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Yale Scientific


MAY 2022

VOL. 95 NO. 2 • $6.99
















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How to Make a Hot Jupiter

Brianna Fernandez

Jupiter-like planets in extremely close orbits their stars have puzzled astronomers for decades. Yale

researchers think their characteristic orbits could be caused by powerful and random “kicks” from

other planets and stars, and this answer may hold the key to planetary system formation.

12 Tortoises Then & Now

Sophia Burick

For decades, scientists believed there to be only a single species of giant tortoise on San Cristóbal

in the Galapagos Islands. New research from Dr. Adalgisa Caccone’s research team has identified a

reviously unknown second lineage, prompting newideas about giant tortoise colonization of the

Galapagos Islands.

16 Supercharged Killer Cells: Advances in

CAR-T Cell Therapy

Shudipto Wahed

Yale scientists recently developed a platform for identifying targets for genetic engineering of

CAR-T cells in order to “supercharge” their antitumor efficacy. Their findings may help significantly

improve the therapeutic potential of CAR-T.

19 Putting Order in Disorder

Eunsoo Hyun

Deep-tissue imaging, ultrasound surgery, and optogenetically controlled neurons - researchers at

Yale University explore the possibilities of delivering energy into opaque systems.

22 Scanning DNA Barcodes

Hannah Han

From liver cells to neurons, every cell in your body contains the same genetic code. Yale researchers

recently developed a revolutionary way to differentiate cell types by profiling epigenetic mechanisms

based on histone modifications.


May 2022 Yale Scientific Magazine 3







By Eva Syth

Can you create a family tree for all of humanity, dating

as far back as 50,000 generations? A study from

researchers at the University of Oxford says yes, at

least in part. The researchers developed a new method using

data from both contemporary and ancient DNA samples to

construct whole-genome genealogies, providing insights into

human history and evolution.

The researchers combined genetic data from several different

datasets to carry out this study. Historically, this process has

been challenging due to technical errors in the DNA sequencing

process or the use of different DNA sequencing techniques

altogether. The variation stemming from these issues makes it

hard to accurately combine and compare this genetic data because

researchers cannot tell if the differences in sequences are due to

systematic inconsistencies in DNA processing or variation in the

genetic sequences of the samples themselves. To address this issue,

the researchers used “tree sequences,” graphs that represent the

links between regions of DNA in contemporary samples and the

ancestor where the region first appeared. Consider two samples

of DNA: one contemporary and one old. If both samples shared

a significantly similar sequence of nucleotides, they would be

considered “connected” in the graph.

With this challenge solved, the researchers combined eight

datasets and used an algorithm to yield a network of twentyseven

million ancestors. The researchers found that the network

reflected key moments in human history, such as the first human

migrations. Who knows — with this technology, you might be

able to meet your great-great-great…grandparents. ■

By Nathan Wu

What do ant colonies and the Internet have in

common? Both are complex networks that manage

large amounts of traffic. In ant colonies, this traffic

comes from ants scurrying about, while on the Internet, it

comes from packets of data sent between users. In these systems,

computing is “distributed”: system components only know

what is happening locally. Rather than constantly monitoring

everything and making micro-adjustments to keep the system

stable, components respond to specific events, obeying general

algorithms that collectively keep the whole system running.

Scientists at Cold Spring Harbor Laboratory recently found

that ant colonies use additive-increase/multiplicative-decrease

algorithms to forage for food. These are the same algorithms

used by the Internet to manage data traffic. With the Internet,

the system responds by additively increasing the transmission

rate if data is successfully sent and received. If sent data is not

received, the transmission rate is decreased multiplicatively.

Similarly, if an ant foraging for food successfully returns, the

colony will additively increase the number of ants sent, while

if ants fail to return, the number of ants sent out on the next

trip is multiplicatively decreased.

Ant colonies are robust and avoid complete collapse despite

their unpredictable outside environment. Many engineered

systems, however, fail completely at the slightest tampering.

Further study of distributed biological systems may reveal

what makes them so hardy. Perhaps Internet engineers can

learn something from ant colonies—the two are more alike

than they may initially seem. ■

4 Yale Scientific Magazine May 2022 www.yalescientific.org

The Editor-in-Chief Speaks



As technology continues to advance, information and communication

have never been more widespread and accessible, whether that be

through news outlets, social media, or links sent from family, friends,

and colleagues. The most challenging aspect of this “information revolution” is

parsing through billions of ideas and critically thinking about them—viewing

accepted beliefs with a grain of salt instead of blindly accepting their validity.

Science has always invited questions, which in turn lead to improvements

when it comes to pre-existing beliefs and technologies—entertaining ideas

and updating theories according to the latest evidence. In this issue of the Yale

Scientific, we see this trend manifest itself in all fields of science. In oncology,

researchers use a novel CRISPR Cas-9 technique to create a more flexible

platform for anti-cancer treatments (pg. 16). In biomedical engineering, a new

technique called spatial-CUT&Tag allows for more comprehensive epigenetic

mapping over previous methods (pg. 22). In ecology, researchers uncover a

previously unknown lineage of the Galapagos giant tortoise (pg. 12). In physics,

a new technique in energy delivery pushes the boundaries of what was previously

thought possible in tissue imaging and other medical applications.

Our cover article explores planetary orbital patterns that contradict previously

assumed knowledge. Scientists were surprised to find Jupiter-like planets in

extremely close orbits to their stars since they had previously believed that gas

giants orbited far from their stars. Uncovering the mechanics behind these

systems may produce insights into planetary system formation in general (pg. 14).

From science, we can apply these techniques to all aspects of life, to filter

through the information we receive, and to constantly revise our understanding

of the world, whether that be academic, political, or personal. And we seek to

have a more open and iterative approach regarding information and ideas to

drive compassion in a world that often lacks understanding.

As always, thank you to the mentors, staff members, and masthead who make

Yale Scientific possible. Thank you to Yale departments, the Yale Science and

Engineering Association, and the Yale Alumni Association for their support

and for allowing us to communicate within and beyond Yale’s campus. And of

course, thank you to our readers for joining us in exploring science, both in

terms of the discoveries and principles science teaches us.

About the Art

Jenny Tan, Editor-in-Chief

Have you ever wondered how

to make a hot Jupiter? Brianna

Fernandez dives deep into the

science behind how these gaseous

giants form, how we observe them,

and what we can learn about their

orbits. This cover has the artist’s

depiction of a hot Jupiter in space.

Anasthasia Shilov, Cover Artist


May 2022 VOL. 95 NO. 2



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

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

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Psychology / Ecology & Evolutionary Biology, Archaeology














Picture this. You have no clue how to solve an expertlevel

Sudoku puzzle and are given two options: you can

either ask a group of five people to work together on

it or ask five individuals to solve the puzzle independently.

Which do you choose?

At Yale, Professor of Psychology and Linguistics Frank Keil

and PhD student Emory Richardson presented people with

scenarios just like this, contrasting group discussion with

crowdsourcing—getting information from a large group

of people. “You can think of this as a choice between two

network structures: in the group, everyone can influence

everyone else. In the crowd, you get independent answers,

which means that you avoid groupthink, but you also miss

out on the benefits of sharing information,” Richardson said.

Richardson and Keil showed kids and adults three types

of questions: questions they could answer conclusively

through explicit reasoning (e.g., solving a sudoku puzzle),

and two kinds of questions for which reasoning would

not be enough—popularity (e.g., what most people in

the world say their favorite fruit is) and hard perceptual

discrimination (e.g., determining whether an opaque

box contains thirty or forty marbles just by listening to a

recording of it being shaken). They found that even sixyear-olds

prefer reasoning in groups just as strongly as

adults. However, while they are more likely to crowdsource

to answer the “non-reasoning” questions, younger kids are

less sensitive to the risks of thinking as a group than adults.

“Intuitions about when to collaborate in groups and how

to structure our groups could be part of what makes our

species so successful,” said Richardson. ■

Society has evolved in many ways since the beginning of time,

and it will continue to do so in the decades to come. Given the

inherently social nature of the human species, social networks

are important in helping us understand this societal evolution.

A study co-led by Yale anthropologist Jessica Thompson in

collaboration with institutions across Africa and North America

studied the population structure of sub-Saharan African foragers.

Their research provided new evidence of major demographic

changes at the end of the Late Pleistocene epoch around 11,700

years ago and the beginning of the Holocene epoch, the current

epoch which began approximately 11,650 years ago.

The researchers obtained ancient DNA from six individuals

from East and South-central Africa. They discovered that

the ancestry of these individuals came from three source

populations: two of them were the expected Eastern and

South African lineages, but the third brought an unforeseen

revelation. In it, they identified a central African rainforest

hunter-gatherer lineage. This new piece of genetic evidence

supports the hypothesis that the end of the Pleistocene epoch

marked the onset of increased regionalization, indicating less

residential mobility and more settlement establishment.

This blend of archaeology and genetics is a rare find, with

researchers from Malawi to Canada collaborating on this

project. “It was a deliberate decision to do it this way,” Alex

Bertacchi, a graduate student part of the Yale research team

said. “Months of the discussion focused on how to put in true

effort to place genetics and archaeology on equal footing…

and I think it [was successful]”. Continuing to combine these

two fields of study could lead to even more discoveries about

how our world today came to be. ■

6 Yale Scientific Magazine May 2022 www.yalescientific.org

Molecular & Cellular Biology / Earth & Planetary Sciences

















Since the start of the acquired immunodeficiency syndrome

(AIDS) pandemic in the early 1980s, researchers have

been working to combat the devastating health problems

associated with the human immunodeficiency virus (HIV). One

obstacle standing in the way of curing AIDS is the presence of

HIV DNA in a transcriptionally inactive latent state, in which the

virus temporarily stops making copies of genetic material needed

for viral proliferation. In this state, HIV can evade immune cells.

Current antiretroviral therapy medications inhibit HIV replication

by blocking reactivated latent viruses. However, a small percentage

of cells harbor latent HIV-1 proviruses, a form of viral genetic

material incorporated into host cell DNA that escapes detection.

Jack Collora, a graduate student in the Yale Department of

Microbial Pathogenesis, is trying to understand how HIV-1,

the most common type of HIV, can survive in the presence of

antiretroviral drugs. His single-cell multiomics studies measure

levels of different molecules in individual cells and analyze them

to characterize cell types and functions.

Collora discovered that it could be possible to treat HIV-

1 by targeting a type of immune cell called cytotoxic CD4 + T

cells, which are infected by the virus, as well as factors that

cause clonal expansion, which is a process in which normal

cells accumulate disease-causing genetic changes. “We found a

subpopulation of CD4 + T cells that harbor HIV very effectively,”

Collora said. “They might be expressing certain proteins that

make them resistant to being killed by other CD4 + T cells and

have a genomic profile that allows it to proliferate more readily.”

Future research will aim to understand why CD4 + T cells

are so good at harboring HIV, enabling the development of

treatments that target these mechanisms. ■

When it comes to climate change, there has been a

persistent discrepancy between what computer models

predict and what history tells us. Though computer

models forecast a rise in temperature at the poles, these predictions

are nowhere as extreme as what previous fossil studies had

suggested: Earth’s poles may have been as warm as the tropics.

Daniel Gaskell, a micropaleontologist—an expert in a field

that studies microfossils—recently earned his PhD from

Yale in the Department of Earth and Planetary Sciences. He

emphasized the importance of ensuring that computer models

are accurate since their predictions are used prevalently.

Gaskell investigated the fossils of an amoeba-like single-celled

organism called foraminifera to assess temperature patterns over

the past ninety-five million years. Foraminifera shells form fossils

found on the seafloor. When foraminifera are alive, their shells

incorporate prevalent oxygen isotopes into their calcium carbonate.

Water temperature determines what oxygen isotopes, or different

forms of the oxygen element, are available for incorporation.

Using foraminifera shells from different time periods and

locations as measurements for historical global temperature,

Gaskell found that current computer models are more

accurate than previously believed. The foraminifera data

disagreed with past studies: temperatures at the poles did not

match temperatures at the equator when global temperatures

were hotter. “Our data are saying that the poles did get

warm… but didn’t get nearly as warm as these previous

reconstruction methods would predict,” Gaskell said.

Gaskell emphasized that while it is unlikely that the Arctic

will become a tropical destination, climate change is still an

important issue with many uncertainties. ■


May 2022 Yale Scientific Magazine 7






How fMRI Scans and

Transformative Modeling Can

Predict Attentional Ability



In a world where our attention is pulled every which way by

strategic advertisements and technicolor screens, our attention

may be our most valuable commodity. Our brains have limited

cognitive capacity, and it would be impossible to attend to every

visual or sensory stimulus we encounter in our daily lives. This

means our brains have developed an elaborate system to selectively

process the information most relevant to us at any given time. But

how do we even measure attention? To date, attentional functioning

is primarily measured through a flurry of surveys and hours-long

questionnaires—a costly and weary process. Given its fluctuations

and multi-faceted nature, an individual’s attentional functioning

cannot be boiled down to a single number, so researchers have

sought a quantifiable, standardized measure of attention.

The Visual Cognitive Neuroscience Lab, led by Dean Marvin

Chun, set out to answer this question precisely. Using a creative

combination of fMRI neuroimaging and connectome modeling,

Kwangsun Yoo, an associate research scientist at Yale, Monica

Rosenberg, an assistant professor of psychology at the University of

Chicago, and the rest of the team recently reported their functional

magnetic resonance imaging (fMRI)-based general measure of

attention in Nature Human Behaviour. To cover multiple aspects

of human attention, the team collected fMRI data from ninety

participants. The researchers measured volunteers’ brain activity

while they performed three separate attention-demanding tasks.

“Since we aimed to predict general attentional function, we had to

use multiple task-based fMRI data,” Yoo said.

Let’s back up a bit. Using data from an fMRI scan, researchers

can generate an individual’s whole-brain pattern of functional

connectivity or how certain signals in distributed brain regions

fluctuate over time. This is called their connectome—almost like a

brain fingerprint. Each person’s functional connectome is unique

and related to aspects of their abilities and behavior. Their ‘brain

fingerprint’ can then be fed into a connectome-based predictive

model (CPM) to predict your attentional ability. “It’s kind of like

listening to an orchestra, and all these instruments are going on at

the same time, and there’s a certain harmony and rhythm in the

way the brain areas become active and inactive at any given time,”

Chun said. “Our model does something as simple as capturing all of

that, and converting it into a matrix of numbers, where each cell is a

correlation between two brain areas.”

The team trained nine CPMs on this fMRI correlation data, all

of which demonstrated strong predictive powers of participants’

attentional ability across all three tasks. The team could even re-train

the CPMs on the mean of normalized performance scores across all

three tasks, a ‘common attention factor,’ and use the models to predict

overall attention ability rather than task-specific ability.

Now comes a seriously creative part of this paper. Task-based

connectomes collected while the participant actively engages in a task have

much more predictive power than rest-based connectomes. However,

rest scans collected while participants are simply lying still in the MRI

scanner by nature are much easier to collect across different research

studies and locations reliably. To this point, Yoo introduces connectometo-connectome

state transformation (C2C) modeling, a novel approach

that seeks to capture the best of both worlds. C2C modeling can

extrapolate from an individual’s rest connectome and accurately generate

their attention-task connectome without requiring the participant to

engage in a task at all! This model-generated attention-task connectome

was even found to improve subsequent behavioral predictions. The novel

approach increases the predictive value of rest scans and may free future

researchers from the burden of collecting multiple scans or ensuring

every task is perfectly standardized across participants.

