cells and turn them into

transplantable neurons over several steps.

Scientists take donor cells—usually from

skin or blood—and reprogram them

into induced pluripotent stem

cells (iPSCs). These special

cells are like blank slates,

with the power to

develop into almost

any type of cell in

the body. For

patients with

Huntington’s,

researchers direct

iPSCs to become

GABA-producing

neurons (induced GABAergic

neurons, or iGABAs) and transplant them

into the striatum.

Many research groups are investigating

different aspects of this approach, exploring

everything from how to generate the most robust

iGABAs to how these grafted cells interact

with diseased host brains. Dustin Wakeman, a

preclinical therapeutic development consultant

and adjunct assistant professor at Yale School of

Medicine, specializes in stem cell-based therapies

for neurological disease. In collaboration with

Kyle Fink, an assistant professor at the UC Davis

Department of Neurology studying animal

models of Huntington’s disease, they recently

published the study in Biology demonstrating

the long-term engraftment and integration of

iGABAs in Huntington’s animal models.

Wakeman and colleagues transplanted

iGABAs into the brains of rats, mice, and

monkeys, animal models that scientists

commonly use to study diseases and their

potential treatments. Months later, they

analyzed brain tissue and found that the human

neurons had survived, matured, and developed

long-range connections with the host brain. “We

showed that these cells could indeed survive for

long periods of time, become the neuronal cell

types that we hypothesized were required, and

actually send neuronal fibers out, innervating

the host brain, which is really important for

function,” Wakeman said.

Neurons are extensively

interconnected, which is

essential for communication

between cells and neuronal

function. To visualize

how transplanted cells integrate into

these networks, researchers used fluorescent

antibodies to label human-specific nerves and

microscopy to trace where graft-derived fibers

developed. They found human fiber presence

across distant brain regions, indicating not

only the survival of the grafts but also their

integration into the host brain circuitry.

Another advantage of these cells is their

consistency. Because iGABAs are commercially

available and can be preserved in freezers,

experiments can be repeated across laboratories

with the same cell population. “Anyone in the

world can buy the same cell,” Wakeman said.

This reproducibility is essential for biomedical

research, allowing different teams to test

therapies on a standardized platform.

Old Mice, New Tricks

While testing the iGABAs, Fink and his

colleagues developed a novel animal model—



FOCUS

Neuroscience

R6/NSG mice. The original R6 mice were

established in the 1990s as the animal model for

Huntington’s disease—they express the mutant

HTT gene and rapidly develop symptoms that

mimic the disease. However, because they have

a healthy immune system, introducing human

cells triggers a strong immune response that

hinders graft integration and compromises the

animals’ own health.

To address this issue, the Fink Lab

introduced the R6 mutation to NSG mice,

which are immunodeficient and do not reject

human grafts. To their pleasant surprise, the

new R6/NSG line not only tolerated the grafts

but also lived longer than R6 mice. “[R6] only

lives between twelve and fourteen weeks, but

when we take the immune system away, the

mouse now lives for about fourteen months

and is much less severe [in Huntington’s

symptoms],” Fink said. The exact reason for

this extension of life expectancy is unknown,

but the prolonged lifespan allows researchers

to observe both slow disease progression and

long-term graft behavior.

Pathological Protein Transfer

The researchers also used their animal model

to study mHTT as a pathological hallmark

of Huntington’s disease. The exact origin of

these misfolded proteins in neurodegenerative

disorders is still an area of debate, but there is

growing evidence that they spread from cell

to cell through a process called pathological

protein transfer. In this process, misfolded

proteins move into healthy cells, where they

trigger other proteins to misfold and form

toxic aggregates, eventually disrupting normal

neuronal function. The prototypical example is

“mad cow disease,” where a misfolded protein

“infects” other proteins, causing them to misfold

too. While neurodegenerative diseases cannot

be transmitted between people, pathological

proteins can be transmitted from cell to cell.

But could this infection process undermine

efforts to graft healthy cells into patients with

neurodegenerative disease? “There’s a disease

modeling angle: what’s happening to human

cells when the huntingtin protein goes into

healthy cells?” Wakeman said.

Wakeman and Fink tested this idea, looking

to see if diseased host cells could cause the

proteins in the transplanted human neurons

to misfold. The researchers observed that

mHTT transferred from diseased host cells to

the transplanted human neurons in mice with

Huntington’s, confirming that pathological

protein transfer might indeed mitigate the

effectiveness of neuron grafting. However,

both Wakeman and Fink find it a minor

complication. Wakeman reasoned that even if

some grafted cells are eventually affected, the

transplantation could still potentially provide

a patient with several years of improved brain

function and quality of life before pathological

proteins begin to impact parts of the transplant.

Further Implications in Medical Research

Another issue in neurodegenerative disease

research is that animal and human neurons

don’t always behave the same way. In classical

R6 mice, Huntington’s disease progresses far

more aggressively than it does in humans. But

now, with human neurons grafted into the

brain, researchers can observe how the disease

unfolds in real time—directly in human cells.

If these grafted neurons receive mHTT and

begin to degenerate gradually, they offer a more

accurate and informative model of human

disease progression.

Additionally, since neurodegenerative diseases

are currently irreversible, early intervention is

key. “There are always windows of when these

therapeutics are the most effective. If cells are

going away, try to preserve as much as you can,”

ABOUT THE AUTHOR

IMAGE COURTESY OF I. WILLIAMS, NICHD

Artist’s rendering of fluorescence labeling highlighting changes in the cerebellum of a mouse with Niemann-Pick

disease type C1 , a progressive neurodegenerative disorder. Animal models help researchers study neurodegeneration.

Fink said. Engrafted neurons offer a window

into early disease changes and may eventually

serve as a testing ground for therapies designed

to halt degeneration in the early stages or before

symptoms emerge.

Fink’s lab is now exploring CRISPR-based

therapies to treat genetic neurological conditions.

“There [are] lots of cool things happening in the

cell transplantation community, combinatorial

therapeutics, and genetic disorders,” he said.

Neuronal cell replacement, as either a therapy

or a disease model, can also be extended to

other neurodegenerative diseases. “You can

do this in Alzheimer’s models with tau, in

Parkinson’s with α-synuclein—they likely share

similar mechanisms. We can use these similar

mechanisms to learn things about different

diseases,” Wakeman said.

While many questions remain about how

pathological proteins cause disease and how to

best intervene, Wakeman and Fink’s work offers

a vital step toward understanding these diseases

and developing therapies against them. With

reproducible human neurons and better mouse

models, the field is steadily moving forward with

more realistic and human-relevant platforms.

Perhaps one day, combinatorial therapies

can rebuild what’s lost in neurodegenerative

diseases—one cell at a time. ■

CRYSTAL LIU

CRYSTAL LIU is a junior in Pierson College majoring in molecular, cellular, and developmental biology.

Besides writing for YSM, she conducts biochemical research at the DiMaio Lab and manages backstage

and administrative duties at Yale Vermilion Theater. She also listens to too much Cantopop and drinks

too much boba.

THE AUTHORS WOULD LIKE TO THANK Dustin Wakeman and Kyle Fink for their time and enthusiasm

about their research.

FURTHER READING:

Marmion, D. J., Deng, P., Hiller, B. M., Lewis, R. L., Harms, L. J., Cameron, D. L., Nolta, J. A., Kordower, J. H.,

Fink, K. D., & Wakeman, D. R. (2025). Long-term engraftment of cryopreserved human neurons for in

vivo disease modeling in neurodegenerative disease. Biology, 14(2), Article 2. https://doi.org/10.3390/

biology14020217


Cognitive Science

FEATURE

BY JUSTIN ZHANG

ART BY DAHLIA KORDIT

Depictions of animals in film are often fictitiously

personified. Popular movie Ratatouille exemplifies

this genre with the cooking rat Remy’s compulsion for

distinct flavor profiles and generational cooking skills. While it

may seem obvious that a real-life rat would not possess Remy’s

culinary literacy, a study published by Elisa Frasnelli, an associate

professor and researcher at the University of Trento, and her

collaborators provide new insight into distinct similarities between

abilities of humans and rats to differentiate different scent profiles.