Finally, the team combined all the above—the common attention

factor, C2C transformation modeling, and CPMs—in a general

attention model that can encapsulate an individual’s overall attention

functioning. Combining C2C and CPM allows researchers to estimate

multiple cognitive measures from a single rest scan. Though the

measure is far from complete, it certainly has the potential to be used

for other mental traits such as intelligence, memory, depression, or

anxiety. “Attention is only a test vehicle,” Chun said, pitching an example

of someone who goes to the doctor for a depressive episode: “Instead of

having these long wait times and hours-long interviews, can we just put

them in a brain scanner and pop out a computerized print-out of what

kind of depression they have, what will the best treatment be? How

powerful would that be? We’re far away from it, but that’s my dream.” ■

8 Yale Scientific Magazine May 2022 www.yalescientific.org

Molecular Biology






An Electrifying Discovery

for Healthcare Applications



The latest advancements in synthetic biology allow researchers

to engineer proteins with specific, desirable properties. These

engineered biomaterials appear in implants, tissue generation, and

drug delivery systems. However, most biomaterials are not electrically

conductive, and most proteins that have been shown to be conductive

are not well-characterized. Designing a protein-based biomaterial that

is electrically conductive would be a large step in creating bioelectronic

materials which can serve as an interface between organic materials, like

the human body, and electronic materials, like implants or prosthetics.

In a recent study published in Nature, researchers from Yale University

engineered a highly electrically conductive protein nanowire that can be

created and purified at scale from E. coli bacteria.

Daniel Shapiro YC’18, the first author of the paper, started this

journey in his senior year at Yale College while working in Associate

Professor of Molecular, Cellular & Developmental Biology Farren

Isaacs’ synthetic biology lab. As a physics major, however, he wanted

to bridge the two seemingly disparate fields of genetic engineering and

physics. “I was walking along West Campus and saw a poster for a talk

by Nikhil Malvankar, who was then a brand new professor, on electron

conductance in bacterial proteins. I thought, ‘This is quantum biology.

This is exactly what I want to do,’” Shapiro said. Shapiro reached out to

Malvankar, and the two worked with Isaacs to develop a collaborative

project focused on making proteins more conductive than usual, using

Shapiro’s experience with synthetic biology to make mutations with

non-standard amino acids (nsAAs).

The biomaterials Shapiro engineered in this research were E.coli pili,

which are short, hair-like projections on the surface of the bacteria. They

are a popular biomaterial to study because they can self-assemble into

a robust filamentous shape, they show excellent material properties for

a protein, and they can withstand a wide range of temperatures and

pH conditions that normally degrade proteins. However, they are not

electronically conductive. With this project, the researchers aimed to

impart electrical conductivity into E. coli using three strategies.

Their first approach was to induce electronic conductivity in E. coli

pili through amino acid mutations at the nanostructure level. The team

tested protein building blocks of phenylalanine, tyrosine, histidine, and

tryptophan. “This first part was [the hardest] because we had to figure


out how to make, purify, store, and measure the conductivity of the

protein,” Shapiro said. Nevertheless, they found that adding tryptophan

increased electrical conductivity by 80-fold.

The team then came across a paper which showed that E. coli pili

could be arranged into different geometric shapes, such as bundles,

lattices, and cubes. “Nikhil saw this, and he was like, ‘Okay, what if we

try that with our proteins—if we bundle E. coli pili, will that increase

conductivity?’” Shapiro said.

The team found exactly that result. They aligned the pili into long,

ordered bundles using a molecule called hexamethylenediamine

(HMD). HMD can align the pili since it is positively charged at both

ends while the pili is negatively charged, acting like a molecular

‘glue’ between the pili filaments. They found that assembling the pili

increased long-range conductivity by five-fold. “If I had to guess why

this happened, it’s because if the electrons flow down the outside of

the proteins, then having a bunch of channels close together makes

it easier to flow between filaments,” Shapiro said.

For the project’s final step, the researchers hypothesized that turning

the pili into a scaffold onto which they could attach inorganic molecules

may allow for higher electrical conductivity. This property would enable

them to attach conductive materials, such as gold nanoparticles, to the

filaments. “The hybrid organic-inorganic biomaterial property means

you can use [the pili] as a scaffold…for gold nanoparticles to make it

highly conductive, but in theory, you could attach it to whatever you

want,” Shapiro said. To create this transformation to a scaffold protein,

the researchers inserted a nsAA called propargyloxy-phenylalanine

(PrOF) into the bacterial pili. This allowed the newly formed hybrid pili to

bind with gold nanoparticles, which increased conductivity by 170-fold.

The applications for this research have widespread medical

effects. “Having proteins that are electronically conductive lets you

interface between your biological self and computers for medical

care,” Shapiro said. The team hopes that their work can be the

foundation for upcoming breakthrough innovations in protein

nanowires and electrical conductivity.

Shapiro is now at Duke University, pursuing a Ph.D. in Biomedical

Engineering and studying how liquid-liquid phase separation of

intrinsically disordered proteins can be used to control gene expression. ■

May 2022 Yale Scientific Magazine 9


Chemical Engineering




Mimicking Biology in

Wastewater Engineering



Wastewater is not something that most people in

developed nations want to, or have to, think about. For

most Americans, as soon as water goes down the drain,

it is out of sight and out of mind. We view waste in our pipes in

the same way we view the waste in our trash cans—as depleted

resources to eject from our homes and businesses.

The current process of wastewater treatment focuses on cleaning

water to reintroduce it into the environment. Through a complex series

of physical, chemical, and biological processes, engineers degrade and

remove contaminants from wastewater to make the resulting water

as safe as possible. However, this process creates solid waste of its

own, ranging from organic materials to plastics to metals. These are

typically addressed via conventional means, such as landfill disposal.

Ryan DuChanois, a researcher at the Yale Department of Chemical

and Environmental Engineering, sought to challenge the idea that

wastewater contaminants are simply pollutants to separate and

discard. “Currently, there is no method to turn waste from wastewater

into something beneficial,” he said. This new strategy evokes the

concept of a circular economy, where materials can restart the life cycle

of manufacturing rather than being disposed of as waste by default.

Unfortunately, conventional wastewater treatment processes use

membranes that cannot separate waste to the level of extracting valuable

ions. Therefore, to achieve his vision of a circular economy, DuChanois

and his team set out to develop membranes with inspiration from the

material already capable of this level of specificity: our cells.

Biological ion channels are built to maintain the delicate flow of

ions in and out of cells, overseeing the exchange of nutrients and

minerals. In addition to being designed to a much smaller scale

than any human-made materials can be, biological ion channels

have an extra special characteristic: “Biological channels utilize

the interactions between species of interest and the channel to

obtain selectivity, and we don’t fully leverage that in the synthetic

membranes we use today,” DuChanois said.

The team emulated the biological approach by constructing a film of

polymers containing binding sites designed to interact with key ions

favorably. They then layered the polymers on top of one another to

create membranes of desired thicknesses. DuChanois tested the rate

at which different ions in water could travel through the membranes,

where the ratio between a desired ion, such as copper, and an

unwanted ion, such as magnesium, indicated the level of specificity

of the membrane. He discovered two surprising trends: first,

conventional logic says that stronger binding interactions between an

ion of interest and the membrane should cause it to get “stuck” in the

membrane, thereby limiting its ability to flow through; on the contrary,

DuChanois found that stronger binding interactions aided some

ions in diffusing across the membrane, consequently increasing the

membrane’s specificity. The relationship between membrane thickness

and selectivity was similarly counter-intuitive. When copper ions of

interest traveled through a membrane, the diffusion rate decreased

as membranes of larger thickness were tested, while unwanted ions

diffused at a rate independent of membrane thickness. As a result, the

selectivity decreased for thicker membranes.

These two new properties provide an important tool for engineers,

potentially enabling the selection of certain valuable ions in wastewater

and recovery for their use in manufacturing. The two-pronged effect of

minimizing the amount of waste produced and increasing the supply

of materials is particularly beneficial for substances that are energyintensive

to obtain normally. An example is lithium, which is required

for energy storage in green technology and electronics. According

to DuChanois, targeting certain wastewater streams from industrial

facilities and oil-drilling sites could allow for more efficient reclamation

due to the elevated presence of ions used in manufacturing.

There are still notable obstacles to applying these membranes and

the concept of resource reclamation from wastewater. For instance,

thinner membranes that are more selective are also more susceptible

to mechanical stability concerns, such as breaking under water flow

pressure. DuChanois has also identified the need to assess various

materials to determine which ions are the most critical and viable

for recovery. Additionally, he hopes to integrate ion-selective

membranes into a more scalable process for industry usage.

Modeling wastewater technology after the evolution-tested

components of the human body has proven an effective method

to foster innovation. Ion-selective membranes can join Velcro and

aerodynamic trains as everyday necessities inspired by nature. ■

10 Yale Scientific Magazine May 2022 www.yalescientific.org

Ecology & Evolutionary Biology



Modeling Microbial

Recruitment and





Picture yourself sitting down for dinner, perhaps a

steamy plate of shrimp-fried rice. The food on your

plate makes its way into your mouth, down your throat,

and into your stomach where it will eventually make its way

down the rest of your digestive tract. Picking up your fork for

more, it may seem that you are enjoying this delicious meal

all alone, but microbes play a key role in the consumption of

your favorite dish. From head to toe, microbes are all around

and even inside you. These communities of microbes benefit

our digestion by keeping our mouths and digestive tracts

healthy but also by helping the food on our table to properly

develop before it ends up on our plate. In fact, microbes in

the gut help process complex molecules in our food and play

a critical role in immune health and individual reactions

to medications. With all these different microbes being

involved in different roles, it becomes difficult to understand

how these different communities interact.

In the study “Top-down and bottom-up cohesiveness in

microbial community coalescence,” Yale ecologists developed a

framework for how microbial communities evolve when joined

together, providing an understanding for a powerful effect that

causes microbes to recruit partners during invasions in a fight

for resources and survival. While it is difficult to visualize the

importance of microbes, recent research has showcased an

ever-increasing understanding of their importance in health

and human life. “Right now we don’t really have a lot of tools

to act on how these communities function and operate, but

starting to understand how they assemble is the first step to

understand how they function,” Juan Díaz-Colunga, first author

of the study and postdoctoral associate at Yale, explained. The

Sanchez lab where Díaz-Colunga works is on the cutting edge of

this research—developing our understanding of how microbial

communities assemble and evolve. With microbial health as a

key player in generalized human health, this understanding is

vital in the effort to create therapies that can restore microbial

health for a variety of sick patients.

This paper uncovered that there are essentially two realms of

microbial community coalescence. The first realm showcases

that just a few key species can determine the outcomes of

whole communities as they come together and interact. This

phenomenon is known as “top-down coselection” and means

that dominant microbes can influence their partners in the

same way that a skillful soccer player might form a team with

a couple of younger players. Alternatively, the collection of

interactions from less abundant species can alter the microbial

community significantly. This alternative, known as “bottomup

coselection,” means that less dominant microbes can

determine the composition of their community the same

way that novice soccer players can choose who they want to

include in their game if they got to the field first. This creates

an impactful change in the distribution of resources and

determines what species survive.

Understanding this process can be leveraged to engineer

healthcare therapies, but also impact agriculture, food

fermentation, and many other sectors. “On the single species

level, we do have tools to do this, strategies like directed

evolution allowed humans to select for specific traits and

turn wolves into dogs,” Díaz-Colunga said. Engineering

microbial communities could increase agriculture yield and

nutrition. In fact, it could be used to fortify the nutritional

value of the rice on our plate, or deal with an entirely

different issue—the presence of arsenic in rice that is created

as a byproduct of the metabolism of certain microbes.

Seeing the diverse roles that microbes play, from our dinner

plate to our gut showcases all the future opportunities that

microbial engineering will be able to impact.

Although natural microbial communities have a high degree of

complexity, analyzing the fundamental interactions of microbial

species can allow us to understand how microbes may interact

with a vast number of different communities and environmental

conditions—setting the framework for new technologies and

innovations based off microbial communities. ■


May 2022 Yale Scientific Magazine 11


Evolutionary Biology




DNA from tortoise bones

reveal an unknown lineage

of Galapagos giant tortoise


The Galapagos Islands have been an

archetypal example of evolution

and natural selection since

1835, when famed naturalist Charles

Darwin set foot on their remote shores.

Upon arriving on the islands, Darwin

discovered animals that were similar

in many ways but differed in their

adaptations to the unique environment

of their respective home islands. These

observations led Darwin to develop his

revolutionary theory of natural selection,

detailing how populations of organisms

change and adapt to succeed in their

specific environments.

One of the most iconic residents of the

Galapagos Islands is the Galapagos giant

tortoise. After arriving at the Galapagos

Islands from mainland South America

millions of years ago, the tortoises slowly

evolved into fifteen unique species across

ten of the islands in the Galapagos, with

twelve of these species surviving to this

day. These species are all specifically

adapted to succeed in the isolated

environments they

inhabit. For



believed that

the tortoises of

San Cristóbal Island—one

of the oldest islands in the Galapagos

archipelago—belonged to a single lineage.

However, Adalgisa Caccone, a Senior

Research Scientist in Yale’s Department of

Ecology and Evolutionary Biology, along

with a team of eleven colleagues, recently

found evidence of a second, long-extinct

lineage of tortoises on San Cristóbal

Island. In her group’s new study, published

in Heredity in February, Caccone and

her team sequenced DNA from museum

samples of tortoises more than a century

old, suggesting the existence of a

previously unknown lineage of tortoises.

A Long Time Coming

The story of this groundbreaking

discovery began nearly three decades ago

when Caccone and her husband, Professor

Jeffrey Powell of the Department of

Ecology and Evolutionary Biology, first

became interested in studying the giant

tortoises to save them from extinction.

This threat has haunted the tortoise

population since the arrival of humans

to the Galapagos. To early fisherman and

whalers, the turtles were a meal, not an

evolutionary miracle. “They were a

good source of fresh food because

you can keep them on the boat

without food or water for up to six

months,” Caccone said. “It’s been


that 250,000

tortoises were taken

across the islands.”

Caccone was confident that the key to

managing endangered tortoise populations

lay in piecing together the puzzle of their

evolutionary origins. In collaboration

with the Galapagos National Park and the

Charles Darwin Foundation, she began

collecting samples from the surviving

populations of Galapagos tortoises.

The next step in uncovering the story of

the tortoises’ evolution was interrogating

their DNA. “We started sequencing small

fragments of genes, like the mitochondrial

DNA, some nuclear genes, and genotyping

microsatellite loci,” Caccone said. “We

started building the story.” By comparing

the DNA data of the living populations,

Caccone could identify similarities and

differences, generating new understandings

of how the tortoises might have spread

across the islands and adapted.

Her efforts in uncovering these patterns

led her to San Cristóbal Island. “San

Cristóbal is one of the oldest islands of

the Galapagos Islands, so it likely plays

an important role in understanding how

the colonization of the islands started,”

Caccone said.

Still, a piece of the evolutionary puzzle was

missing. “ We soon realized that there were

some questions that we could not address

because we needed the DNA of the extinct

species,” Caccone said.

12 Yale Scientific Magazine May 2022 www.yalescientific.org

A Surprising Solution

Caccone and her team found their

solution in unexpected places: historical

samples from a single living tortoise and

tortoise bones collected from a cave during

an expedition to San Cristóbal in 1906,

which had been stored away in museum

collections more than a century ago.

Caccone set to work sequencing DNA from

these samples—a particularly challenging

task due to the age of the samples.