In the slim yet robust field of interspecial olfactory science,

the study and comparison of scent processes across

different species, there is much debate on the deftness of

human versus non-human olfaction. It is hypothesized

that humans use both linguistics and cognitive categories

to discern different scents. By assigning labels to different

smells, humans can compensate for their relative paucity

of olfactory receptors compared to other mammals. Such

a reduction in olfactory capacity seems to be paired to

our optical development through evolution. “From an

evolutionary point of view, the idea that we have less olfactory

receptor genes is thought to be explained with the fact that we

improved our vision […] while humans are primates and can

rely on vision more, other animals are heavily reliant on olfaction,”

Frasnelli said. Knowing this, it’s reasonable to argue that in gaining

capabilities such as cognition-based categorization, we

compromised some of our olfactory receptors.

While this thought process seems sound, there have

been no studies attempting to disprove the notion

that non-human animals are unable to categorize scent

profiles to better differentiate scents. Frasnelli’s study suggests

otherwise. In order to discern whether rats would categorize

and generalize scents, rats were trained in isolated

chambers to smell two grape varieties, each with four

brands of wines summing to a total of eight distinct

wines. The rats were trained using a reward system to

push a lever when they correctly identified one grape

variety over the other. Two new wines, one of each

grape variety, were added, and the rats were tested to

see if they could correctly select the same grape variety.

“We knew that they were amazing at discriminating

smells, so that wasn’t so surprising. But the fact that

they could generalize was really striking,” Frasnelli said.

Seven of nine rats passed this test, supporting the notion

that rats were using a generalization and categorization

strategy to choose wines.

“[What was] especially intriguing was

that there was one specific wine, which was

a challenging one even for us as authors […] we

even smelled it and we tasted it at some point,”

Frasnelli said. While the positive results support

the notion that rats could generalize wines and possibly other

scents into groups, this peculiar caveat suggests that cognitionbased

categorization may not be necessary for distinguishing

smells. Even with human cognitive abilities, the

researchers were unable to differentiate between this

wine and other wines of the same grape variety. One

possible explanation is that similarities in human

and rat olfaction arise as a result of similarities in

olfactory receptor genes. It is difficult to test the

viability of this theory, however, as humans

are known to utilize different perceptual

dimensions simultaneously in order to elevate

our olfactory senses. For example, when we

drink wine, we also smell and use our tactile

senses on our tongue to help us discern the wine

based on its other qualities. Meanwhile, the rats

in the experiment were only allowed to smell

the samples. Due to these different perceptual

dimensions, it is hard to conclude the exact

source of the similarities and differences underlying

olfactory acuity across species. Regardless, one thing is

clear: humans and rats are more similar than we

previously thought.

Frasnelli’s inspiration for such an

unorthodox study arose during a wine

tasting experience, sparking an interest

as to whether animals could also

differentiate wines. While this abrupt

project began as simple curiosity, the

results could overturn the current

beliefs of processes and factors that

underlie non-human olfaction. “I

think that [an important] question that

arises from these studies is whether

language is important to form those

[scent] categories,” Frasnelli said.

Frasnelli is excited to explore future

directions that could reveal more about

this connection, informing future research

involving rat models. ■



FEATURE

Immunology

LONG B REMEMBERED

MAPPING MEMORY FORMATION ACROSS

IMMUNE TISSUES

BY ABIGAIL JOLTEUS

Think of your immune system as a

personal bodyguard—one that not

only defends you in the moment but

also keeps a detailed record of past invaders.

The next time the same pathogen strikes, your

body reacts swiftly, neutralizing the threat before you

even notice. But how does this remarkable memory work, and what

determines how long it lasts?

B cells are critical to the immune system, producing antibodies that

recognize and neutralize harmful microbes. “[Antibodies]

are remarkable proteins that do two major things: they

tag pathogens for destruction by the rest of the immune

system; they also neutralize pathogens directly by

binding to the parts of the virus that enable it to enter

cells, blocking that process,” Michael Swift, a

lead co-author of a recent Stanford study, said.

After an infection clears, some B cells become

memory B cells, which remain on standby to

rapidly respond to future encounters with the same

pathogen. Others turn into long-lived plasma cells,

continuously secreting antibodies for decades. “These cells

provide the longest-lasting protection, offering a continuous supply

of antibodies from infections you had decades ago,” Swift said. This

dual system ensures both immediate recall and sustained protection.

While previous studies have mainly focused on B cells in the

bloodstream, this study examined the bone marrow, spleen, and

lymph nodes in the immune system at rest—not during an active

response such as infection or vaccination. “One motivation for our

study was understanding where long-lived B cells reside and how

long-term memory is shared between the bone marrow and other

tissues,” said Ivana Cvijović, the other lead co-author. The

researchers examined multiple human tissues, tracking

how B cells mature and differentiate. Their findings

revealed a surprising aspect of B cell behavior:

while most B cells independently determine

their fate, one subset of proliferating antibodysecreting

cells, the ASC-3, shows coordinated

behavior within lineages. This is an intriguing

exception to the general pattern of independent decisionmaking.

“When B cells respond to infection,

they form lineages—families of related cells that

differentiate into memory and plasma cells,” Swift

said. This supports the view that cell fate decisions

are generally not coordinated within a lineage. One

of the study’s most unexpected discoveries was that the

ART BY ALONDRA MORENO SANTANA

immune system continuously

populates immune memory

over time. “Our data revealed that B cells could

migrate to the bone marrow—or any tissue—at any point

during the process of refining antibodies. In other words, longterm

antibody memory doesn’t just form at the end of the immune

response; it develops continuously from the start,” Swift explained.

This finding challenges the previous assumption that plasma

cells only arise after a "temporal switch" which occurs late in an

immune response.

Another key finding was the widespread distribution of ASCs

across various tissues. “Rather than centralizing antibody

production, these cells seem to have the ability to

disperse across all the tissues we sampled,”

Swift said. Importantly, this applies to the

ASC-3 subset of plasma cells, which are

potentially not long-lived, showing that

ASCs can be distributed more broadly.

Understanding how B cells develop

long-term memory has major implications

for vaccine design and immune-related diseases.

“Once these cells are created, they can live for decades, providing

protection against future threats,” Cvijović said. This may help

explain why some vaccines provide lifelong immunity while others

need regular updates.

The study also challenges previous assumptions about

antibody memory formation. The process of antibody

maturation and memory formation is more flexible and

dynamic than previously thought, with immune cells not

restricted to a specific timeline or location for establishing

lasting immunity.

“Our study aims to provide a comprehensive multitissue,

joint single-cell dataset that can serve as a

foundational resource for the scientific community,” Swift

said. The dataset could inspire further studies into the complex

interactions between different tissues during immune responses

and help refine our understanding of cell differentiation and

memory formation.

While many questions remain—such as how B cells migrate

and when key decisions occur—this research is an important

step toward unraveling the mysteries of immune memory.

As scientists continue to explore these mechanisms, their

discoveries may pave the way for new approaches to

investigating autoimmune diseases, vaccine development, and

personalized treatments. ■


Climate Science

FEATURE

SYNAPSE ESSAY CONTEST WINNING ESSAY

THE FIGHT AGAINST

THE FLOOD

Houston’s Flood Crisis

BY VICTOR GONZALEZ

CLEAR CREEK HIGH SCHOOL, TEXAS

ART BY MADELEINE POPOFSKY

In Houston, climate change is not merely a global issue; it is a

personal threat that brings devastating floods. Rising temperatures

intensify rainfall, causing excessive rain, hurricane storm surges, and

overwhelming floods. These events disrupt lives, damage infrastructure,

hinder economic growth, and cause financial hardships. They are all part

of one of the city’s heaviest challenges, flooding, which continues to grow

with every passing year. To protect Houston’s future, the call for inventive,

sustainable strategies is necessary across all communities.