Using micro-CT scans, which use x-rays

to build a 3-D image of the interior of

an object on a very small scale, Caccone

and her team could determine the

sections of the old bones most likely to

contain preserved DNA. They sequenced

small sections of DNA from each bone,

overcoming the challenges of working

with tortoise bones that were hundreds

of years old and highly degraded. “What

you want to get is a sample that has a good

amount of DNA preserved in it,” Caccone

said. “Usually, bones are much better than

tissues, because the external mineralized

portion of the bone protects the DNA.”

Caccone expected to find a variety

of DNA sequences related to the single

existing haplotype, or set of DNA

variations, found in the living tortoises

from San Cristóbal. Instead, she found

something very surprising. “We found that

unlike in the existing population, there was

variation, and that the variation was not

related to the existing haplotype,” Caccone

said. “It was something different. That’s

when we said, okay, there’s something

interesting here. Let’s get to work.”

And work they did—Caccone and her

team convinced the Galapagos National

Park, with which they are working in

close collaboration, to organize a field

expedition over San Cristóbal Island to

check if there were any tortoises related

to the lineage from the cave samples.

The team collected hundreds of samples

across the island, searching in remote

places never previously sampled before.

Caccone and her team selected a random

collection of 129 blood samples from

living tortoises to test if any showed

signs of relatedness with the samples

collected in the cave.

The genome-wide analyses of samples

from living tortoises did not reveal any

intermixing between the two lineages,

suggesting the existence of an entirely

different, long-dead lineage of tortoises

on San Cristóbal Island. “The key finding

is that the mitochondrial haplotypes for

these cave specimens are highly distinct

from the haplotype that’s in the living

population,” Evelyn Jensen, first author

on the Heredity paper and lecturer at

Newcastle University, said in a podcast

with Heredity. “The common ancestor of

the cave and the living lineages diverged

probably about 700,000 years ago. So, the

tortoises that died falling into the cave

are of a totally different lineage from the

tortoises that live on the island today.”

New Ideas from Old Bones

Jensen and Caccone’s discovery has

brought scientists closer to completing

the puzzle of giant tortoise evolution and

colonization in the Galapagos Islands. It

has also powerfully demonstrated the

importance of analyzing both historical

and contemporary samples when

studying these tortoises. “If we’re just

looking at the populations that have

survived to the present day, we’re missing

some important pieces of the puzzle

for reconstructing evolutionary

patterns,” Jensen said in the

Heredity podcast. “Just when we

think we have the story worked

out, we look at some dusty old

bones in the museum. Now

we’re potentially having to

do a major rethink of our

understanding of how these

species arose and colonized

the Galapagos archipelago.”


Evolutionary Biology

Caccone and her team are already

working on their next step—obtaining

more comprehensive DNA samples from

the historical samples. The DNA data from

this study is limited to mitochondrial DNA,

a form of DNA that is more abundant and

easier to isolate. However, this subset of

DNA lacks much of the broader genetic

information of the tortoises, limiting options

for genetic analysis. In the future, Caccone

hopes to isolate and sequence nuclear DNA,

or DNA from the tortoise’s chromosomes,

which will provide a much more complete

picture of the genetic differences between the

cave tortoises and the existing population.

The ability to compare full nuclear DNA

sequences between extinct and living

populations holds the potential to elucidate

new knowledge about the relationship

between these two tortoise lineages. Further

sequencing might even confirm that this

unique lineage is an entirely new tortoise

species—the evolutionary secrets within

these bones have yet to be fully revealed. ■



SOPHIA BURICK is a first-year Molecular Biophysics and Biochemistry major in Timothy Dwight College.

In addition to writing for YSM, Sophia sings with the New Blue, Yale’s oldest women’s acapella group, and

works as a research assistant at the Yale School of Medicine.

THE AUTHOR WOULD LIKE TO THANK Adalgisa Caccone for her time and enthusiasm about her



Jensen, E. L., Quinzin, M. C., Miller, J. M., Russello, M. A., Garrick, R. C., Edwards, D. L., Glaberman, S., Chiari,

Y., Poulakakis, N., Tapia, W., Gibbs, J. P., & Caccone, A. (2022). A new lineage of Galapagos giant tortoises

identified from museum samples. Heredity. https://doi.org/10.1038/s41437-022-00510-8

Burgon, J., & Jensen, E. (2022, March 16). Galápagos giants. Heredity Podcast.



May 2022 Yale Scientific Magazine 13




Investigating the orbits of large

exoplanets to uncover the mysteries

behind solar system formation


If you’re reading this, you likely live in a

solar system. I’d venture to say that you

live on Earth, too, making you a resident

of its solar system. Given these assumptions,

you’re likely familiar with its structure: four

rocky planets on the inside followed by four

gaseous planets on the outside, all orbiting

the Sun in nearly identical equatorial planes.

This structure feels standard, safe. But every

tellurian astronomer was forced to confront

this biased assumption upon the discovery of

the first extrasolar planet.

In 1995, astronomers Didier Queloz and

Michel Mayor discovered planet 51 Pegasi b,

the first known planet found outside of the

solar system. This planet is large, hot, and

extremely close to the sun-like star that it

orbits—much closer than Mercury is to the

Sun. It is what is now called a “hot Jupiter,”

a gas giant planet with an orbit extremely

close to its star. This single planet scrambled

astronomers’ understanding of solar system

formation since they had previously assumed

that gas giants orbited far from their stars,

much like our beloved Jupiter. Now that over

5,000 exoplanets have been discovered, we can

create a “normal distribution” of solar systems,

and ours is far from the center of the bell curve.

Though they are familiar to us, our

system’s orbits, which transit the equator

of the Sun, are just as extreme as orbits

wherein a system’s planets orbit from pole

to pole. So while large, gaseous planets

completing orbits around their stars in

just a few days may seem foreign to us, it

is frequently observed in other planetary

systems. The only problem is that we don’t

understand how they do it.

Yale astronomy researchers Malena Rice

and Greg Laughlin are tackling this issue

head-on. Fifth-year Ph.D. student Malena

Rice was studying how a warm Jupiter, a

gas giant with an orbital period of over

ten days, fit into existing planet formation

theories when she noticed an interesting

correlation. “I made about a hundred

plots looking at how this planet fits in with

the bigger picture of all the [previous]

measurements… and I realized that, no

matter how you look at them, the eccentric

planets tend to be more misaligned,” Rice

said. This misalignment of eccentric hot

Jupiters, or those with more elliptical

rather than circular orbits, could be the key to

understanding how they form.

Heat Your Jupiter to 2000 °F

But how did hot Jupiters get their

characteristic elliptical orbits in the first

place? This issue has separated astronomers

into a few different camps. Perhaps hot

Jupiters formed in their original places in a

process called in situ formation. However,

this is difficult to do because there isn’t a lot

of planet-forming material near the stars

they orbit. Others argue that they might have

formed farther out and migrated inward,

shepherded by other planets in the solar

system through gravitational interactions.

In this process, the hot Jupiters would spiral

slowly and gradually toward the inner orbits

of the system. There is strong support for this

latter theory in astronomical communities.

The third camp argues in favor of higheccentricity

migration, a framework in which

hot Jupiters are born farther from their host

stars or the stars that they orbit. Through

scattering and nudging from other sources, the

hot Jupiters are knocked onto highly elongated

orbits and spiral inwards to reach much closer

orbits over time. “One way to distinguish

which of these is actually correct is by looking

at whether or not hot Jupiters are aligned with

the plane of their host star’s equator,” Rice said.

In general, we expect host stars to spin in the

same direction as their surrounding disks of

dust, gas, and other debris. These disks form

around newly-made stars to eventually form

planetary bodies through collisions of the

orbiting particles. In the beginning, everything

should form in the same plane. So, planets

that are misaligned or orbiting in directions

different from their host stars could indicate

that the system underwent a dynamically

dramatic process. These misalignments require

a kick hard enough to tilt entire systems, such

as one planet tossing another into a different

orbit, a star flying by and tilting the disk, or

one planet being thrown into the host star and

being engulfed. The fact that systems with hot

Jupiters are rarely observed with other planets

indicates that the Jupiters’ would-have-been

neighbors could have been thrown out early

on or engulfed by the chaos caused by the

dramatic inclination shift.

Observe Your Jupiter Transiting Its Star

Hot Jupiters are incredibly well-studied by

astronomers because they are the easiest to

observe. To detect these planets, astronomers

14 Yale Scientific Magazine May 2022 www.yalescientific.org

use the transit method, a detection technique

where astronomers measure how much light a

planet blocks as it passes or transits its host star.

“You get the size of the planet by looking at how

much of the starlight has been blocked, you get

the period by seeing how often it happens, and

you get information about the orbit from the

duration of the transit,” said Greg Laughlin,

Yale professor of astronomy.

Over the past decade, a lot of effort has gone

into measuring the angles between planetary

orbits and the stars’ equators. Enough of these

measurements have been collected such that

patterns are now starting to emerge. One

of the most interesting patterns is that stars

that are more massive than the Sun by about

twenty or thirty percent tend to show planets

that are badly misaligned, whereas the stars

that are less massive than the Sun tend to

show better alignment.

Extrapolate Your Jupiter’s Evolutionary


Researchers Malena Rice and Greg Laughlin

found that when the planet’s orbit had a higher

eccentricity, there was more misalignment.

This finding aligns with the idea that the planets

get to their current locations through scattering

rather than steady, slow disk migration. “That

doesn’t mean that high-eccentricity migration

is the only process that could take place, but is

probably dominant—if you assume that it’s the

only mechanism at play, it is consistent with all

of our observations,” Rice said.

For now, they need more data, but what

they’ve collected so far is promising, confirming

that disks should be aligned with their hosts. If

wide-orbiting warm Jupiter planets had started

in misaligned orbits, they would continue to

have those peculiar orbits since they orbit too

far from their host star to be realigned over

time. So, the fact that we mostly see aligned

systems, particularly on wider orbits, further

indicates that something drastic happened to

the closer-orbiting hot Jupiters after they had

all formed to become misaligned.

This result isn’t what would be expected, as it

implies that these hot Jupiters rely on random

events rather than a systematic process. “I had

assumed either that the planets are forming in

situ or that they're migrating, and I hadn't really

appreciated the fact that we can explain the

distribution simply through chaotic scattering

and planet-planet interactions, kinds of oneoff

events,” Laughlin said.

But what advantages does characterizing

these planetary systems bring? Having

two well-studied types of planetary systems

is much better than just one, especially when

those two systems are fringe-type oddballs on

each end of the spectrum. From these systems,

one can interpolate between the two extremes

and extrapolate the evolutionary histories of

more average systems. “What’s really exciting

about this paper is that it gives us really good

reason to believe that this very dramatic set of

events, which are

unlike anything

that happened

in the solar

system, is actually

happening on a

regular basis,” Rice

said. “It’s providing

a completely new

perspective on

the different ways

that planetary

systems form;

we are starting to

piece together the

possibilities and

move away from

being biased by

our one exquisitely

detailed data

point.” ■




BRIANNA FERNANDEZ is a junior in Pierson College studying astronomy and earth and planetary

sciences. In addition to writing for YSM, she is one of the magazine’s layout editors. Outside of YSM,

she researches exoplanets with Professor Debra Fischer and advocates for incarceration-impacted

individuals with the Yale Undergraduate Prison Project.

THE AUTHOR WOULD LIKE TO THANK Malena Rice and Greg Laughlin for their time and enthusiasm

in sharing their research.


Rice, Malena, et al. “Origins of Hot Jupiters from the Stellar Obliquity Distribution.” The Astrophysical

Journal Letters, 926(2), 2022, https://doi.org/10.3847/2041-8213/ac502d.




May 2022 Yale Scientific Magazine 15





Establishing a platform to discover

useful targets of CAR-T engineering



By Shudipto Wahed

Art by Malia Kuo

Emily Whitehead’s entire world turned upside

down in 2010 when, at the age of five,

she was diagnosed with B-cell acute lymphocytic

leukemia (ALL), the most common

childhood cancer. After two years of

unsuccessful chemotherapy, all hope seemed to be

lost. Her doctors recommended she be taken home

to Philipsburg, Pennsylvania, to die peacefully with

her family around.

Fortune was on the Whiteheads’ side, however. A

combination of persistence and perfect timing led

their treatment search to the Children’s Hospital of

Philadelphia, which had just received approval for

treating their first refractory ALL patient using a

novel, yet promising approach: CAR-T cell therapy.

16 Yale Scientific Magazine May 2022 www.yalescientific.org



Chimeric antigen receptor (CAR)-T cells

are an engineered variant of T cells—white

blood cells in our bodies integral to the immune

response against infection. The term

“chimeric” refers to how the antigen-recognizing

part of the receptors derives from

extracellular antibodies. These cells are

equipped with T cell receptors (TCRs) on

their surfaces, allowing them to recognize

virus- or bacteria-infected cells. Similarly,

cancer cells can display tumor-specific antigens

(markers) that enable their recognition

and destruction by this mechanism. A

specific subset of these T cells, called CD8+

T cells, which are distinguished by expressing

CD8 molecules on their surface, are

referred to as “killer” or “cytotoxic” T lymphocytes

(CTLs) because they can trigger

immune cell-mediated death of target cells.

Could CTLs then serve as “living drugs”

against cancer? Over the past few decades,

medical researchers have grown keen to answer

this question, hoping to improve the

rather lackluster survival rates of prevalent

forms of cancer treatment such as surgery,

chemotherapy, and radiation.

Israeli immunologist Zelig Eshhar was

the first to produce CD8+ T cells with

genetically engineered TCRs modified to

recognize the antigens of choice. These

were the first-generation CAR-T cells.

CAR-T cells thus offered an exciting opportunity

to harness the existing machinery

of the immune system to target and kill cancer

cells simply by engineering TCRs to specifically

target antigens displayed by tumor

cells. University of Pennsylvania immunologist

Carl June pioneered the development of

second-generation CAR-T cells, engineered

to kill leukemia cells in mouse malignancy

models. At this time, he encountered a hospice-referred

Emily Whitehead.

CAR-T Cell Therapy—The Contemporary


To the delight of everyone involved, Emily’s

cancer went into remission immediately

following the administration of June’s

CAR-T therapy. In June 2012, she was released

from the hospital, and today, she remains

cancer-free. This event marked a pivotal

point in cancer immunotherapy: a later

clinical trial showed that ninety percent of

refractory ALL patients receiving CAR-T

achieved complete remission for a disease

that would have otherwise proven fatal.

To date, six CAR-T cell therapies have


been FDA-approved for treating various

blood cancers. The treatment process is

similar for each type of CAR-T therapy. A

patient’s blood is first removed to isolate

CD8+ T cells. These cells are then genetically

engineered, often using CRISPR-Cas9

and/or lentiviral gene-editing technology, to

remove the natural TCR and insert a CAR

directed towards the antigen of choice. Other

modifications, such as removing inhibitory

molecules and introducing co-stimulatory

molecules, are often performed. These

CAR-T cells are then cultured in a laboratory

setting to grow millions of anti-cancer

T cells, which are finally re-infused into the

patient to target and kill malignant cells.

While CAR-T remission and survival

rates have at times considerably exceeded

other therapy options, access remains

poor. Due to the complexity of the procedure,

a singular infusion can cost up

to $500,000, excluding other costs such

as hospital stay and follow-up protocols.

Additionally, geographic barriers can

limit patients’ access to this life-saving

treatment as fewer than two hundred

centers in the U.S. are authorized to administer

the treatment.

Moreover, several limitations have prevented

widespread adoption and greater

efficacy. While all currently approved

CAR-T cell therapies target blood cancers,

their effectiveness in solid tumors has been

lackluster. A major challenge is improving

the persistence and proliferation of CAR-T

cells post-infusion since they often do not

survive long enough to mediate long-term

cancer control. Additionally, identifying

and targeting “neoantigens,” antigens that

are specifically expressed or overexpressed

by tumor cells, has been challenging for

CAR-T cells.

CRISPR Engineering and the Next


To further improve the function and

specificity of CAR-T cells, researchers

have experimented with the ability to

boost T cell function via genetic engineering:

whether by knocking out (deleting)

inhibitory receptors or inserting co-stimulatory

genes. The innovation of CRIS-

PR-Cas9 gene-editing technologies vastly

improved this capability. By using RNA as

a guide to direct DNA cleavage at specific

regions in the genome, CRISPR-Cas9-mediated

editing tends to be more precise

than previously used techniques, resulting

in fewer off-target side effects.

Over the past few years, researchers

have mostly used CRISPR-Cas9 gene-editing

technologies to screen the genome of

CD8 + T cells for knockout targets by identifying

genes that, when silenced, augment

antitumor efficacy.

Associate Professor Sidi Chen, Associate

Research Scientist Lupeng Ye, and their team

at the Yale School of Medicine recently published

a paper in Cell Metabolism outlining

their development of a CRISPR activation

(CRISPRa) gain-of-function (GOF) screen

in CD8+ T cells. While previous CRISPR

screens only focused on identifying knockout

targets, a GOF screen would identify

genes that, when overexpressed (“knockedin”),

would enhance CAR-T function.

Thus, this novel platform helps identify

a new class of gene-editing targets that can

be harnessed as functional boosters for

CAR-T cell therapy optimization. “CRIS-

PRa screen is very, very new in immune

cells and completely different from prior

knockout screens. We try to find several

targets that can reprogram T cells and

use CRISPR engineering to ‘knock-in’

these targets into engineered T cells so the

CAR-T can have boosted function when

killing cancer,” Ye said.

Identifying Useful Targets for CAR-T


With a primary gain of function

screening method, the researchers

sought to identify genes that, when activated,

would enhance the “degranulation”

ability of CD8+ T cells. Degranulation,

the process of releasing cytotoxic

molecules from internal secretory vesicles,

is one of the primary mechanisms

by which CTLs mediate the killing of

their target cells.

A key characteristic of CRISPRa is

that it uses truncated “dead-guide” RNA

(dgRNA) instead of traditional “single

guide” RNA (sgRNA). Whereas sgRNA

binds to Cas9 and cuts a specific target

sequence, “dgRNA […] can also complex

with Cas9 and bind to targets, but cannot

cleave DNA,” Ye explained. Instead, the

dgRNA is designed to contain two special

loop structures that recruit proteins involved

in DNA transcription, ultimately

resulting in overexpression of the genes

the dgRNAs are meant to target.

May 2022 Yale Scientific Magazine 17



The authors of this study began by designing

a mouse genome-scale dgRNA library

targeting more than 22,000 genes, which will

be delivered to CD8+ T cells isolated from

Cas9-transgenic mice to conduct CRISPRa.

Using an immunogenic mouse tumor model,

researchers co-cultured dgRNA-transduced

tumor-targeting CD8+ T cells with their target

tumor cells. After four hours, the authors

measured the levels of CD107a, a molecule

expressed after degranulation. Then, the researchers

used fluorescence-activated cell

sorting to isolate CD8+ T cells with CD107a.

Genetic sequencing revealed which dgR-

NAs were most significantly enriched in the

CD107a+ population. “If the gene is highly

enriched, the signal will be really strong. We

picked the targets with the strongest signals to

do our initial validation,” Ye said. One of the

screen’s top hits, the PRODH2 gene, led to increased

degranulation and more rapid proliferation

in CD8+ T when overexpressed compared

to control cells. Could PRODH2 serve as

a functional booster for human CAR-T cells?

Metabolic Reprogramming Supercharges

CAR-T Cells

Indeed, Chen’s team confirmed that

PRODH2 overexpression in human CAR-T

cells, either by CRISPR knock-in or traditional

lentiviral delivery, enhanced tumor

killing and proliferation. These findings


Leukemia is a cancer of the body’s blood-forming tissues, usually involving white blood cells. CAR-T therapy

against B-cell acute lymphocytic leukemia (ALL) is convenient because CAR-T cells can be designed to

indiscriminately target and kill all B cells, which are considered to be effectively non-essential.

were validated in three in vitro cellular models:

leukemia, multiple myeloma, and breast

cancer. These effects were replicated in vivo,

using human tumor xenograft models for

the same three cancers in mice. PRODH2

overexpression led to reduced tumor growth

and greater survival in CAR-T cell therapy.

But why? The authors performed various

profiling techniques to gain insights into the

mechanism underlying how PRODH2 overexpression

enhances CAR-T cell antitumor

efficacy. mRNA sequence analyses showed

that PRODH2 knock-in significantly altered

gene expression of the cell cycle, activation/

effector function, and metabolism-related

programs in CAR-T cells.


PRODH2’s effects on CAR-T cell antitumor

efficacy seemed to be driven by metabolic

reprogramming related to proline, an

amino acid building block. “If we overexpress

PRODH2, then proline metabolism

will be reprogrammed,” Ye said. Metabolomics

data of PRODH2-overexpressing CAR-T

cells revealed increased biochemical activity

of the pathway and alterations in other intersecting

metabolic pathways, such as the metabolism

of arginine, another amino acid. In

fact, the cancer-killing ability was improved

when direct substrates of PRODH2 were

supplied to PRODH2-knockin CAR-T cells,

but not in control CAR-T that normally lack

the enzyme. This confirmed that the metabolic

activity of PRODH2 was responsible

for enhanced cytotoxic activity.

Hope for the Future

Chen’s team established a novel, genome-wide

GOF screening technique in

primary CD8+ T cells that can identify desperately-needed

functional boosters in a robust

and unbiased manner. The beauty of the

screen is its versatility. “This doesn’t have to

be T-cell or cancer-specific—ours is a flexible

and broad platform that can be utilized

to perform screens on virtually any other

type of immune cells,” Chen said. “This platform

can be a broadly enabling technology

for us and everyone else in the world to utilize

GOF screens in various systems, including

stem cells, NK cells, macrophages, and

even other cells relevant to other diseases.”

In the future, the authors wish to validate the

other targets identified in their screen. They

hope to ultimately translate their work into

clinical practice by improving the anti-cancer

efficacy of CAR-T therapies. ■


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

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

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

Council and an analyst in the Yale Student Investment Group.

THE AUTHOR WOULD LIKE TO THANK Associate Professor Sidi Chen and Associate Research Scientist

Lupeng Ye for their time and enthusiasm about their research.


Ye, L., Park, J. J., Peng, L., Yang, Q., Chow, R. D., Dong, M. B., … & Chen, S. (2022). A genome-scale gainof-function

CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T

therapy. Cell Metabolism, 34(4): 595-614, https://doi.org/10.1016/j.cmet.2022.02.009

“Car T Cells: Timeline of Progress.” Memorial Sloan Kettering Cancer Center, 2022, https://www.mskcc.


18 Yale Scientific Magazine May 2022 www.yalescientific.org

Wave Physics





Focusing delivery

of energy into

diffusive systems

for applications in

neuronal control

and tissue imaging






Why is the sky blue?” is perhaps one

of the first, most vexing questions a

kid can ask their parents. After all,

how do you explain to a three-yearold

that the answer lies in the scattering of light in

opaque diffusive systems?

In our day-to-day lives, scattering occurs

when particles pass through a medium—such

as air or water, for example—and collide with

other particles, resulting in a change in their

trajectory. “Scattering of light is very common,”

said Hui Cao, a Professor of Applied Physics at

Yale University, focusing on mesoscopic physics,

nanophotonics, and biophotonics.

May 2022 Yale Scientific Magazine 19


Wave Physics

“The sky looks

blue because blue

light is scattered [more]

strongly than red light,

and the reason why

we look opaque is

that there’s strong

scattering by the cells

in biological tissues.

That’s why we cannot

see through most

biological tissues.” We

encounter many things

in everyday life that we

cannot see through or send

information through—all

because of this strong

scattering of light.

H o w e v e r ,

scattering can

cause challenges in

applications such

as medicine, where

the opacity—or lack

of transparency—of

human tissues can limit

their visualization and


In recent years, researchers

have explored different

ways to transmit energy

through diffusive systems.

In medical applications,

for example, it is critical

to focus on delivering

and depositing energy

inside systems such as

human tissue instead of

simply sending energy

through the system.

Medical applications

include procedures like

photothermal therapy,

which uses heat generated by

near-infrared light to treat cancer, or deep

tissue imaging, which allows researchers

to image whole tissues without dividing

them into thinner sections.

Can’t We Just Send Light Into the System?

One of the greatest challenges in depthtargeted

delivery of light—in other

words, sending light into a specific spot

in the system—is that energy scatters in

multiple directions and diffuses upon

entering the system.

Previous research relied on controlling

the wavefront of the input energy wave to

limit diffusion, which allowed researchers to

focus light on a specific spot in a scattering

medium. A wavefront is an imaginary

surface where all the points are at the same

phase in their wave cycle (think of the ripples

you see when you drop something in water).

Shaping the wavefront involves controlling

the distribution of wave intensities and

phases in the input beam.

However, this method was less practical

for real-world applications because medical

targets such as tumors or neurons often

sprawl over a region rather than remaining in

a single focal spot. The upper limit on energy

deposition in a region at a certain depth in a

diffusive system, which is important to know

for practical applications of this technique,

was also unclear using this method.

Another difficulty lies in observing the

delivery of light into the system. “Scientifically,

it’s really easy to study sending something

into a system and measure something coming

out of a system—you just put a camera on one

end and input on the other,” said Nicholas

Bender, formerly a Yale doctoral student in

Cao’s lab and now a postdoctoral researcher

at Cornell University. “What’s hard to do is

to understand what this light is doing inside

a system because by observing the system,

you may interfere with it.” Simply put, trying

to see what was going on in the system could

mean inadvertently altering whatever process

was underway within it.

Lasers and Math

To confront this issue of targeted energy

delivery into diffusive systems, researchers at

Yale University performed a comprehensive

series of experiments, numerical simulations,

and theory. “I like to call it ‘creating and

controlling disorder, randomness, and chaos

with lasers,’” Bender said.

The team began by defining a matrix that

mathematically described the relationship

between the laser beam input into a diffusive

system and the way the light was distributed

across a region of specific depth in the system.

By running repeated simulations of virtual

disordered systems, the research team plotted

what different input beams would look like at

various points within the system.

The maximum energy that could be

delivered to the target region corresponded

to the largest eigenvalue of the deposition

matrix. Eigenvalues are factors

representing the scales of eigenvectors,

which are characteristic vectors in linear

algebra. The input wavefront could be

found from the eigenvector associated

with that largest eigenvalue.

Causing Chaos (On Purpose)

One unique feature of this study was the

experimental setup. The researchers devised

an experimental platform consisting of

a two-dimensional disordered structure

(picture a rectangular slab with holes

that randomly let light through) where

the optical field could be analyzed by the

researcher looking down at the platform

from above (from the third dimension).

“ This is new,” Cao said. “Before, people

usually made a three-dimensional sample.

With three-dimensional scattering, when

you send in the light, you cannot see it, so

you don’t know [which wavefront is best]

to deliver light. But by using this system,

we’re able to peek in, to take a look from the

third dimension, and say, ‘Oh, we see! This

is where we can deposit and how much.’”

For example, if you rolled a marble into a

non-transparent box, you wouldn’t be able

to see its path or where it stopped. If you

rolled that marble onto a sheet of paper, you

would be able to look down onto the paper

and track the marble’s progress.

According to Cao, creating this

experimental setup was not an easy process.

“It’s absurd how much effort we had to put

into making this disordered system just the

way we want it,” he said. “I mean, calibrating

and controlling disorder is ridiculous…it’s

crazy and great and horrible to do,” Bender

said. This breakthrough experimental

technique allowed the researchers to observe

scattering and light delivery with a degree of

control that had never before been possible.

Using a spatial light modulator, a device

that controls the intensity and phase

of light emitted, the researchers could

shape the wavefront of a laser beam in

one dimension. They found the twodimensional

field distribution inside the

system—the field of randomly scattered

light in the platform.

The two-dimensional sample consisted of

a silicon-on-insulator wafer with photoniccrystal

sidewalls to keep light inside the

system. The team added random optical

scattering to this system by etching a

20 Yale Scientific Magazine May 2022 www.yalescientific.org

Wave Physics


random array of holes in the wafer. When

the laser beam was sent in, some of the

scattered light would come out of the holes

and into the path of a reference beam. A

camera then recorded these interference

patterns. “Basically, by shaping the incident

wavefront using a spatial light modulator,

we can control how we’re going to send

the light in,” Cao said. “By finding the

correct wavefront, we can deposit light

into different target areas deep inside.”

This experimental platform allowed

the researchers to directly map the

diffusive system at any depth. “Once

we have this system that allows us to

see what light is doing inside a random

disordered system, we can essentially

say, ‘Okay, instead of just describing

the relationship from the input to the

output, we can describe the relationship

of the light from the input to anywhere

inside,’” Bender said.

This experimental setup allowed the

researchers to create a system where the

disorder could be controlled, precisely

tuned, and analyzed. By optimizing the

laser input wavefront, they were then

able to maximize energy delivery.

This is a unique and novel set up—

one that has fundamentally changed

the ways light can interact with opaque

systems. “We’re the only people who can

actually do this study,” Bender said. “We

can control the input with very, very

good precision using the spatial light

modulators we have available. We can

make the waveguides any way we want

just because of the technical capabilities

we have in the facilities at Yale.”

The Theory

The research team also built a theoretical

model to predict the maximum amount

of energy that could be delivered to a

certain depth in the system. Theoretical

modeling was important in showing

the researchers the limits of their new

technology. “What’s the fundamental

limit? How well can we reach it, and what

determines this limit?” Cao said.

Through mathematical calculations,

the team found that energy enhancement

depended on the sample thickness and

depth of the region. Energy enhancement

was also affected by the transport

mean free path of the system, which


The unique experimental platform designed for this study.

is the distance light can travel in a

random system before it loses all of the

information about the initial direction of

propagation. They then experimentally

measured the internal field distribution

at different depths to find the deposition

matrix for regions in a diffusive system.

They found that the highest possible

energy enhancement occurs at threefourths

of the system’s thickness.

Moment of Discovery

This research differs from

previous studies in the field

because it focuses on deposition

instead of energy transmission.

“Everybody doing wavefront

shaping was looking at the

transmission matrix or some version

of the transmission matrix,” Bender

said. Compared to transmission,

having disorder after the region of

light deposition can result in light

traveling backward, interfering with

the light going forwards, leading to a

greater energy enhancement than

in the case of transmission.


Controlling Randomness


The ability to control random wave

scattering allows for energy deposition

into specific regions of opaque systems.

“This is interesting for medical applications

or anything dealing with a real system

because most systems are disordered

to some extent,” Bender said. Research

into this type of targeted energy delivery

could be used in applications ranging

from the optogenetic control of

neurons to tissue imaging. “There

are people in [the] community

trying to do imaging through

the skull. They try to send the

laser beams through the skull for

both a diagnosis and also to try to

simulate neurons,” Cao said.