Houston’s low topography and proximity to the Gulf Coast already

make the city prone to extreme weather, but climate change intensifies

the weather into a recurring threat. The change in global climate patterns

is fueled by global greenhouse emissions, some of which originate from

Houston’s own industrial activities.

A study published in Anthropocene, a journal that explores how

people interact with nature and Earth’s systems, found that under a highemissions

scenario, the annual probability of receiving over five hundred

millimeters of rainfall, about nineteen inches, could increase twenty-fold

from 0.05 percent in the late twentieth century to one percent by 2100.

This increase represents more than numbers on a spreadsheet; it translates

to potential loss of life and devastating harm to the city.

Hurricane Harvey—one of the nation’s most destructive hurricanes on

record—brought widespread destruction to Houston in 2017, with over

sixty deaths and 125 billion dollars in damage. The storm left numerous

families displaced and communities shattered.

Kevin Smiley, assistant professor of Louisiana State University’s

Department of Sociology and lead author of a 2022 study about climate

change-attributed impacts of Hurricane Harvey, demonstrated through

hydrological flood models that fifty percent of flooded properties would

not have been affected had the effects of climate change been absent. In

Harris County, this statistic translates to approximately fifty thousand

houses—potentially billions saved and a considerable reduction in the

number of lives lost. The county’s sizable Latinx population illustrates the

inequitable nature of such impacts and underscores the need for resilience

efforts that prioritize safety in vulnerable communities.

Since 2017, Houston has implemented multiple flood mitigation

projects in an effort to reduce risk and protect vulnerable communities.

A notable project is the North Canal Project, designed to amplify

water conveyance and minimize flood water elevation during major

storm events. Located at the critical point where three

interconnected waterways meet flowing toward Galveston

Bay, the project will begin construction in 2026. The city of

Houston estimates that it will reduce the risk of flooding

for hundreds of homes in the downtown area. As part of a

growing system of green solutions, the North Canal Project

is a key step towards Houston’s long-term safety planning—

acknowledging the intensity of flood events and the necessity

of comprehensive water management strategies.

Another solution that will take effect is the Inwood Forest

Stormwater Detention Basin, designed to hold stormwater

runoff until heavy rain has passed. The detention basin will

hold 1,200 acre-feet of water, approximately 391 million

gallons. Houston flood experts expect the Inwood Forest

Stormwater Detention Basin to protect over 4,400 structures in the

White Oak Bayou and Vogel Creek watersheds. Rather than

diverting waterways, like the North Canal Project, the project

will allow for storage and controlled release into larger bodies

of water.

While Houston’s ongoing projects focus on eliminating the

risk of flooding, it turns out that there might be additional

ways to leverage stormwater for sustainability and resistance

efforts. A study by the Department of Environmental Research

in South Korea, where flooding is a persistent problem,

suggests stormwater harvesting as a highly effective solution

to maintain flood elevation and risk factors. Paired with

regional planning, this filtration strategy has the potential

to reduce risks and strengthen local endurance to climate

change. These actions could also benefit the local economy

through aquifer recharge and agricultural irrigation, along

with alleviating other systems across the Houston area.

Climate change remains a global crisis, but for Houston,

it is measured in flooded homes, damaged lives, and

considerable economic impact. As climate change continues

to intensify rainfall patterns, Houston must continue adapting

its infrastructure to conquer the dynamic nature of these

challenges. Through large-scale innovation and fighting against

the flood, Houston should not just endure—it must evolve. ■



FEATURE

Physics

ORDERED CHAOS

SPONTANEOUS SWIRLS

EMERGE IN DENSE HUMAN MOTION

BY MAX WATZKY | ART BY ALONDRA MORENO SANTANA

People gather en masse for many

reasons—sports games, musical

festivals, religious services, and

protests comprise just a few examples.

But in all cases, there is something

exhilarating about being part of the

crowd. Especially in the wake of

pandemic-era lockdowns and the

rise of virtual interaction via social

media, coming together in person can

be a liberating or even transcendent

experience. It is an opportunity to lose

yourself in the larger collective, to be a

part of something much greater than

any individual on their own. Crowds

are powerful.

But anyone who has ever been in a

crowd knows how hazardous they can be.

In especially dense crowds, the sheer mass

of people presents immense dangers.

Under enough pressure from the bodies

of the people surrounding them, a person

can be asphyxiated or have their bones

broken while still standing up. And if you

drop your glasses, don’t even think about

bending down to pick them up—you

could very easily find yourself trapped,

trampled, or worse. Add in unpredictable

motion and widespread panic, and large

gatherings can turn into mass casualty

events, called “crowd crushes,” in the

blink of an eye.

In recent years, it seems that crowd

crushes have become even more common.

In November 2021, a crowd crush at

Travis Scott’s Astroworld Festival killed

ten concert-goers and left twenty-five

others grievously injured. In October

2022, a crush at a Halloween festival

in Seoul killed 159 people and injured

197, marking the deadliest disaster in

South Korea in almost a decade. And

most recently, in January 2025, a series

of deadly crushes at the Kumbh Mela

pilgrimage festival killed dozens and

injured perhaps hundreds more.

On the ground, these were terrifying

scenes of pure chaos. But to François Gu,

who recently earned his PhD in physics

at the French university École Normale

Supérieure (ENS) de Lyon, these crowds

are anything but chaotic. As he was

beginning his studies, his mentor Denis

Bartolo showed him a video of a massive,

dense crowd in Pamplona, Spain. The

crowd was gathered for the Chupinazo,

the kickoff of the Festival of San Fermín,

a massive, raucous celebration which

features the famous “running of the

bulls.” Rather than perceiving chaos,


Physics

FEATURE

Gu saw the seeds of order. “I was pretty

amazed by what we could see. It’s the

kind of video that has a ‘wow’ effect—to

see that many people crammed together,

shoulder to shoulder, torso to torso, and

to see everyone moving simultaneously.

I really wanted to understand what was

going on,” Gu said.

After years of researching the physical

properties of large gatherings, Gu,

Bartolo and their collaborators published

a paper in Nature entitled “Emergence of

collective oscillations in massive human

crowds.” Their results were shocking—

the team found that once a crowd hits

a certain density threshold, it begins to

exhibit patterns of oscillation, organizing

into waves of density which churn around

in massive vortices. This large-scale

collective behavior offers key insights

into the nature of crowd dynamics, and

may lead to future breakthroughs in

crowd monitoring and crush prevention.

The source of their findings was

an ingenious piece of intuition: that

large, dense crowds behave like a

continuous fluid-like material, rather

than an ensemble of individual particles.

Treating the crowd as a fluid meant

that the team only had to keep track of

a few key variables—the density and

velocity at every point over time. This

treatment also helped the team simplify

the problem, eliminating potentially

erroneous assumptions about the physics

of interactions between individuals. “By

treating crowds as continuous media,

we didn’t have to assume anything

about the interaction rules between the

pedestrians. We could just measure some

macroscopic properties of the crowd,”

Gu said.

In order to measure these density and

velocity fields, Gu and the team employed

a sophisticated machine learning tool to

track how individuals move throughout

a crowd. The team tested their algorithm

on video data from the Chupinazo, which

provided several benefits. First, the crowd

at the Chupinazo assembles each year in

the exact same place, allowing the team

to control for extra potential variables.

Second, the Chupinazo crowd always

grows slowly over the course of an hour,

meaning that the team could pinpoint

the relationship between crowd density

and any emergent effects.

The team analyzed the data using

a Fourier transform, a mathematical

tool which can tell us how different

frequencies comprise a convoluted

signal. Just like how a chord on a piano

might be decomposed into many musical

notes, a complex field of motion can be

decomposed into many oscillations at

different speeds. Applying the Fourier

transform to their velocity field data, the

team found something surprising. Below

a density threshold of four people per

square meter, the crowd moved loosely

and chaotically, as expected. In the Fourier

transform, this motion manifested as

“zero-frequency oscillation,” jerky and

unpredictable movement with no obvious

patterns. However, above this threshold,

the Fourier transform suddenly jumps to

life, bursting with activity along an entire

spectrum of oscillatory frequencies—

now, the crowd moves in enormous

vortices. “This transition from zerofrequency

oscillations to oscillations

with a finite frequency—this is when the

threshold of four people per square meter

is hit,” Gu said.

But what actually causes these

oscillations? The team found they could

model the system of people pushing

against each other as one gigantic mass,

held in place by an array of springs. If the

mass moves too far away from the center,

the springs push it back into place,

providing a restorative force. However,

the mass can move around the center

with minimal resistance, allowing it to

move in broad circular orbits.

Going forward, the team believes

that understanding these collective

oscillations will be key to preventing

future crowd crush disasters. As evidence,

they point to data from the Love Parade

disaster in 2010, a now-infamous crowd

crush in Germany which killed twentyone

people. Analyzing the data, the team

found that the same oscillations they

observed in the Chupinazo were present

at the Love Parade. “To get a grasp of

what kind of oscillations we’re talking

about—it’s five hundred people, several

dozens of tons all moving in the same

direction. Now imagine you are standing

next to a wall, and you have that amount

of people coming at you,” Gu said.

However, what makes these oscillations

so useful is that they appear long before

crowd crush conditions emerge. “The key

result is that we can detect the onset of

these oscillations while they’re still very

small—too small to be seen on a video.

We know that if these oscillations appear,

and the crowd continues getting denser,

it’s probable these oscillations will grow at

higher densities,” Gu said. This fact means

that in the future, authorities might be

able to use camera data to predict crowd

crush behavior long in advance, allowing

them time to implement measures which

could save lives. “By just measuring the

velocity field, and analyzing its spectral

properties, you can detect the onset of the

oscillations, and maybe you can prevent

an accident […] up to twenty minutes in

advance,” Gu said.

Going forward, Gu hopes to keep using

physics on a tangible scale, applying

his skills towards real-world problems.

Having recently graduated from ENS de

Lyon, he is now moving to the US, where

he’ll continue working on problems

related to physics and urban life at MIT.

“At MIT, I’ll be joining the Senseable City

Lab. I’m going to switch a bit, and work

in urban science. I’m excited to apply my

physics expertise to make cities more

resilient and sustainable,” Gu said. ■



FEATURE

Cellular Biology

THE VESICLE EXPRESS

ENGINEERED BACTERIA BOOST ORAL DELIVERY

BY MICHELLE CHEON

ART BY AASTHA PAUDEL AND ELLIOT LICHTMAN

The stomach is both a gatekeeper

and a destroyer, designed to

reduce everything we consume

into its most basic components before

permitting passage into the bloodstream.

While essential for immune defense,

the gatekeeper poses a lethal barrier for

protein-based therapeutics. Proteins are

fragile by design: uniquely structured,

carefully folded, highly reactive, and

easily dismantled by acid and enzymes

long before they reach their targets.

For decades, researchers have tried to

outsmart this problem by shielding

protein drugs from the gut, layering

them with coatings or reformulating

them in capsules. But what if the

solution isn’t to outwit the stomach’s

defenses, but to enlist a courier the body

already recognizes and trusts?

Protein therapies, from insulin to

monoclonal antibodies, have historically

been administered by injection as

decades of research failed to make

oral delivery more efficient.

Through the 1970s

and 1980s, pharmaceutical companies

explored protective coatings designed

to resist stomach acids, only to watch

those drugs dissolve too early or remain

unabsorbed. The cost, inconsistency,

and clinical failures of these trials led

to a pivot toward injectables. However,

this route is far from ideal. They require

trained personnel and often deter

patients, especially those with chronic

conditions, from consistent use

due to pain or anxiety. The idea

of a swallowable protein drug, one

that could travel safely through the

gut and still work systemically, never

truly died—it just needed help from a

new vehicle.

The stomach is filled with hydrochloric

acid and proteases, which are enzymes

that chop proteins into amino acids.

Even if a therapeutic protein avoids

being degraded in the stomach, it enters

the small intestine where it faces a

gauntlet of bile salts and more enzymes,

designed to further

digest complex

molecules. If

the protein

remains intact, it then confronts the

intestinal barrier: a tightly packed

layer of epithelial cells joined by “tight

junctions” and coated in mucus, both of

which block unwanted substances. For

therapeutic proteins, the gut is a hostile,

nearly impenetrable environment.

Scientists have attempted to circumvent

these hurdles through a variety of

strategies. Some have tried wrapping

proteins in nanoparticles—tiny

synthetic or biological shells

designed to protect their contents.

Others have developed coatings

that resist digestion and only dissolve

in the less acidic environment of the

small intestine. Some approaches involve

co-administering enzyme inhibitors

to temporarily disarm the digestive

enzymes that would otherwise dismantle

the drug. Each of these methods tackles

one part of the problem, but none

have proven to be a comprehensive

fix. Nanoparticles can be difficult to

manufacture with consistent quality,

and enzyme inhibitors can interfere with

normal digestion. What remains is a

fundamental need for a system that can

protect protein drugs through the gut,

help them enter circulation efficiently,

and be practical for long-term use. Such

a system would also need to be stable,

scalable, biocompatible, and efficient.

That’s where the type zero secretion

system (T0SS) comes in. Developed

by a team of researchers in a study led

by first-author Xu Gong and senior

author Yun Yang’s team at Beihang

University, T0SS repurposes a natural

feature of gram-negative bacteria:

outer membrane vesicles, or OMVs.

These vesicles, which bud off from

the bacterial membrane, are normally

used by microbes to communicate and

interact with their environment.


Cellular Biology

FEATURE

For this team of researchers, T0SS

emerged from a personal motivation.

“My husband struggled with gout,

having to lie on his side when it flared,”

Yang said. “When we looked into

available treatments, I found there

wasn’t a single safe or effective drug to

cure, treat, or even mitigate it. That’s

why I decided to develop a new kind of

biological drug.”

The breakthrough came when

Gong discovered that specifically

engineered bacterial vesicles could

transport therapeutic proteins into the

bloodstream. “The limitation of altering

the genetic makeup of bacteria to treat

diseases is that all the drugs delivered

by probiotic bacteria are limited to the

gut area,” Yang said. “We wanted

to break this limitation.” The

researchers engineered

E. coli Nissle 1917,

a probiotic strain

considered safe by

the Food and Drug

Administration, to

overproduce these

OMVs and to fill them with

therapeutic proteins. To achieve

this, they deleted a gene called nlpI,

which suppresses vesicle formation,

thereby boosting OMV production

nearly threefold. Proteins of interest

such as uricase or lactate oxidase—

enzymes that help break down uric and

lactic acid, respectively—were tagged

with signal peptides. These signal

peptides are short amino acid sequences

that direct the proteins into the area

between the bacterium’s inner and outer

membranes, where OMVs form.

What makes this discovery more

fascinating is its serendipitous nature.

“We accidentally discovered that the

altered membrane vesicles of the

bacteria could enter circulation,” Yang

said. “After that discovery, we decided

to use this altered membrane vesicle as a

delivery platform to deliver uricase into

the circulation.”

This approach is striking not only

for its creativity, but for its efficiency.