This study pushes the boundaries

of what was previously thought to

be possible. “Traditionally, people

[think that] if something looks white,

then you just cannot see through it,”

Cao said. “I wish more people knew

that actually, that is not true. Random

scattering is not something just

impossible to control.” ■


EUNSOO HYUN is a junior in Berkeley College majoring in Biomedical Engineering. Outside of writing

for YSM, Eunsoo enjoys painting, learning new languages, and dancing with the Yale Jashan Bhangra


THE AUTHOR WOULD LIKE TO THANK Professor Hui Cao and Dr. Nicholas Bender for their time

and enthusiasm about their research.


Bender, N., Yamilov, A., Goetschy, A., Yılmaz, H., Hsu, C.W., & Cao, H. (2022). Depth-targeted energy

delivery deep inside scattering media. Nature Physics. 18: 309–315. https://doi.org/10.1038/s41567-


May 2022 Yale Scientific Magazine 21


Spatial Transcriptomics / Chemistry



Profiling epigenetic mechanisms on a genome-wide

level using spatial-CUT&Tag



Within each cell of the thirty

trillion that comprise your

body, bundles of threadlike

chromatin float in a nebulous shape

defined by the nucleus. This collection of

chromatin contains the human genome—

the catalog of genetic material that encodes

every cell, from the neurons in your brain

to the keratinocytes lining your skin. But

if each nucleus contains the same catalog

of genetic information, what differentiates

one cell from another? The answer lies

in the process of gene regulation—

which genes are activated and which are

repressed. This concept is fundamental to

the expanding field of epigenetics: the study

of how cellular mechanisms can change the

reading of genetic code without altering the

sequence of nucleotides itself.

Previous technologies have allowed

scientists to study these epigenetic changes

on a single-cell level by analyzing gene

or protein expression. However, these

methods required scientists to dissociate

the tissue section into individual cells

and to break those cells down further

for analysis. In doing so, researchers lost

spatial information that indicated where

the epigenetic regulations were occurring

within the tissue—details that were key to

understanding cellular function.

Researchers in the Fan Lab at Yale and

the Gonçalo Castelo-Branco Group at

the Karolinska Institute in Sweden have

developed a novel technique called spatial-

CUT&Tag. The method allows them to

map out epigenetic gene regulation in

the original tissue section using grids

composed of 20-micrometer pixels, an

area equivalent to a single neuron in the

brain. This technique represents a huge

leap forward in the field of spatial omics

and was recently published in Science.

“What has been missing in terms of

[past] technology is that you don’t really

see single-cell information in a kind of

genome-scale, unbiased way, [while it is]

still in the original tissue environment,” said

Rong Fan, a Yale professor of biomedical

engineering and the principal investigator at

the Fan Lab. “Over the past couple of years,

people realized how important that tissue

spatial information is in the development

of technology for spatial transcriptomics.

Now, we can see [gene regulation] pixel by

pixel, just like your TV.”

The Importance of Spatial-CUT&Tag in

Visualizing Histone Modifications

Fan and his colleagues focused on using

spatial-CUT&Tag to identify a specific

mechanism for epigenetic regulation, called

histone modification.

To understand the process of histone

modification, we first have to visualize

how DNA is packaged within the

nucleus. The average nucleus of a human

cell is only six micrometers in diameter,

22 Yale Scientific Magazine May 2022 www.yalescientific.org

Spatial Transcriptomics / Chemistry


less than half of the width of a human

hair, but it must contain approximately

six feet of DNA. To optimize space

within the cell, the ribbon of DNA is

first coiled around clusters of positivelycharged

proteins called histones, like a

thread strung with beads. These histones

are then grouped together, forming long

ropes called chromatin fibers, which are

condensed into chromosomes.

In histone modification, however, these

histones are altered with chemical groups that

cause sections of the DNA to unwind, leaving

certain genes exposed and easily accessible

to transcription complexes. Depending on

whether the genes are unwound or wound,

gene transcription may be activated, causing

the production of proteins associated with the

gene, or inhibited, resulting in the ‘silencing’

of the gene. Using spatial-CUT&Tag, the

researchers achieved enough precision to

see the histone modifications themselves in

individual cells.

“This is completely mind-blowing. You

can see the mechanism that controls gene

expression, rather than just the expression

of the individual genes, pixel by pixel in a

tissue matrix. So, once you have that, the

greater impact is [that] you’ll know what

type of cells there are and

what gene expression

d e t e r m i n e s

types of tissue


Fan said.

Previously, one of the most commonly

used methods to detect specific histone

modifications was ChIP-Seq, which “pulls

down” specific histones from the cellular

mixture using antibodies and analyzes

the DNA associated with those histones.

However, Fan said that ChIP-Seq is a

tedious, time-consuming process that

requires a large sample of cells. Spatial-

CUT&Tag expedites this process and

provides an unimaginably large amount of

data in comparison.

“[With spatial-CUT&Tag], the data

now is equivalent to doing thousands of

ChIP-Seq, but precisely from every tiny

pixel of your tissue and doing thousands

of those covering the entire tissue section.

That was just science fiction a number of

years ago,” Fan said.

Achieving this level of precision took three

years of work, and the final version of the

novel spatial-CUT&Tag technology required

a combination of three existing techniques:

microfluidic deterministic barcoding,

CUT&Tag chemistry, and next-generation

sequencing (NGS).

How Spatial-CUT&Tag Works

To carry out spatial-CUT&Tag, the

researchers first performed standard

CUT&Tag on mouse embryos and brain

tissues. CUT&Tag is a common procedure

used to analyze interactions between

histones and DNA and determine which

proteins are associated with which DNA

binding sites. This process required

tagging specific histone targets with

antibodies, Y-shaped proteins with

conformations that perfectly bind to

histones of interest, marking them

for further analysis. The next step of

CUT&Tag involved cleaving the DNA

strands coiled around the histone,

isolating these protein-associated genes.

Finally, synthesized DNA strands, called

adapters, were added to the ends of the

sectioned genes. These adapters proved

to be important later on, as they served

as “landing docks” for the attachment of

lab-made DNA “barcodes.”

The next step, called microfluidic

deterministic barcoding, allowed

scientists to track epigenetic modifications


May 2022 Yale Scientific Magazine 23


Spatial Transcriptomics / Chemistry


Yanxiang Deng, a post-doc in the Fan Lab, pipettes

fluids at his bench. Deng spearheaded the effort to

develop microfluidic devices that served as a key

component of the spatial-CUT&Tag experimental


back to their locations within the original

tissue sample. This novel technology,

developed by the Fan Lab three years

ago, provided researchers with crucial

spatial epigenetic data that were lost

when performing regular CUT&Tag.

Microfluidic deterministic barcoding

involves labeling cells containing specific

histone modifications with “barcodes”,

which are unique combinations of DNA

strands that the scientists can track to

reconstruct a visual map of epigenetic

modifications. To carry out microfluidic

barcoding, the researchers developed two

microfluidic devices.

The microfluidic devices contained

fifty microfluidic channels each and were

positioned atop each other at perpendicular

angles to create a grid containing 2,500

intersection points, with the tissue sample

placed underneath. The researchers then

flowed fifty unique DNA strands through

the microfluidic channels in each device,

creating 2,500 distinctive combinations

of DNA strands, or “barcodes.” As Fan

explained, each microfluidic channel forms

a long, straight road with a particular

street name, and every cell settled at an

intersection sits like a unique house along

this road. The “barcode” functions as a cell’s

address: a sign-post declaring its location.

“If we know the address code of every

single pixel there, we know where that

house, [or the cell], is located. Basically,

we give every single tiny piece of tissue in

a whole tissue section a unique address

code,” Fan said.

In the procedure, the “barcodes” adhered

to the adapters attached to the selected

genes during the first step of CUT&Tag.

The researchers then photographed the

model to ensure that they could align the

arrangements of different cell types in the

tissue with the spatial data they gathered

from spatial-CUT&Tag. Afterward, they

performed next-generation sequencing,

which allowed them to determine the

DNA sequences of the selected genes.

With this data, they conducted a robust

computational analysis that required

much trial and error to perfect.

“Computationally, there are no

existing pipelines to analyze the spatial

epigenomics data. It took a lot of effort

to borrow the modules developed by

others and generate the whole pipeline

we needed to analyze the data,” said

Yanxiang Deng, a post-doc in the Fan Lab

and the first author of the Science paper.

After months of trouble-shooting and

optimization, they compiled their results.

The researchers found that the epigenomic

map developed by spatial-CUT&Tag

accurately distinguished between the

distinct cell types present in embryonic

and postnatal mouse tissues. In fact, in

one experiment, the epigenomic data

formed distinct stripes that correlated

with the cortical layers in a mouse brain,

demonstrating that spatial-CUT&Tag

could differentiate cell types based on

histone modifications. They validated the

results by running ChIP-Seq tests on the

same tissue samples.


Implications in Cancer Research and

Next Steps

Looking ahead, Fan and Deng want to

expand their study of histone modifications

to other epigenetic mechanisms, including

DNA methylation. The researchers are also

thinking about developing 3D epigenomic

maps, updating the 2D grids generated with

spatial-CUT&Tag data.

“We’re working on combining with other

modalities because these technologies are

working [on] one molecular layer each time.

We are working on co-profiling different

layers of molecules [...] to understand gene

regulation networks,” Deng said.

Deng acknowledged that the development

of spatial-CUT&Tag opens up a wide range of

biological applications—most notably, identifying

epigenetic mechanisms underlying cancer.

Cancerous cells may arise due to epigenetic

alterations, and the difference between a healthy

and malignant cell can be traced back to histone

modifications. “Potentially, if you’re looking at

a disease, [you can use spatial-CUT&Tag to

determine] what actually drives the disease,” Fan

said. “[You can see what is happening at] the

mechanistic level and can target specific histone

modifications in specific loci to develop new drugs

that really target the root of the disease initiation.”

Yet there is still much to be explored;

even with the development of spatial-

CUT&Tag, questions about the future of

cancer epigenetic research linger.

“Now the door is open,” Fan said. “[With

spatial-CUT&Tag], you can begin to gather

data and think about how to target the cancer

with a completely new approach and [find] a

potentially much more efficacious and much

more personalized [treatment] one day.” ■


HANNAH HAN is a first-year prospective HSHM and MCDB double-major in Grace Hopper

College. Beyond writing and editing for YSM, Hannah conducts breast cancer research at the

Yale School of Medicine, volunteers for Splash and HAPPY, and contributes to various literary

publications on campus.

THE AUTHOR WOULD LIKE TO THANK Professor Fan and Dr. Deng for their time and enthusiasm

about their work.


Deng, Y., Bartosovic, M., Kukanja, P., Zhang, D., Liu, Y., Su, G., Enninful, A., Bai, Z., Castelo-Branco, G., & Fan,

R. (2020). “Spatial-CUT&Tag: Spatially resolved chromatin modification profiling at the cellular level.”

Science, 375(6581): 681–686, https://doi.org/10.1126/science.abg7216.

Liu, Y., Yang, M., Deng, Y., Su, G., Enninful, A., Guo, C. C., Tebaldi, T., Zhang, D., Kim, D., Bai, Z., Norris,

E., Pan, A., Li, J., Xiao, Y., Halene, S., & Fan, R. (2020). “High-Spatial-Resolution Multi-Omics Sequencing

via Deterministic Barcoding in Tissue.” Cell, 183(6): 1665–1681, https://doi.org/10.1016/j.cell.2020.10.026.

24 Yale Scientific Magazine May 2022 www.yalescientific.org

A Sixth Sense from

a Sixth Finger


Cognition / Neuroscience


is real, and the truth is not.” So said the wife

of the late Philippine dictator in The Kingmaker, a 2019


documentary film. Although this quote embodies her

distortion of the historical narrative surrounding her husband’s rule,

it also describes how people are sometimes fooled by their senses. We

commonly assume that our perceptions provide infallible information

about our bodies and the world around us. The brain’s vast neural

networks integrate senses—including smell, temperature, and light—

to help us make sense of stimuli in our environment. For instance, we

become aware of a burning fire through the smell of smoke, the heat it

gives off, and the ringing of the fire alarm. Given that our bodies do not

change drastically throughout our lives, our brains are accustomed to

providing a unified experience of these stimuli.

However, recent research has suggested that we can alter how the

brain represents the human body and trick it into

perceiving the existence of imaginary body parts.

Denise Cadete, a psychology Ph.D. candidate at

Birkbeck, University of London, created a

sensory illusion in which participants felt

a sixth finger on their hand. To create this

illusion, the participants placed their hands

on both sides of a vertical mirror so that the

reflection of the right hand would appear

where the left was placed, with the left

hand itself hidden from the participant.

Experimenters then stroked each finger

on both hands simultaneously, starting

with the thumb and ending with the pinky

finger. Finally, experimenters made twenty

double strokes, one stroke on the table next

to the right pinky and another along the

outer side of the pinky.

Though the left hand remained hidden

from sight, participants could see the

reflection of the







right hand

where the left should be

so that it looked as though

the experimenter was

actually stroking the

left hand and

the empty space

next to it. As a result, many participants reported feeling a phantom sixth

finger on their left hand. Furthermore, experimenters were also able to

vary the length of this sixth finger. By altering the length of the strokes they

made on the table, researchers created the sensation of a sixth finger fifteen

centimeters long, or twice the length of the pinky, and 3.8 centimeters

long, or half its length.

Reactions to this perception differed from person to person, but the

word participants used most often was “strange,” even for those who did

not report feeling a sixth finger. Matthew Longo, professor of cognitive

neuroscience at Birkbeck and Cadete’s research supervisor, explains that

this illusion comes from the “temporal synchrony” of the right pinky

being stroked and the eye simultaneously seeing the same movement in

empty space. “[These coordinated events] are a very powerful cue to the

brain that there’s some causal link between these two things,” Longo said.

“The parts of the brain that are integrating visual and tactile information

aren’t interfacing directly with our high-level semantic knowledge.

Instead, they are doing something more basic and automatic.” In other

words, the brain does not use logic, reason, or language to make sense

of stimuli. It’s as if the brain creates its own muscle memory to integrate

sensory information quickly and automatically.

Given that our mental representations of the body are now known

to be quite flexible, this study raises questions about the aim of creating

prosthetic and robotic body parts. Should prosthetics be designed as

replacement body parts trying to embody the appearance of the original

counterparts? Or should they simply be tools, similar to Swiss army

knives, each with unique functions? Cadete believes it is too

early to tell, even though she and Longo were invited to tour

Imperial College London to determine if this research

can inform designs of robotic body parts.

What’s next? Cadete is now attempting to create

the experience of a curved sixth finger. “In theory,

it makes sense that we have some flexibility for

[perceiving] length because our bodies become

longer as we develop into adulthood,” she said.

“However, the shape [of our bodies] is more or less the

same throughout our lives.” Nevertheless, their results look

promising. Though the line between perception and reality can

sometimes be warped, it is likely that for the foreseeable future,

we will not grow phantom fingers on our hands. That is, until

evolution or robotic hands prove otherwise. ■

May 2022 Yale Scientific Magazine 25


Artificial Intelligence






Lego Hogwarts, Lego Krusty Krab, Lego Death Star. Sure.

Fine. But what if there was an artificially intelligent,

maze-solving Lego robot car? Well, that’s exactly what

Paschalis Gkoupidenis and his team at the Max Planck Institute

for Polymer Research in Mainz, Germany, have created.

The idea of artificial intelligence (AI) is the ability to harness

the brain’s efficiency at processing information on a technological

level. Currently, a popular approach to achieving AI is the

functional representation of biological information processing

systems with artificial neural networks. These artificial networks

are achieved by “executing algorithms” which loosely represent

the function of the nervous system in traditional computer

architecture. While this field has shown great promise

for complex processing and efficient computing,

the nature of AI’s programming limits its

interactions with our living world and

its many triggers and signals. In this

manner, it also lacks the efficiency

and computing capacity to model

biological systems.