In the case of green fluorescent

protein, the encapsulation efficiency

was 97.9 percent, a rate far superior

to what is typically achieved with


synthetic loading techniques which

use electric fields or sound waves to

disrupt membranes. Experiments

further demonstrated that OMVs could

simultaneously carry multiple distinct

protein cargos—enabling, in theory,

combination therapies. When delivered

orally to mice, the vesicle-encapsulated

proteins resisted degradation in

simulated gastric and intestinal fluids

and were detected in organs like the liver

and kidneys hours after administration.

Perhaps most importantly, the

encapsulated proteins retained their

activity, meaning they were still

functional and able to carry out their

intended biological tasks. In experiments

with hyperuricemic mice, which serve

as models for gout and other uric acidrelated

disorders, OMV-delivered

uricase significantly reduced

serum uric acid levels—restoring

them nearly to normal—while

improving kidney function and

lowering inflammatory markers.

Mice that received uricase

through conventional secretion

systems or unmodified bacteria

showed little to no improvement. The

difference lies in stability and delivery

range: T0SS enables proteins to survive

longer and reach farther.

Beyond animal models, the system

showed promise in preliminary human

studies. Uricase-loaded OMVs were

found to reduce uric acid levels by over

forty percent in serum samples from

hyperuricemia patients within thirty

minutes, with no effect on glucose levels.

Likewise, lactate-loaded OMVs lowered

lactate in lung cancer serum samples

without altering unrelated biomarkers,

indicating specificity. These findings

underscore the clinical potential

of T0SS as a programmable

therapeutic platform that could

be adapted to carry different

drugs for different diseases.

If the system scales successfully,

it could transform the treatment

landscape for several chronic and

metabolic disorders. “Compared to other

kinds of drug delivery systems, bacteria

can be engineered to sense and respond

to signals from the microenvironment,”

Yang said.

We accidentally

discovered that the

altered membrane

vesicles of the bacteria

could enter circulation.

Diabetes management, long dominated

by insulin injections, might one day rely

on OMV-encapsulated insulin taken

as a capsule. Autoimmune diseases

that currently depend on injectable

monoclonal antibodies could become

more manageable with oral therapies.

Enzyme replacement therapies for rare

genetic disorders—often burdened by

high cost and invasive delivery—might be

made more accessible through bacterial

vesicle delivery. The implications are

enormous, both for global health and for

pharmaceutical design.

Still, hurdles remain. One concern

is batch-to-batch variability in OMV

composition. Yang acknowledges these

limitations; the team is now working

to improve gut barrier penetration and

circulation time. While the engineered

bacteria produce vesicles with high

encapsulation efficiency, OMVs are

biologically heterogeneous by nature.

Standardizing doses, ensuring

consistent bioavailability, and addressing

potential immune responses to repeated

exposure are challenges that will need to

be addressed before clinical translation.

The team is also working on optimizing

vesicle purification and scaling

production for industrial use.

The foundational insight—

using the microbiome as a drug

delivery engine—leans into the

body’s symbiotic relationship

with bacteria rather than relying

on synthetic materials. By turning

engineered probiotics into therapeutic

factories, the researchers have opened

a new avenue for oral biologics.

Their work suggests that future pills

may be living systems that collaborate

with our bodies in real time. ■


FEATURE

Biochemistry

FOLDING FORTUNE

DNA ORIGAMI SPRINGS INTO ACTION FOR

BIOMARKER DETECTION

BY LYNN DAI

ART BY AASTHA PAUDEL

The geometric reasoning skills used

to construct Lego structures—a

grocery store, a single-family home,

or even the Louvre—rarely apply in the

realm of biosensors and genomics, where

there is a stronger focus on mechanisms

of membrane systems and pharmaceutical

pathways. But for a team of Caltech

researchers behind a recently published

paper in the Proceedings of the National

Academy of Sciences, the intersection of

these two seemingly disparate disciplines

yielded a new molecule revolutionizing the

quantification of the relative concentrations

and activities of nucleic acids and proteins:

the lily pad sensor. This reagentless

biosensor capable of detecting biomarkers

continuously is built from DNA origami,

a material synthesis technique that folds

DNA into precise, nanoscale shapes. It is

like a molecular spy: adaptable, relentless,

and poised to transform medicine.

For first co-author Matteo Guareschi,

a PhD candidate at Caltech’s Rothemund

Lab, DNA origami symbolized the optimal

combination of the best parts of biological

and physical engineering. Coming from

an electrical engineering background

Biosensors made from DNA translate biological signals into electrical readouts on microchips like

these, which are a part of many modern computing devices.

IMAGE COURTESY OF JIAHAO LI

that did not provide specific training in

biochemistry or biophysics, Guareschi

stumbled on the field nearly by accident.

“I realized many things you can do

with DNA, you can also do in the silicon

electron world,” he said. “I got really

interested in biological sensing with the

idea of taking a molecule like DNA, which

we usually think about as a molecule of

life, and re-engineering it for completely

different purposes such as treating it as

a material or as a computation device.”

In bridging his engineering background

with the molecular intricacies of biology,

Guareschi embodies the very fusion

that DNA origami represents—where

structural imagination meets biochemical

precision, enabling a new era of biosensing.

So, what exactly is DNA origami? Picture

a microscopic Lego: DNA strands folded

and assembled together into customdesigned

structures, all at a scale so small

it boggles the mind. “What is really unique

is the very sort of fine-grain resolution

that we have on a DNA origami molecule,”

Guareschi said. “We can end up deciding

or programming things at the subnanometer

level.” This level of precision is

typically beyond reach for the silicon chip,

an advantage that makes the DNA origami

technique so special.

The device itself, dubbed the “lily

pad sensor,” is a flat, disk-shaped DNA

origami tethered to a gold electrode by a

long, flexible DNA leash. This biosensor

relies on the DNA origami structure to

detect the presence of an analyte through

a carefully designed interplay of binding

and signaling mechanisms. In its resting

state, the sensor floats far from the surface,

quiet and unassuming. But when a target

molecule—a biomarker like DNA, RNA,

or a protein—shows up, it binds to the

origami and causes structural changes that

bring the origami closer to the electrode,

producing a measurable electrical current.

This motion brings dozens of tiny reporter

molecules called methylene blue (MB)


Biochemistry

FEATURE

near enough to the surface to generate an

electrical signal. The system is akin to a

drawbridge lowering to let the signal cross.

The origami is anchored to the surface

by a long DNA linker, which serves a

dual purpose. First, the linker acts as a

tether, preventing the origami from being

washed away during experimental steps

such as adding or removing solutions

from the chip. Second, it maintains a

sufficient distance between the origami

and the surface in the absence of the

analyte, ensuring a low baseline “off”

signal. This design balances the need for

stability with the requirement for a clear

distinction between the “on” and “off”

states of the sensor.

“The idea behind the sensor was to

maximize the contrast between the off and

on state,” Guareschi said. “Keep it very far

from the surface in the off state—very low

signal; bring it very close to the surface in

the on state—very high signal.”

Utilizing the design combining the lily

pad DNA origami with the DNA anchored

to gold electrodes, the team achieved a

stunning one thousand percent boost in

signal—outmatching more traditional

methods like electrochemical DNA and

aptamer-based sensors that typically yield

only two hundred to four hundred percent

signal gains.

Traditional tests like the enzyme-linked

immunosorbent assay or polymerase chain

reactionare the lab-coat-clad tortoises of

the biosensing world: slow, expensive, and

reliant on skilled hands to add chemicals

step-by-step. This new sensor, though, is

a hare—reagent-less, meaning it needs no

extra ingredients to work. “Your blood or

any other biological fluid could flow in

our sensor, and over time, it keeps getting

measured without an external operator,”

Guareschi said. It’s a device that could

one day sit inside a patient, continuously

tracking biomarkers like a glucose monitor

does for diabetics.

But the device’s real superpower is

its versatility. Unlike older sensors that

need a bespoke redesign for every new

molecule they detect, this one’s modular.