Alternatively, biological neural

functions can be directly emulated

with unconventional devices,

circuits, and architectures. This

hardware-based paradigm of braininspired

processing is known as

neuromorphic electronics, which

can potentially be far more efficient

at computing and processing. Still,

in order to learn, intelligence requires

“embodiment” through a physical or

virtual body to receive environmental signals

and act on the environment. “Robotics, with

its combination of a physical body and embedded

neuromorphic electronics made of organic materials, can offer

exceptional capabilities in distributed control, learning, and

perception,” Gkoupidenis said. By connecting the sensors with

the actions of an intelligent machine, the associations between the

electronics and the sensors (known as “sensorimotor integration”)

allow the machine to perceive the environment. When these

associations change as a function of time, machines can learn and

improve performance towards a target behavior.

“This idea came after a morning coffee discussion with

Professor A. Salleo in southern France. Back then, I was a

postdoc researcher in France, and Salleo was on sabbatical from

Stanford,” Gkoupidenis said. “This was a really interdisciplinary

project, so planning required knowledge in a wide range of

disciplines and techniques such as electronics, microfabrication,

3D printing, and of course, robotics and biology.”

With this team, Gkoupidenis outfitted a Lego car with a

neuromorphic circuit, which could be shrunk down to a few

micrometers, similar to the size of biological neurons. This circuit

created a connection between the sensors and the robot’s motors,

which are used to help the robot car perceive its surroundings and

move around within it. “The key property of the circuit is that it’s

trainable, meaning that its electrical properties change gradually.

This is achieved by gradually accumulating and storing ions inside

the devices when the robot fails to achieve its task.” The robot’s

mission was to make its way out of a maze of hexagonal unit

cells in a honeycomb pattern. The researchers created

a path towards the maze’s exit by putting visual

cues (circle arcs) at specific maze intersections

that indicate a left turn, with right-turning

as the baseline movement. Every time the

robot failed to find the exit, it would hit

the borders of the maze with its touch

sensor. This interaction was then

received by the neuromorphic circuit,

allowing the robot to gradually learn

the correct route out.

Spoiler alert: the Lego robot car

found the exit!

What is incredible about

Gkoupidenis’ research is their

use of organic materials to make

the circuit, which can conduct both

electrons and ions. By using ions as the

carriers of information instead of electrons,

as in classic electronics, neuromorphic devices

more realistically emulate biological processes.

Furthermore, organic devices are soft, flexible, and even

stretchable, potentially allowing these circuits to be distributed

on a robot—which is exactly what happens in living organisms

where intelligence is literally distributed everywhere

throughout their body. These concepts can be useful across a

wide range of robotic systems, whether at home or in industry,

agriculture, and the oceans. “We will see similar concepts in

the future in smart bioimplants, for instance, artificial limbs

or bioelectronic devices that learn gradually to live efficiently

and together with their ‘owners.’ This will be a new type of

hybrid, artificial-biological intelligence, in which both worlds

operate synergistically,” Gkoupidenis said. ■

26 Yale Scientific Magazine May 2022 www.yalescientific.org


Material Science





If you find it difficult to brush and floss regularly, you might be in

luck. Researchers from China and the US engineered an artificial

alternative to enamel that was designed to be even stronger. But

could this man-made enamel trick a tooth fairy?

Enamel is the tooth’s outer shell responsible for shielding teeth

from damage. This tissue usually serves the body for over sixty

years and cannot be regenerated. In addition to enamel’s incredible

durability, it possesses outstanding viscoelasticity—the ability to

endure vibration and deformational damage for long periods, such

as when chewing. While viscoelasticity is key to enamel’s longevity,

its hardness allows teeth to bite through tough material. However,

these mechanical properties are traditionally considered trade-offs

and are difficult to reproduce in man-made materials.

The challenge was to figure out how to copy what nature had

already designed. The key to enamel’s seemingly paradoxical

combination of properties turned out to be its hierarchical structure

of elements, represented by the dense packing of nanowires

interlaced with soft organic matter. The organic material is known

as the amorphous intergranular phase (AIP), which effectively forms

a connection between adjacent nanowires through strong chemical

bonds. According to Lin Guo, corresponding author and Beihang

University Professor of Chemistry, the abundance of unsaturated

chemical bonds in amorphous materials allows for this tight binding.

“The notion of functional complexity, which requires some amount

of order and some amount of disorder, is the great representation

for this amorphous, disordered layer on the surface of the nanorods

forming enamel,” said Nicholas Kotov, corresponding author and

University of Michigan Professor of Chemical Sciences and

Engineering. “The inside of [the enamel’s




nanorod structure]

is ordered for the

stiffness, and the

outside is disordered

for the adaptability of

the interfaces.”

The interface is the area

between the inorganic material—

the surface of the nanowires—and

the polymer around it. The AIP

acts as a buffer layer that not only

facilitates the transfer of force but

strengthens the interface. A strong

interface is essential to

protecting the nanowires

from environmental

attacks by acids, alkaline substances, and sharp temperature

changes, while enhancing enamel’s mechanical performance. This

dynamic layer effectively restricts the propagation of cracks that

tend to occur along the interfaces.

In order to successfully arrange the structural elements of their

synthetic enamel, Kotov drew inspiration from previous studies

of chemical engineering processes based on self-assembly. The

self-organization of nanorods was achieved through a double

freezing technology approach. By applying a freezing gradient,

the nanorods were forced to align along one axis, resulting in

their proper parallel alignment.

“Everything in living matter is based on self-organization,” Kotov

said. “This is ubiquitous. Manufacturing based on self-assembly is

very attractive for its low-temperature requirements, high energy

efficiency, and applicability to a multiplicity of structures—from

nanoparticles to nanorods to microscale particles to microscale

and nanoscale dental works.”

To test this structure’s strength, the team applied an external load

to a sample of their synthetic enamel. The nanowires initially slid

in response, but the confinement of the organic matter in the gaps

between nanowires restricted motion. This hierarchical structure

ultimately improved crack deflection, allowing the synthetic

enamel to withstand more force than natural enamel.

“Does it mean that we have created material better than what has

been created by living organisms after billions of years of evolution?

The answer is yes, that’s exactly the case,” Kotov said.

Kotov proposed using this synthetic enamel to engineer ‘smart

teeth.’ These sophisticated implants would detect disease inside of

the mouth through sensors for anything from bacterial composition

to inflammation. This enamel would afford these implants the same

type of protection as normal teeth.

Beyond teeth, the simplification of enamel down to layers

enables this structure to be built at multiple scales. The successful

reproduction of tooth enamel opens the door to engineering other

high mechanical performance materials.

“The combination of high hardness and stiffness plus

viscoelasticity, strangely enough, is very much needed for buildings

because of earthquakes, especially for sensitive structures such

as nuclear plants,” Kotov said. “So, scaling up the preparation of

materials like enamel and implementing enamel-like materials in

other areas of technology are squarely in our plans.”

For the inexperienced tooth fairy, this synthetic enamel could

pose an evolutionary feat thanks to its strength. But to trick

a seasoned tooth fairy, more research on mimicking the 3-D

structure of teeth will be required. ■

May 2022 Yale Scientific Magazine 27


Quantum Physics / Optics

A Real-Life Infinity Stone


Using optics to harness a

unique state of matter

By Anavi Uppal

In grade school, many of us learned

that there are three basic states of

matter in the universe: solid, liquid,

and gas. However, in recent years, scientists

have created several more, including

one state that seems to bend the laws of

physics: a “time crystal.” While it may

sound more like an Avenger’s oddity than

a scientific reality, time crystals have

unique properties that can be used for

extremely precise timekeeping. Previously,

they have been very difficult to create

and maintain. Now, researchers from the

United States and Poland have innovated

a new way of creating time crystals that

could allow them to leave the confines of

sophisticated laboratories and be used for

everyday applications.

Most people are familiar with normal,

garden-variety crystals: quartz, diamonds,

snowflakes. These crystals consist

of repeating patterns of atoms layered on

top of each other to form a 3D structure.

In 2012, theoretical physicist and Nobel

laureate Frank Wilczek wondered if a

similar phenomenon could exist where

a crystal’s pattern would repeat in time

rather than in 3D space. The crystal’s default

state would be to switch back and

forth between two different structures.

What makes time crystals so strange

and unique is that they spontaneously

break time-translation symmetry, which

says that a stable object will act the same

throughout time.

We have an intuitive sense of time-translation

symmetry for objects in our daily

lives. For example, imagine that you’re

holding a tray with a rubber ball on it. You

tilt the tray from side to side, making the

ball roll across the tray repeatedly. You

expect the ball to make one trip across

the tray each time it is tilted—however, if

the ball suddenly decided to rocket back

and forth across the tray fifty times faster

than the speed of your tilting, you would

certainly be very surprised. This change

breaks time-translation symmetry, just

like time crystals do. Time crystals are

naturally not in static equilibrium, making

them a new state of matter.

Scientists first created a time crystal

in 2016, and several groups have devised

different versions of time crystals since

then. However, they all have one unfortunate

characteristic in common: they

can’t ever be taken out of the lab due to

their complicated and precise configurations.

In fact, after a certain amount

of time, even the crystals in the lab will

devolve and stop their periodic motion.

These factors severely limit the lifetime

of time crystals and prevent them from

being used for everyday applications

outside the lab. However, a few groups

of scientists have proposed to the creation

of a time crystal out of light that

wouldn’t be bound by these limitations,

and one recently succeeded in creating

one of these time crystals.

In 2018, Hossein Taheri was a recently

graduated electrical and computer engineering

Ph.D. who had just started his lab at the

University of California at Riverside. While

visiting a friend for lunch at the California

Institute of Technology and chatting about

physics projects, his friend mentioned a curious

concept he had never heard about before:

time crystals. When he returned home

that day, he found and read a review article

that discussed time crystals, and it struck a

chord with him. “Within a few days, I was

just thinking that, well, we can create something

with these properties!” Taheri said.

He shared his thoughts with Andrey

Matsko, a group lead and collaborator

at the NASA Jet Propulsion Laboratory

working with quantum and nonlinear optics.

Matsko agreed that their work might

relate to time crystals and greenlighted

delving further into this line of research.

In their first couple of papers, they wrote

very cautiously about the concept. “But

little by little, we realized that, well, we

are on the right track. Why not shoot

higher?” Taheri said. Taheri then decided

to contact and collaborate with Krzysztof

Sacha, a physics professor at Jagiellonian

University and one of the first

researchers to study time crystals.

Their team’s approach is simpler

and less expensive than those previously

used to create time crystals.

They shine two lasers into a tiny

crystal cavity roughly two millimeters

28 Yale Scientific Magazine May 2022 www.yalescientific.org

Quantum Physics / Optics


across, and the beams bounce around the

walls of the cavity. The beams are stabilized

using a method called self-injection

locking, which was developed by a team

at OEwaves Inc. led by president and CEO

Lute Maleki. If the beams are tuned to the

correct power and frequency, the interacting

light eventually spontaneously resonates

at a frequency entirely different from

the properties of either input laser beam,

creating a time crystal in the cavity. Previous

studies had only ever used solid-state

physics to create time crystals—theirs was

the first to use light and optics.

Their light-based time crystal is revolutionary

because it isn’t subject to the

limitations of solid-state physics. Previous

solid-state time crystals required

extremely cold cryogenic environments

and complicated, expensive equipment.

In contrast, optics work just fine at room

temperature and can also create time crystals

with a much longer lifetime. “What we

are offering with this work is that if you

have a resonator and two lasers, and you

spend probably a few thousand dollars on

your setup, you in principle can generate a

time crystal,” Taheri said. This pioneering

innovation makes the study of time crystals

vastly more accessible and could

pave the way for using time crystals

in everyday applications.

The main application of lightbased

time crystals comes

from their remarkably accurate

timekeeping abilities.

While they are some

orders of magnitude less

precise than state-ofthe-art

atomic clocks,

they aren’t picky about

their environmental

conditions and can

thus provide highly

accurate timing while

being rugged enough

to load onto a plane

or car. This

tradeoff in precision is necessary since

the time crystal generated by the team

cannot be more stable than the two lasers

that created it. In order to have more

stable lasers, the environment around

the crystal would need to be tightly controlled,

or the system setup would have

to be more complicated.

Light-based time crystals could also enable

entirely new avenues of physics research

through the creation of bigger time crystals.

The “size” of a time crystal refers to the ratio

between two different time periods: the time it

takes for one complete back-and-forth structure

change of the time crystal and the period

of the laser’s light waves. A “bigger” time crystal

has a larger ratio. Most previous time crystals

only had a size of two or three, while this

research team’s light-based system could create

crystals with a size of twenty or even fifty. These

bigger time crystals would essentially provide

scientists with a larger “laboratory

space,” allowing them

to do more complicated


ments. In particular, larger time crystals can be

used to mimic condensed matter time crystal

experiments that are otherwise difficult or even

impossible to conduct in smaller time crystals.

But beyond this known application, the study

of the crystals themselves is still young and

could result in fascinating new science that researchers

can’t yet imagine. “This, for me, is the

most interesting application,” Matsko said.

It’s extraordinary that just ten years after

Frank Wilczek’s musings about the existence

of time crystals, we are now close to

seeing them outside the laboratory. But this

transition from a dream to reality isn’t a

novel process—even the first cell phone was

inspired by Star Trek’s sci-fi communicator

devices. Scientists who dare to adventure

have the incredible power to forge these

far-fetched ideas into our world’s reality. ■

Ann-Marie Abunyewa

Art By


May 2022 Yale Scientific Magazine 29




How an unexpected

part of the cerebellum

regulates food intake



We all have that friend. The one

who can eat donuts and ice

cream—essentially whatever

they want—without gaining weight. On

the other extreme, some people seem to

gain weight no matter how little they eat or

how much they exercise. So, what exactly

is it that allows one person to remain thin

without much effort but requires another

to struggle to avoid gaining weight?

On the most basic level, your weight

depends on the number of calories

you consume, store, and burn up, but

each of these factors is influenced

by a combination of your genes and


They can affect

your physiology

and behavior, ranging

from how fast you burn

calories to what types of food you

choose to eat. The human body maintains

a delicate balance of “adaptive feeding”

to ensure sufficient food intake and limit

consumption to maintain a stable body

weight. In the face of environmental

changes and food availability, this balance

ensures body weight homeostasis. Today,

this equilibrium is greatly skewed to favor

a positive energy balance. As a result,

the increasing prevalence of obesity

highlights the need to better understand

body weight control.

A team of researchers led by Dr. Albert

Chen at the Scintillon Institute, Dr.

Nicholas Betley, and Dr. Aloysius Low at

the University of Pennsylvania recently

found that a distinct group of neurons

in the cerebellum—a region of the brain

that had previously never been linked to

hunger—controls appetite. The project

began with an unexpected finding by

Chen’s team, who noticed that they could

make mice eat less by activating a small

group of neurons known as anterior

deep cerebellar nuclei (aDCN) within

the cerebellum. Despite their specialty in

spinal and cerebellar circuits involved in

motor control, Chen and Betley contacted

their colleagues—Dr. Laura Holsen

(Brigham and Women’s Hospital), Dr.

Roscoe Brady (Beth Israel Deaconess

Medical Center), and Dr. Mark Halko

(McLean Hospital)—affiliated with

Harvard Medical School to see whether

this phenomenon could be observed in

humans with eating disorders.