Swap out a few DNA pieces, and it’s ready

for a new target. “The other big thing for

us was that it can be adapted to a large

range of analytes,” Guareschi said. The

team proved this concept by testing

it on everything from nucleic acids to

proteins like streptavidin (a protein

isolated from the bacteria widely used

in biotechnology) and platelet-derived

growth factor-BB, a biomarker tied to

cancer and tissue repair.

Building this molecular marvel wasn’t

all smooth sailing. One headache was the

MB reporters. The team wanted as many as

possible—up to two hundred per origami—

for a stronger signal. However, too many

MBs caused the origami to clump together

like overzealous party guests. “We found

that only once we went down to seventy

and took a lot of other precautions […]

we could see good origami formation,”

Guareschi said.

Unlike Guareschi’s initial expectations,

the team observed that the origami didn’t

lie flat over the single-stranded DNA,

but rather curled up at the edges. This

deformed mechanism was caused by MBladen

strands flapping around in Brownian

motion—random, jiggling movement of

tiny particles suspended in fluid—which

bent the structure into a U-shape.

“It’s that point where you understand

that the cartoon sketch you have of

something is not quite the reality of the

system,” Guareschi said. “Since this is a

modular sensor, we knew we needed to

adapt it to different analytes, but it’s not

‘quite snap your fingers and that’s done’.

We need to think about the geometry of

these techniques.”

To make the origami adaptable

to analytes of different sizes, the

team tweaked the “curtain”

of DNA strands holding the

MBs—a method akin to

adjusting a shower curtain

rod to fit the tub. For bigger

molecules, a longer curtain

was key to ensuring the MBs

could still reach the electrode.

Looking ahead, Guareschi

said the goal is to turn the

lily pad DNA origami into

a self-contained system

that can measure nucleic

acids and protein levels

in a lab setting without

needing dedicated

personnel to run it.

Further experiments

will continue to

optimize the biocompatibility of DNA with

other biomolecular materials such as plasma

and components of cells’ plasma membranes.

“The optimization of the [DNA

origami system] is one of the things I’m

most proud about in the paper because I

really enjoy the insight that comes from

trying to understand what is happening

at the molecular level,” Guareschi said.

“We only get the readout of the issue,

and we don’t know which reason we can

attribute it to. There’s all sorts of things

that are happening that we don’t see. So

being able to play with these geometric

parameters was really interesting to

understand what is happening on a more

biomolecular level.” ■



Profile

SHORT

MOLLY HILL

FEATHERS AND FIELD NOTES

YC ’25 BY MICHELLE SO

During the pandemic, Molly Hill (YC ’25) spent much of

her time thinking about birds. Growing up in Pasadena,

a suburb northeast of downtown Los Angeles, Hill didn’t

have easy access to abundant natural spaces. “When I visited

family in Michigan, I really loved how much nature there was,”

Hill recalled. “In Pasadena, in the city, there wasn’t as much

nature as I wanted.”

Still, Pasadena—and the Greater Los Angeles Area—is home to

a surprising number of nonnative species of birds, often descended

from escaped pets or introduced populations. During the COVID-19

pandemic, Hill began observing Indian peafowl, or peacocks, as

part of an independent research project with the American Birding

Association. What began as curiosity soon turned into a passion.

Hill joined the Moore Lab of Zoology at Occidental College, where

she helped demonstrate that one subspecies of the azure-hooded

jay, a vibrant Central American bird, should be recognized as a

distinct species.

Now a senior at Yale, Hill has already made an impressive mark in

ornithology. She is a 2024 Barry Goldwater Scholar, a selective award

given to undergraduates pursuing research careers in the sciences,

engineering, or mathematics. At Yale, she joined the lab of professor

Richard Prum, where she investigated the shimmering iridescence of

birds by examining hundreds of museum specimens at the Peabody

Museum of Natural History and the American Museum of Natural

History in New York.

But Hill was drawn to another mystery in the bird world: why do

some species take years to reach full adult plumage? Most songbirds

mature in just one year, but others—especially colonial seabirds—

don’t. To investigate, Hill spent time at the Bowdoin Scientific Station

on Kent Island in New Brunswick, Canada. Her research team

placed plastic models of gulls at different maturity stages—young

immature, adult immature, and breeding adult—near a nesting

colony to observe how adult gulls reacted.

Her preliminary results showed that gulls were more aggressive

toward adult-resembling models than younger-looking ones.

Hill’s findings suggest that delayed plumage maturation may offer

a survival advantage. “They

don’t breed, but they are able to

learn how to be a colonial bird

without getting beat up,” Hill

said. This pattern is also seen in

other colonial seabirds—such as

albatrosses, gannets, and loons—

which return to communal

nesting sites before reaching

breeding age, allowing them to

develop social and colonial skills.

At Yale, Hill is double majoring

in Ecology and Evolutionary

IMAGE COURTESY OF MOLLY HILL

IMAGE COURTESY OF MOLLY HILL

Biology (EEB) and the Humanities and has found her place in

both scientific and creative communities. She joined the Yale EEB

Undergraduate Group and helped revive the Yale Birding Student

Association in 2024, serving as an officer. She also served as Editorin-Chief

of The Environmentalist, a magazine under the Yale Student

Environmental Coalition that features poetry, essays, and stories

focused on environmental advocacy. “It feels important to not just

do research about birds but share that research with other people

and, overall, raise awareness for bird conservation,” Hill said.

For her EEB senior thesis, Hill returned home to study Los

Angeles’ wild parrot populations—specifically red-crowned and

lilac-crowned amazons, rumored to have originated after a pet

store fire. Fascinated by their vocalizations, Hill has been studying

how the urban environment affects communication of these highly

intelligent social animals. “I actually wrote an essay about the LA

parrots for The Environmentalist,” she said. “Unlike invasive species,

the parrots don’t seem to be competing with native species or hurting

the native ecosystem. They’ve established a new niche for themselves

utilizing other non-native food sources like ornamental fruit trees. ”

Meanwhile, her humanities thesis explores animal behavior through

a series of essays—blending her own fieldwork with reflections on

the broader world of zoological research.

Although she doesn’t yet know where she’ll be in the next five years,

Hill is certain birds will still be a constant in her life. She’s especially

drawn to questions about animal communication, cognition, and

behavior, and envisions herself doing fieldwork, teaching, or working

with a conservation nonprofit or the US Fish and Wildlife Service.

Her next endeavor takes her to the forests of New Zealand, where

she will be studying the kea, a large parrot native to the island

country. “They’re really cool and intelligent,” Hill said. Continuing

her work on gull plumage maturation, Hill is eager to see how far

she can soar. ■


SHORT

Profile


JOSIE JAYWORTH

A

fluke in a chemistry experiment seven years ago led

Josie Jayworth (GSAS ’24) to discover a new chemical

anchoring group—one that would later become the

foundation of her PhD thesis. Her work focused on the surface

attachment of small molecules to metal oxides, exploring their

potential application in solar-powered energy storage. Could

this unexpected quirk pave the way for sun-charged fuel?

The answer, as it so often goes in research, turned out to be

inconclusive. The big questions that Jayworth posed weren’t

ones that could be answered overnight or even over a decade.

A chemist who often says she thinks like an engineer, Jayworth

felt an urgency to act more directly on the climate crisis.

“I really enjoyed the research I was doing, but it felt a few too

many steps away from application for climate problems that I

felt,” Jayworth said.

In the final year of her chemistry PhD, Jayworth began

seeking out opportunities that felt closer to real-world impact.

She found that opportunity at the Yale Center for Business

and the Environment (CBEY), where she was introduced to

her current role as an Environmental Innovation Fellow,

jointly supported by CBEY and the Tsai Center for Innovative

Thinking at Yale.