The Harvard scientists had previously

collected a data set of functional

magnetic resonance imaging (fMRI) of

fourteen individuals with Prader-Willi

syndrome (PWS), a rare genetic disorder

characterized by insatiable hunger,

developmental delay, and behavioral

problems that can lead to life-threatening

obesity. The researchers recorded the

brain activity of these subjects while

they viewed images of food either after

eating a meal or after fasting for at least

four hours. A new analysis of the data

30 Yale Scientific Magazine May 2022 www.yalescientific.org



Brain's Brake

on Overeating

compared to the fMRI scans of unaffected

individuals confirmed that the deep

cerebellum was the only brain region

that showed a significant difference in

neural activity between PWS and control

subjects. To precisely define the subgroup

of neurons in the cerebellum responsible

for this phenotype, Low, a Ph.D. graduate

of Chen’s lab, transferred to Betley’s lab

at the University of Pennsylvania, which

specializes in studying homeostatic and

hedonic feeding circuits.

“It had always been a graduate school

dream of mine to do a project together

with Nick,” Chen said. “In fact, a lot of the

collaborators on this project had worked

together on the same floor in graduate

school [at Columbia University], so we were

determined to make this project work.”

“It was through Low’s dedication,

however, that we were able to see this

collaboration through,” Betley said.

“Every project for a graduate student runs

into difficulty—Low had discovered an

incredible feeding phenotype but could

not get the phenotype independent of a

reduction in locomotion.” While Low had

observed that the specific activation of

the aDCN in the cerebellum reduced food

intake in mice, he also needed to prove

that this phenotype was independent of

locomotion, which was also known to be

regulated in the cerebellum. Furthermore,

since the cerebellum had never been

linked to appetite regulation before, the

proof had to be indisputable. For example,

if the activation of the aDCN reduced the

motor skills of the mice, which caused the

subsequent decrease in food intake, they

would not be able to definitively conclude

that the aDCN was a direct feeding center.

“We were close to killing the project

so many times,” Chen said. “But,

by continuing to pursue his theory

and performing over a hundred new

experiments, Low was able to define

the precise subpopulation of neurons

involved in regulating feeding—and

that was the entire difference,” Betley

said. Once Low had developed mice

models where the feeding phenotype was

completely isolated from locomotion,

they could conclusively prove that the

aDCN really was a feeding center rather

than a center that affects feeding through

a change in locomotion.

Further experiments then elucidated the

mechanism behind the feeding phenotype.

The activation of aDCN activates ventral

tegmental area dopamine neurons that

release dopamine in the ventral striatum,

a region of the brain involved in reward

processing, motivation, and decisionmaking.

The team had observed a strong

correlation between levels of ventral

striatal dopamine and reduction in food

intake after aDCN activation. This seems

paradoxical since higher dopamine

levels should reinforce food intake while

decreasing dopamine levels may result

in anorexia. However, the long-lasting

increase in baseline dopamine levels

can reduce its responsiveness to food.

Increasing baseline levels blunt how the

brain’s pleasure center responds to food,

similar to how the effects of drug intake

are blunted over time.

The team also observed that the

reduction in food intake did not

cause any metabolic compensation or

increased food intake to make up for

the missed meal. Caloric deficits in

animals usually cause their metabolism

to slow down, but this was not observed

in the mice models with activated

aDCN. Thus, these findings have

great potential to address obesity,

as a reproducible caloric deficit will

ultimately result in weight loss.

Today, Chen and Betley continue

their collaboration to test whether

they can manipulate aDCN activity in

patients with PWS using a noninvasive

intervention known as transcranial

magnetic stimulation (TMS). They

are hopeful that TMS can be used to

activate aDCN activity to reduce food

intake in patients with PWS. These

experiments could not only lead to a

clinical trial to treat PWS but also open

up new avenues for treating other types

of eating disorders.

Chen and Betley hope that their

research will change how scientists view

neuroscience and how the general public

views obesity more broadly. Their findings

are only the latest in a series of discoveries

revealing that different regions of the

brain are not simply responsible for one

specific subset of behaviors but rather

overlap in their functions to regulate

human behavior. Thus, Chen and Betley

hope that large collaborations between

experts in different brain regions will

become more common.

Moreover, they hope that these findings

will change how we view individuals with

obesity. Unfortunately, it is common

to blame people with obesity for their

condition. However, rather than blaming

a person for their lack of control or

willpower, we might be more sympathetic

to their condition, understanding that

obesity is a disease. As we continue to

learn more about how our brain, genetics,

and environment impact our bodies, we

will become more equipped to address

eating disorders in a more compassionate

and constructive manner. ■


May 2022 Yale Scientific Magazine 31


Nuclear Energy



Producing a





Fusion – the ambitious goal of energy

research and science fiction material

from Iron Man to Star Wars. Though

touted as the ultimate solution to our

search for a clean and cheap energy source,

practical fusion energy has eluded our grasp

for decades since its theoretical conception

in the late 1920s.

During fusion, two isotopes of hydrogen

– deuterium and tritium – are subjected to

extreme heat and pressure until they form

a plasma and subsequently coalesce into

helium. During this process, a small fraction

of the mass is converted into astronomical

amounts of thermal energy. The process is

far more sustainable, productive, and safe

than any current energy source, but a series

ICF Fusion Apparatus


of physics and engineering challenges have

long prevented retrieving a net gain in

energy. However, recent developments at

the National Ignition Facility (NIF), such as

having the fusion fuel heat itself, are rapidly

changing that narrative.

Just east of San Francisco, the Lawrence

Livermore National Laboratory, which hosts

the NIF, has been tackling fusion since the

1960s. The multi-billion-dollar campus was

created to engineer a particular path towards

fusion: inertial confinement fusion (ICF). In

this method, the inertia of the fuel keeps

itself stationary for less than a billionth of

a second, during which intense heat and

pressure force its compression.

Inside the apparatus, deuterium-tritium

fuel is contained within a diamond capsule,

hovering at the center of a cylinder called a

hohlraum. Lasers surround the hohlraum

and inject light into openings on the

hohlraum’s ends at various angles. Some

lasers–outers–strike the hohlraum at a

greater angle and farther from the capsule

than others called inners, and both cause

X-ray emissions. These X-rays converge

on the capsule like hammers on hot metal,

carrying energy that ionizes the diamond

surface, producing an explosion. This

explosion generates pressure that initiates

an implosion, compressing and heating the

capsule and fuel to the point of fusion.

These reactions operate on a small

scale.Only two hundred micrograms of

fuel are used, the energy entering the

hohlraum–1.9 megajoules–is only enough

to run a computer for a few hours, and

the fusion yield is currently less than

that. However, the power involved is on

a massive petawatt scale due to the speed

at which the energy is consumed and

produced. Burning more fuel requires

extra control, a future goal for the team.

Fusion research proceeds through a

stairway of milestones. “[Each milestone]

slowly tips the balance in the fusion

plasma between [energy] losses and

gains,” said Omar Hurricane, the colead

author of two breakthrough papers

recently published in Nature. After the

first milestone—initial fusion with some

self-heating—comes fuel gain, where

fusion yield surpasses the energy input.

Next is the burning plasma state, where

self-heating by helium nuclei produced

during fusion eclipses external heating.

Finally, ignition. Much like a rocket,

ignition allows fusion reactions to take

off. Ignition overcomes all cooling

processes, and the fusion reactions

become self-sustaining.

Following the launch of ICF experiments

in 2009, the NIF achieved fuel gain in

2014. Subsequently, hundreds of scientists

at the NIF set their eyes on the next

milestone of the burning plasma state.

However, they encountered one central

problem: asymmetric implosions.

“We’d like this nice spherical compression

to maximize the transfer of kinetic energy.

We put energy into the shell, it flies

inwards, and it carries the fusion fuel on

the inside, and at some point, it runs out

of any place to go, converting that kinetic

energy into internal energy. That’s what

heats the fusion fuel up,” Hurricane said.

32 Yale Scientific Magazine May 2022 www.yalescientific.org

Nuclear Energy


In an asymmetric implosion, the pressure

is unevenly distributed around the capsule

and fuel, inducing movement of the capsule’s

center of mass during the implosion. The

kinetic energy of that movement is siphoned

from the input energy, representing a major

leakage in the conversion of the fuel’s kinetic

energy into internal energy. Asymmetry

can be produced by imperfections in the

capsule, in the lasers and their resultant

X-rays, and in the inward movement of

plasma generated when the lasers strike

the hohlraum.

The scientists approached

these problems through a

combination of theoretical

physics, experimentation,

and iterative development

of simulations. They soon

discovered a problem:

previous simulations

weren’t accurate in predicting

the interference to the laser beams

from laser-generated plasma.

For example, a plasma

cloud generated by the

outers, which strike the

hohlraum nearest to where the

lasers enter, can expand rapidly and interfere

with the inners, producing asymmetries.

“It’s been a very iterative set of steps

where we go from doing experiments,

seeing something wrong, figuring out

what’s wrong, how to fix it, implementing

the fix, doing another experiment, and the

whole cycle starts over and over again,”

Hurricane said. “That’s what a lot of science

is … but you do steadily make progress, and

that’s what we’ve done

over the last decade.”

Of the many

proposed solutions,

only two could be selected for testing due

to limited resources. The first solution

implements cross beam energy transfer

(CBET), allowing one laser to transfer its

energy to the other laser, given correct

engineering of the laser wavelengths. CBET

permits energy transfer to the inners,

producing a more symmetric implosion. The

second solution addresses the issue of the

outer-laser-generated plasma interference.

Creating pockets in the hohlraum at the

site where outers hit increases the distance

the plasma must travel

toward the

center. This

gives inners more

opportunity to travel without interference,

decreasing laser asymmetry.

Now that asymmetry is less of a limiting

factor for energy transfer, the researchers

have enlarged the fuel-capsule target,

which increases the heating tendency

of the fusion fuel relative to its cooling

tendency. As further solutions to fuelcapsule

asymmetry are developed, the fuel

load can be increased, producing more

efficient fusion reactions.

The NIF tested these three innovations

in combination and found that they had

And the whole cycle starts over and over

again. That’s what a lot of science is … but

you do steadily make progress.

achieved a burning

plasma state, making

substantial energy

gains in the process. Their maximum

fusion yield was 0.17 MJ, about ten times

smaller than the input laser energy but

ten times greater than the energy input

into the fuel, far surpassing the fuel gain


While the significance of burning

plasma for energy research is undeniable,

the limited yield and scalability of the

reaction hinder its applicability. A viable

power source requires ignition, the

efficient capture and conversion of released

thermal energy into electric energy, and

a yield surpassing the hundreds of

megajoules required to

operate the fusion reactor.

Yet, the burning plasma

milestone provides a

strong foundation for the

future of fusion. “It’s an

existence proof… that

maybe this is possible, that

we’re not all crazy, and we’re not

wasting our time (entirely)

working on this stuff.

That being said, it’s also

showing it’s actually much

harder than people originally expected,”

Hurricane said.

The first of these requirements, and the

last milestone from the physics end of

fusion research, has already been achieved

by the NIF–ignition! In unpublished

results, the team achieved an energy

yield of 1.35 MJ, approximately 70% of

the input energy. Further research will

focus on overcoming engineering hurdles

to improve energy yield, increasing fuel

volume while avoiding asymmetry, and

better simulating compression dynamics.

Unlike what science fiction often

leads us to believe, these developments

are not straightforward solutions

designed by a few notable people but

are decades-long projects requiring

the input of generations of scientists

and engineers repeatedly redesigning,

testing, and troubleshooting. As the

hundreds of scientists and staff at the

NIF have demonstrated, the future of

fusion is bright. Although we are still far

from having miniature Suns powering

our everyday devices, we now have

experimental confirmation of a selfheating

and even igniting plasma. ■


May 2022 Yale Scientific Magazine 33






YC ’22

Yale senior Jennifer Miao (YC’22) was recently awarded the

Gates Cambridge Scholarship, a prestigious fellowship that

fully supports Miao’s pursuit of a Ph.D. at the Laboratory

of Molecular Biology at Cambridge (LMB). At Yale, Miao is a

member of the Trumbull community, enjoys leading Yale’s running

club as the captain, and is currently working at the Mariappan Lab

on Yale’s West Campus.

Despite Miao’s incredible dedication to her scientific pursuits,

she has not sacrificed her passion for the outdoors. Miao runs

every morning despite long hours at the lab. When asked how

she juggles her many commitments, she explained that she does

not see her daily runs as a burden. “It really helps with balancing

the stresses of lab, schoolwork, and just college life. It also helps

to sort of get new ideas and just get away from work and come

back to it with a sort of renewed vigor,” Miao said.

Miao’s scientific journey started when she was a high school

student working in a lab at UCLA under Associate Professor

Jose Rodriguez. She used X-ray crystallography to structurally

elucidate the core of an infectious prion fibril which has been

implicated in many neurodegenerative diseases. This work

ultimately culminated in a paper detailing a new approach to

resolving protein structures.

Miao explained that a huge problem in structural biology today

is the loss of critical information from the diffraction pattern

returned by X-ray crystallography. This issue is, in part, avoided

by using a related protein model in different stages to refine the

existing model. However, Miao worked on adapting a new way

to circumvent this issue by using fragments of a non-related

protein model of the structure and obtaining an atomic structure

through electron diffraction. Using this technique, Miao eventually

published another paper displaying her findings on the core of

prion fibrils and their relationship to a right or left orientation.

Miao spoke at the prestigious 2019 CCP4 Study Weekend at

Nottingham University, U.K. During her first trip to the U.K., she

describes having enjoyable conversations with Phil Evans, a former

group leader at the LMB, and Randy Read, a crystallographer at

Cambridge University.


When it comes to influential scientists and research mentors,

Miao has no shortage of inspiration. Miao’s first mentors in

academia were Rodriguez and David Eisenberg of UCLA. Her

unwavering focus as an undergraduate to obtain a Ph.D. comes

from her love of the exploratory and collaborative manner with

which Rodriguez encouraged his students to work. She fell in love

with academia because her work with Rodriguez was curiositydriven,

as very few answers were known for the questions she was

studying in his lab. “[I] enjoyed thinking about and planning my

experiments every day,” Miao said.

While Miao was pretty set on pursuing a Ph.D., she was unsure

whether it would be in the US or the U.K. “What really influenced

me to look into the U.K. was Dr. Rebecca Voorhees at Caltech

because she also did a Ph.D. at the LMB and was very enthusiastic

about it,” Miao said.

Miao will be pursuing structural biology research elucidating the

mechanism of mitochondrial protein recruitment from the cytosol,

which would be influential in mitochondrial metabolism research.

Miao is most excited about the community that facilitates diverse

scientific discourse at LMB. “The culture is quite different from

the US. There is coffee time and tea time every day, where most

of the labs gather in the canteen on the top floor of the building

to talk about science. At the canteen, there is an abundance of

expertise across so many disciplines,” Miao said.

In parting Yale, she advises any prospective STEM

student interested in academia to fearlessly pursue

their research passions and find great mentorship

among the approachable research faculty. “Don’t

[be] afraid to [...] ask for help or get advice

from professors. They’re always willing to

spend time to help undergraduates,” Miao

said. She cited her experience working

with renowned RNA biologist Joan

Steitz. “People I thought would be

completely unapproachable were

actually very down-to-earth and

easy to talk to,” Miao said. ■

34 Yale Scientific Magazine May 2022 www.yalescientific.org





YC ’92

With the advent of social media networks like

Facebook and Snapchat, our world is increasingly

connected and complicated. Understanding the

nature of these networks now requires wading through enormous

amounts of information and performing overwhelming computations.

This problem will only multiply in the future, making arriving at any

meaningful conclusions about data unimaginably difficult.