Now, Jayworth mentors students as they develop

environmental innovation projects. These range from

3D-printed sustainable homes to oyster shells repurposed as

water filtrates, and even a partnership with the David Geffen

School of Drama at Yale to recycle and reuse set materials.

For Jayworth, the shift from conducting research to helping

others explore solutions was a natural evolution—one rooted

in her desire for tangible progress.

Jayworth is no

stranger to juggling

multiple interests. As

an undergraduate, she

was both a chemist

and a varsity longdistance

runner. Today,

she still runs regularly,

is married to a crosscountry

coach, and

serves as president of

the New Haven Road

Runners. Though many

view marathons as

solitary feats, she sees

them as communal.

“I’m not a remarkably

mentally tough person,”

Jayworth said. “I think

IMAGE COURTESY OF JOSIE JAYWORTH

ENVIRONMENTAL MENTOR AND COACH

GSAS ’24 BY MAKENA SENZON

IMAGE COURTESY OF JOSIE JAYWORTH

I’ve just been really lucky to be on a team here where my

friends are all very similar in speed to me, and so we just

get to run a lot together and chat. For me, it’s really such a

social thing.”

Jayworth sees the same pattern in research. Though each

scientist may work on their own project, collaboration is often

what drives progress. She admits that in her current role, she

sometimes misses the daily camaraderie of lab work or group

runs. But she finds purpose in helping students chart their

own paths toward climate solutions—and in supporting them

through the early stages of uncertainty and ambition.

She believes change often begins with small individual actions

that ripple outward. “As a vegetarian, I understand [that] myself

alone, not eating meat doesn’t really matter,” Jayworth said. She

noted that the growing number of people adopting plant-based

diets has led to having more accessible options.

These small decisions—what we eat, how we travel, how

we support sustainability—can snowball into broader shifts.

At Yale, Jayworth helps students recognize not just their

responsibility but their capacity to create change.

“It is the support staff’s job to keep students going and

also temper it a little bit so it doesn’t burn out immediately.

Students come with all of their ideas and things that they want

to accomplish,” Jayworth said. “I think that was really fun

because it’s a cool experience to get to meet that excitement

and work with them on climate solutions.” ■


AIR-BORNE

THE HIDDEN HISTORY OF THE LIFE WE BREATHE

BY ANNIE CUI

SCIENCE

IN

IMAGE COURTESY OF MISTINA HANSCOM VIA PENGUIN RANDOM HOUSE

Carl Zimmer (YC ’87) begins Air-Borne as an audience member at the

Skagit Valley Chorale’s May 2023 performance, imagining the drift

of microscopic droplets—suspended particles carrying viruses and

bacteria, exhaled and inhaled by all in the chorus. He then uses a carbon

dioxide monitor to grasp this invisible exchange, tracking rising carbon

dioxide concentrations in the air around him as a proxy for microscopic

droplets.

While Air-Borne explores the weightless world of airborne microbes, what

makes it exceptional is Zimmer’s ability, like a carbon dioxide monitor, to

connect the invisible science with the real people who discover and live it.

In 2020, a Skagit Valley Chorale rehearsal became one of the first

confirmed COVID-19 superspreader events in the US. At the time,

scientists believed respiratory diseases spread mainly through droplets—

heavy particles expelled when people cough or sneeze—which were thought

to fall to the ground quickly and transmit infection only during closerange

interactions. This understanding was reflected in official guidance

from the World Health Organization, which recommended maintaining a

minimum distance of one meter from others, especially those who were

coughing, sneezing, or showing signs of illness

Zimmer follows a small group of scientists who worked to overturn this

assumption, showing that COVID-19 could be spread not just through

droplets but through the air itself, carried on tiny aerosol particles. In the

case of the Skagit Valley Chorale, it could even be “spread on a song.”

The scientific battle to prove airborne transmission began long before

COVID-19. Zimmer traces this scientific journey, highlighting pioneers like

Louis Pasteur, Joseph Lister, and William and Mildred Wells, whose research

helped piece together the invisible transmission pathways of infectious

disease. He takes readers through the hidden microbial ecosystems that

surround us, from microbial clouds in subway systems to bacteria-laden

gusts of wind drifting through the skies, and even to battlefields, where the

US and the Soviet Union experimented with the airborne spread of anthrax

and smallpox as tools of biological warfare.

Zimmer’s reporting is both rigorous and poetic. He explains how airborne

pathogens move, adapt, and impact our health, while also critiquing

conventional public health messaging. He weaves science into story, showing

how a better understanding of airborne transmission could have prevented

the “failure of imagination” that delayed early pandemic responses.

Air-Borne reveals the wonder of the unseen world—the “gaseous ocean

in which we all live, which infiltrates our bodies, which our own bodies

transform and then return to the great transparent sea, that contains exhaled

viruses that can then be inhaled.” His exploration of airborne life lingers in

the imagination long after the final page, much like the unseen particles

that surround us—ever-present, shaping every breath we take. ■


THE DEADLY RISE OF ANTI-SCIENCE

A SCIENTIST’S WARNING

BY ESTELLA WITTSTRUCK

In this technological age, media platforms are overflowing with news to the point that

it can be difficult to discern what is or isn’t true. One particular American scientist is

familiar with the danger of rampant misinformation: Peter Hotez (YC ’80), a physicianscientist

specializing in vaccine development and tropical diseases. At the forefront of

vaccine advocacy, Hotez is both a Nobel Peace Prize nominee and recent recipient of the

Winslow Medal from the Yale School of Public Health. He is also the author of The Deadly

Rise of Anti-Science: A Scientist’s Warning, a book that examines the rise of anti-science

sentiments from the anti-vaccine movement and future implications for science itself.

The Deadly Rise of Anti-Science explores how the anti-vaccine movement accelerated

in the US around the misconception that vaccines cause autism in children. This false

belief originated from a now-retracted 1998 paper published in The Lancet, which

alleged that the measles, mumps, and rubella (MMR) vaccine induced autism in twelve

children. Although numerous studies have since proven that there is no link between

the MMR vaccine and autism, the anti-vaccine movement has continued to target other

vaccines and immunization practices. In Hotez’s book Vaccines Did Not Cause Rachel’s

Autism, written about his daughter , Hotez debunks anti-vaccine claims by presenting

scientific literature on the genetic factors involved in early fetal brain development that

contribute to autism.

The anti-vaccine movement has evolved into a political campaign centered around

the idea of “health freedom,” with the debunked link between vaccines and autism

resurfacing in rhetoric from US Department of Health and Human Services Secretary

Robert F. Kennedy Jr.. Right-wing platforms such as the Republican Tea Party in

Texas, the House Freedom Caucus, and Fox News have reinforced this movement.

On an episode of the Health & Veritas podcast, Hotez commented on the fact that

“freedom” in the context of health has become a rallying cry for anti-vaccine believers.

His outspokenness on the issue has made him a target, drawing threats from a selfproclaimed

“army of patriots,” along with persistent stalking and harassment both

online and in-person. As such, Hotez argues that common labels like “misinformation”

or “infodemic” are insufficient, suggesting chaos rather than coordination. “The point

of the book is to say [that anti-vaccine propaganda is] organized, it's well-financed, and

THE

SPOTLIGHT

it's politically motivated,” he said.

Hotez fears that the recent anti-COVID-19-vaccine movement is only the prelude

to further resistance against science that could extend from childhood immunizations

to international research. He links this sentiment to the growing distrust of scientists,

which he attributes to perceptions of elitism. “I think for me, it’s been one of the hardest

books I’ve ever had to write,” Hotez said. “It’s the hardest thing to talk about because it

means you have to talk about partisan politics.”

“The United States of America is built on a nation of science and technology,” Hotez

affirmed multiple times in the podcast. Indeed, the country would not be where it is

today without innovations like the lightbulb, railroads, or computers. Even as science

and politics collide, it remains an American right to hold one’s own opinion. Consider

the impact of the anti-vaccine movement—or the EPA’s plans to lay off thousands of

scientists—and ask yourself: what will anti-science do for you? ■


IMAGE COURTESY OF PETER HOTEZ’S OFFICIAL WEBSITE


COUNTERPOINT

THE CANCER GAP

Why Ignoring Sex Differences in

Treatment May Have Cost Lives

Research has identified that sex differences play an

important role in non-reproductive cancers—

not only in how cancers develop, but also in how

patients respond to treatment. Despite mounting evidence,

clinical oncology often continues to follow a “one-sizefits-all”

model, overlooking sex-based distinctions in

genetic targets and drug efficacy. This oversight can

lead to suboptimal treatment strategies, overlooked

drug interactions, and long-term disparities in cancer

outcomes for both men and women. In response to this

gap, Xinyi Shen, a PhD candidate in the Johnson Lab led

by Associate Professor of Epidemiology Caroline Johnson,

collaborated with researchers to develop OncoSexome—a

multidimensional knowledge base that catalogs sex-based

differences in cancer.

The need for such a resource is pressing. A study by the

American Cancer Society found a high incidence of cancer

diagnosis among patients unter fifty years old in the US;

in 2021, women in this age group were eighty-two percent

more likely to be diagnosed than men. Furthermore, a

2024 study published in Nature from the National Cancer

Institute analyzed 288 clinical trials and found that in

122 of them, female patients had better survival rates and

treatment outcomes than their male counterparts.

“Through OncoSexome, we intend to show how

environmental factors, genetic information, and drug

response differ with sex to give more insight into cancer

causes and therapeutics, improving outcomes for patients,”

Johnson said.

To build OncoSexome, Shen combed through the

scientific literature and multiple databases—including the

World Health Organization and The Cancer Genome Atlas

Program—to compile a large dataset of sex-based oncology

findings. She partnered with Feng Zhu, a professor of

pharmaceutical sciences at Zhejiang University, to organize

and publish the database.

“There were pockets of information, but it was all over

the literature,” Johnson said. “There were also databases

with missing aspects to how cancer is multifaceted with

various causes.”

To account for the complexity of cancer, OncoSexome

contains data describing sex-based differences in cancer

BY HIEN TRAN

IMAGE COURTESY OF STOCKSNAP

across four distinct domains: drug response, biomarkers,

risk factors, and microbial landscape.

The drug response domain includes information for

2,051 anti-cancer drugs. OncoSexome outlines sexbased

differences in drug efficacy, adverse reactions,

pharmacokinetics, and hormonal interactions—

highlighting how treatment effects can vary between men

and women. The biomarkers domain contains data on

12,551 sex-based biomarkers related to immune responses,

genetic variation, and hormonal regulation in the context

of various cancers. These biomarkers play a critical

role in diagnosis and monitoring, as well as informing

personalized treatment plans. The risk factor domain

focuses on environmental carcinogens and lifestyle-related

risks, cataloging how these variables interact differently with

male and female biology to influence cancer development.

Finally, the microbial landscape domain includes data on

1,386 microbes, detailing their sex-specific abundances and

statistical correlations with cancer incidence. Not only can

this data aid in the prediction of cancer development, but

it can also contribute to cancer prevention when analysed

with other attributes such as biomarkers and risk factors.

In addition to its breadth, OncoSexome is designed to be

interactive and user-friendly. The homepage introduces

the platform’s four core domains and allows for intuitive

navigation. A prominent search function enables users

to browse by domain or specific cancer type, allowing

researchers, clinicians, and public health professionals to

quickly find sex-specific data relevant to treatment planning

and study design. A dedicated “Manual” section provides

guidance on how to navigate the platform efficiently.

Since its launch, OncoSexome has attracted global

attention. The platform has been accessed over four

hundred thousand times, with an average of more than

twenty thousand visits per week. Users span North

America, South America, Asia, Africa, and Oceania,

underscoring the growing demand for sex-specific cancer

research tools.

Ultimately, OncoSexome offers a powerful new avenue

for clinicians and researchers to integrate sex-based

biological differences into the understanding, prevention,

and treatment of cancer. ■


ON

SCIENCE

TRIAL

AN ERASURE OF IDENTITY

THE DANGERS OF TRUMP’S “TWO SEXES” POLICY

BY EDIS MESIC

ART BY ALONDRA MORENO SANTANA

On January 20, 2025, President Donald Trump issued

Executive Order 14168, titled “Defending Women from

Gender Ideology Extremism and Restoring Biological

Truth to the Federal Government.” Commonly known as the

“Two Sexes” executive order, the directive outlines a series

of policies that claim to defend women’s rights by erasing the

concept of gender identity. The order’s opening policy states:

“Accordingly, my Administration will defend women’s rights

and protect freedom of conscience by using clear and accurate

language and policies that recognize women are biologically

female, and men are biologically male.”

Beyond asserting a binary understanding of biological sex, the

order ends the use of gender identity as a form of identification

on passports, visas, and Global Entry cards; proposes freezing

grant funding for programs supportive of “gender ideology”;

and aims to rescind all Biden-era executive orders that affirm

gender identity. While the language of the order promises a

return to more “scientific” terminology, what truth—if any—

lies within this promise, and what greater consequences might

it have for both science and healthcare?

Meredithe McNamara, a practicing pediatrician and assistant

professor of pediatrics at Yale School of Medicine, makes

clear that any binary definition of biological sex or gender

identity erases the complexity of the human experience.

Biological sex encompasses a group of traits—chromosomes,

hormones, anatomy—that don’t always align neatly into “male”

or “female” categories. Gender identity, meanwhile, refers

to a person’s internal sense of belonging in a gendered social

group. While distinct, both biological sex and gender identity

are multidimensional aspects of identity with firm biological

underpinnings.

McNamara likens the reality of sex and gender identity to

an impressionistic painting with a variety of colors and brush

strokes—a collection of nuanced patterns that appear different

when viewed from far away or at a certain angle.

“And then imagine if you create an image that’s just black and

white and it’s a couple concrete shapes on a page,” McNamara


said. “That’s the difference between reality and the way this

political determination of sex and gender plays out.”

In addition to scientific inaccuracies, the order also threatens

access to gender-affirming care. According to the Columbia

University Department of Psychiatry, gender-affirming

medical and psychosocial care has been shown to improve

the mental health and well-being of transgender and gendernonconforming

youth. Trump’s order seeks to roll back this

care, which would endanger the well-being of individuals who

benefit from these treatments.

Another critical concern is the erasure of intersex individuals.

By mandating that “male” and “female” are the only acceptable

forms of self-identification, the executive order denies the

existence of people with variations in sex characteristics. As

McNamara emphasizes, both intersex and transgender people

deserve equitable healthcare—but the “Two Sexes” order

constructs new barriers through a rigid, anti-science framework.

She notes that while intersex individuals comprise a small

portion of the population, their needs are often misunderstood

by politicians lacking clinical experience.

To McNamara, this executive order is symptomatic of a larger,

alarming trend: the growing encroachment of policymakers

into the practice of medicine. She argues that policies affecting

people’s health should be treated as healthcare interventions—

ones that are being imposed without consent or input from

medical professionals and patients. In other words, the “Two

Sexes” executive order’s endorsement of a binary system of

identity has the power not only to influence healthcare but

also to dictate it. The administration’s policymakers are not

healthcare practitioners and lack the knowledge or qualifications

to prescribe and restrict medical treatments.

The result is a profound intrusion into science and medicine—

one that McNamara fears could signal what’s to come. “If the

federal government is going to distort reality through policy

and deeply interfere with scientific truth through borders and

edicts, then basically anything else that we hold dear is on the

table and is at risk,” McNamara said. ■


Interested in getting involved with

Yale Scientific

for writing, production, web,

business or outreach?

Learn more at

yalescientific.org/get-involved

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