This was the dilemma that Daniel Spielman (YC’92), Sterling Professor

of Computer Science and Professor of Statistics and Data Science and

Mathematics at Yale, sought to solve. He wanted to use a technique called

sparsification, which takes large data sets and removes points that do not

contribute important information about the data. He found inspiration

in an almost unrelated field of mathematics. This venture helped him

solve a decades-old problem in the field of operator theory, earning him

the Ciprian Foias prize and the Polya Prize.

Spielman had initially thought that his problem was in the realm of

linear algebra. “It’s one of those courses every math major takes that

talks about finite-dimensional spaces,” Spielman said. However, upon

discussion with visiting professors and his graduate students, Adam

Marcus, a postdoc at Princeton University, and Nikhil Srivastava, a

graduate student at UC Berkeley, he realized that his sparsification

problem mirrored an existing problem in operator theory called the

Kadison-Singer problem, developed in 1959. The Kadison-Singer

problem, which examines how to divide a group into two groups that

are as equal as possible, had previously been discussed in the fields of

quantum physics and computer science but had not previously been

explored in the field of data science.

The Kadison-Singer problem, or the concept of partitioning groups in

general, is relevant in everyday decision-making. Suppose a PE teacher

needs to divide a class of students into two equally skilled teams to

play kickball. To achieve this, he will need to rank the students by their

kicking, throwing, and catching abilities and separate students so that

the two teams are approximately equal in all three abilities. Spielman’s

initial paper proved that the Kadison-Singer problem was an equivalent

restatement of the sparsification problem. In a monumental 2014

paper, Spielman and his colleagues proved the existence of a solution,



countering Kadison and Singer’s decades-long conjecture that not every

mathematical group could be divided equally. Marcus, Srivastava, and

Spielman’s work earned them the Polya Prize in 2014. Proving the

ability to partition groups provided the impetus to explore new ways

to divide networks into relatively equal groups, which aided in network

sparsification: if one group was simply omitted from the network, there

wasn’t any net loss of information. In subsequent years, Spielman and

his team worked on developing mathematical tools to achieve such

data sparsification, for which they received the Ciprian Foias prize in

Operator Theory earlier this year.

Spielman’s transformation of a linear algebra problem into an operator

theory problem reflects his general approach to mathematics. He first

became interested in solving challenging puzzles in the fourth grade,

took college math and programming classes in high school, and pursued

a bachelor’s degree in mathematics and computer science at Yale. He has

always been interested in using computational tools to solve problems.

“There’s a marriage between [math and computer science]. I was once

trying a proof in my undergraduate lab, and a computer program found

a counterexample in a couple of months that I wouldn’t have found in a

hundred years,” Spielman said.

Spielman now employs computation in all of the problems he chooses

to solve. “I keep a list of problems that interest me, and when I am

interested in working on a problem, I check if there’s a similar problem

on my list and if someone’s already worked on similar problems,”

Spielman said. He claims he cannot predict what problem he wants to

solve next. He may continue working on sparsification, networks, or

topics in linear algebra but will inevitably draw inspiration from other

mathematical concepts and fields. “I completely change my research

agenda every few years,” Spielman said.

He is currently working on establishing the Kline Tower Institute

(KTI) for the Foundations of Data Science to sponsor talks between

experts in different fields who want to employ data science techniques

in their work. Ultimately, Spielman encourages every college student to

try some math classes. “You never know what’s going to be useful, so

you should take classes that interest you. Later in life, you may find that

useful connection,” Spielman said. ■

May 2022 Yale Scientific Magazine 35







Can we trust our own reality?

As neurologist Guy Leschziner describes in his recently released book, The

Man Who Tasted Words, the senses of sight, sound, touch, taste, and smell

enable humans to craft an understanding of the world outside the physical body.

“These senses are our windows on reality, the conduits between our internal and

external lives [...] Without them, we are cut off, isolated, adrift,” Leschziner writes.

Moreover, as the phrase “seeing is believing” suggests, humans often rely on sensory

information as infallible evidence obliterating all doubt about the existence of some

entity or phenomenon in the world. However, are the senses accurate?

“What we believe to be a precise representation of the world around us

is nothing more than an illusion, layer upon layer of processing of sensory

information, and the interpretation of that information according to our

expectations,” Leschziner writes. He suggests that the sensory organs fail to

function as accurate witnesses of reality. Therefore, we should question the

reliability of conscious experience. In essence, the nervous system functions

as a supercomputer manufacturing human perception through processes

reconstructing sensory inputs largely without our awareness. That is, the

physical interactions of the sense organs—the eyes, skin, ears, nose, and

mouth—with the external world are merely basic inputs quite disparate from

the nervous system’s construction of perception.

If the nervous system shapes our reality, what happens when neural

processes go awry? Throughout his book, Leschziner describes individuals

with sensory abnormalities. For instance, one patient named James

experiences synesthesia, in which stimulation of one sensory modality

concurrently evokes sensation in another modality. For James, this involves

the fusion of sound and taste, conferring the ability to essentially perceive the

taste of words. The Lord’s Prayer tastes like bacon, the name of his friend’s

wife tastes like chunky vomit, the word “court” tastes like a crispy fried egg,

and his grandmother’s name tastes like rich condensed milk. As James’s story

demonstrates, neurological conditions like synesthesia fundamentally alter

one’s experience and perception of reality.

Humans often rely on the senses for a faithful understanding of the external

world. However, we must recognize the innate limitations of that approach.

“Our experiences and cold, hard reality can be almost entirely divorced, as with

molecules of a particular structure and our experience of smell or flavour,”

Leschziner writes. The brain essentially manufactures a perception far removed

from the physical world. Meanwhile, human perception remains reliant on the

integrity of the nervous system that converts basic sensory inputs into conscious

meaning. “The pathways, from physical environment to our experience of it,

are convoluted and complex, vulnerable to the nature of the system, friable

in the face of disease or dysfunction,” Leschziner writes. As it appears, the

brain functions as the master controller employing unseen manipulations to

manufacture a perception both distinct from physical reality and malleable in

response to structural or functional changes in the nervous system.

Perhaps we cannot trust our own reality. ■

36 Yale Scientific Magazine May 2022 www.yalescientific.org



Your favorite artist takes the stage, and you cheer wildly along with

the ten million other people standing next to you. No single physical

stage could fit a crowd of that size, but there is a place that can.

Welcome to the metaverse. The future that we saw in sci-fi movies has hit

the public as an emerging reality following Facebook’s rebranding to Meta

and the online gaming platform Roblox going public on the stock market.

The metaverse can be defined as many things: virtual reality, the evolution of

the internet, a digital economy, a place where avatars of ourselves interact with

others, and so on. So, to put it more clearly, Yonatan Raz-Fridman on the podcast

“Into the Metaverse” reframes the question from what the metaverse is to what

the metaverse isn’t. “The metaverse is not a device. It’s not something you’re going

to access from your mobile phone, VR goggles, or AR glasses…The metaverse is

the next iteration of the internet,” Raz-Fridman said. A podcast co-hosted by Raz-

Fridman and Matthew Kanterman, “Into the Metaverse” explores subjects from

development and investment to experience within this new space.

Over the past two years, we have seen the effects of the pandemic on human

lifestyle and our dependence on technology for connection and education.

With isolation restrictions loosening in the U.S. and worldwide, most

believe we will return to a state of pre-coronavirus normalcy. However, in

actuality, especially in younger generations, constantly being online has been

ingrained into daily rituals. For example, the average amount of time spent on

Roblox has continued to increase even with more relaxed restrictions. “[The

metaverse is] going to reimagine our lives in virtual spaces,” Raz-Fridman

said. Starting from entertainment and gaming with companies like Roblox,

Epic Games, and Unity, the metaverse will also extend into all industries,

education, workplaces, and fundamentally, how we connect with others.

This novel technology is fascinating, even a bit scary, as there is so much

to look out for. Who will govern the metaverse? Will the major companies

developing the metaverse try to keep it as a closed ecosystem or a walled

garden? Or, will control of the metaverse become more decentralized,

something PERSON USING that A VR HEADSET could align TO ACCESS with THE the METAVERSE. growing popularity of blockchain

technology, NFTs, and cryptocurrency?

There are so many other questions to consider. How do we increase internet

access to more regions of the world that need it? Will the metaverse be a form

of escapism from the real world? Or a place to exploit consumerism in the

virtual world? How do we keep our human connections and identities? How

will the metaverse affect climate change? How to define the metaverse and

questions like these are constantly being discussed and reevaluated on the

podcast—take a listen! The hopeful stances of Raz-Fridman and Kanterman

may alleviate some fears directed toward the metaverse or, at the very least,

can give you some wonderful food for thought. ■





May 2022 Yale Scientific Magazine 37


The Future of Prosthetics

Can Be Found On Venus...


By Hannah Shi


What if prosthetic limbs could act as true

extensions of the human body? Not

just metal machines, but rather, carbon-based

devices that can interact with biological

neural networks. With nearly thirty million

people in need of prosthetics or orthotic devices,

researchers are experimenting with new technologies

that may allow for a new generation of prosthetic

limbs that can drastically improve a person’s

mobility, quality of life, and independence.

Traditional prosthetics use silicon-based technology

with limited bio-compatibility, circuit complexity,

and energy efficiency. While these devices can

restore some mobility and function to a lost limb,

silicon-based solutions are fundamentally incompatible

with the natural processes of ion signaling

found within the body. As such, to allow for effective

brain-machine interfaces, the future of prosthetics

will require the development of artificial devices that

can successfully integrate into biological systems.

Simone Fabiano and colleagues at the University of

Norrköping, Sweden, are exploring this proof of concept.

By developing neuromorphic systems, which

are brain-inspired machines that mimic neural processes,

it may be possible to integrate artificial technologies

with biological tissues. The Venus flytrap,

a carnivorous plant with two leaflets that can snap

shut, was an ideal specimen to test this novel technology.

Not only could the activity of the flytrap’s ion

channels be easily measured, but its closing motion

also served as an obvious sign that the artificial signal

went through. Using carbon-based artificial nerve

cells, Fabiano and colleagues demonstrated that

when a sufficiently high current was applied, Venus

flytraps were able to respond to the electrical stimulus

by snapping shut. These organic electrochemical

transistors (OECTs) are modulated by gate-driven

ionic doping and de-doping, closely resembling the

ion-driven mechanics found in neural systems. In

particular, Venus flytraps snap shut in response to the

release of calcium ions in the cytosol. This enables

the plant to react to the physical stimulation of its

hairs by insects, allowing it to catch its food. By mimicking

the neurochemical processes of the Venus flytraps,

OECTs were able to provide electrical currents

that could be received by organic electrical chemical

neurons (OECNs) to trigger trap closure.

These experiments are not the first time researchers

have been able to control the response of a Venus

flytrap. In 2007, Alexander Volkov of Oakwood

University was able to use an artificial electrical current

to cause the leaflets of a Venus flytrap to snap

shut. While the work of Simone Fabiano shares similarities

with Volkov’s previous research, Fabiano’s

new experiments differ in a few key ways. Importantly,

Fabiano was the first to use carbon-based devices

that resembled the structure of the actual neuron.

By including an artificial synapse, or a tiny gap

which ions jump across, the controlled reactions of

the Venus flytrap in Fabiano’s research were more

closely modeled off the true neurochemical mechanisms

found in nature.

While closing a fly trap may still be a far cry

from controlling a prosthetic limb with your

thoughts, Fabiano and colleagues have demonstrated

the possibility of interfacing OECNs with

biological systems. Inducing the closure of a Venus

flytrap may open the door to creating more complex

brain-machine interfaces that can be applied

to future prosthetic innovations.

Even now, prosthetics use has been associated

with higher levels of employment, reduced phantom

limb pain, and increased feelings of social acceptance.

Still, it is common for patients with prosthetics

to develop osteoarthritis or osteoporosis as

a result of the inherent biomechanical disadvantage

of current technologies. However, with the

rising possibility of creating a seamless brain-machine

interface that can mitigate the biomechanical

drawbacks of traditional prosthetics, it is possible

to invent a new generation of devices that can

overcome the side effects of current prosthetics.

Perhaps someday soon, the artificial nerves used to

control a Venus flytrap will allow patients to have

prosthetic limbs that are a true extension of themselves,

controlled by their own neural networks. ■

38 Yale Scientific Magazine May 2022 www.yalescientific.org








Among the signatures at the 1848 Seneca

Falls Convention for women’s rights is the

name Eunice Newton Foote. With her name

inscribed next to those like Elizabeth Cady Stanton

and Lucretia Mott—both well known in U.S. history

for their advocacy of abolition, women’s rights and

suffrage—she may seem like just another attendant

at the convention, but her legacy was not been fully

recognized until just a few years ago. Today, we recognize

her as the first person to recognize the impact of carbon

dioxide on climate change, preceding John Tyndall, the

scientist previously credited for this breakthrough.

Using a straightforward experimental setup, which

included a cylinder, a likely glass, and thermometers placed

inside, Foote concluded that carbon dioxide and moist air

could absorb heat. Similar to how the glass in greenhouses can

maintain heat inside its walls when it’s cooler outside, certain

gases can trap heat from the sun in the Earth’s atmosphere.

The significance of the greenhouse effect today is that rising

carbon dioxide levels due to the burning of fossil fuels are

contributing to climate change and global warming. Foote had

made the connection that climate change is largely influenced

by varying levels of gases like carbon dioxide and water

vapor in the air; she subsequently published her results in the

American Journal of Science and Arts in 1856. Her paper was

also presented at a conference in the same year. However, Foote

did not present her own article—it was uncommon for women

to have done so. Instead, a summary of her work was given

by Joseph Henry, who would later become the first secretary

of the Smithsonian Institution. His summary would be found

in almost every publication that presented Foote’s findings,

while Foote’s original publication remained unrecognized.

Even though Henry recognized Foote as an equal in science,

her legacy’s absence suggests that others had minimized her

contribution to the scientific community over time.

In 1859, about halfway across the world in Europe, Tyndall

had also found that certain gases absorbed heat and immediately


his findings

to the Royal

Institution. By

1861, he had carried

out further experiments and

published a paper. He had been one of several scientists who,

like Foote, was concerned with the ability of certain gases to

trap heat, and since then, he has received sole credit for the

discovery of the greenhouse effect.

The mere five-year difference between Foote’s discovery and

the publication of Tyndall’s paper raises questions about his

omission of Foote’s name in his acknowledgments. Given that

some publications in the U.S. would not have been widely read in

Europe and vice versa around this time, it is unlikely that Tyndall

took from Foote’s experiment and failed to give her credit.

However, this story still places Eunice Newton Foote’s name

on the long list of women, like Rosalind Franklin, Katherine

Johnson, and Mary Jackson, whose efforts in STEM went

unrecognized for years, and in some cases, for decades or

centuries. Foote’s story reminds us that women and nonbinary

people continue to face discrimination, exploitation, and lack

of due credit in STEM. Her presence at the 1848 Seneca Falls

Convention was no accident—Foote understood that the world

she lived in would not recognize her contributions as a woman,

and she wanted to see that change. Being friends with Elizabeth

Cady Stanton, Foote helped Stanton organize the proceedings

of the entire Seneca Falls Convention. Her signature is fifth

on the Declaration of Sentiments, a seminal work from the

conference that demanded equal rights for women, including

the right to vote. While recognizing Foote’s work is one

more step in acknowledging the talents and contributions of

underrepresented figures in STEM, it is a reminder that the

field of science still has quite a long way to go. ■


May 2022 Yale Scientific Magazine 39

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