YSM Issue 95.2

Yale Scientific
THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION • ESTABLISHED IN 1894
MAY 2022
VOL. 95 NO. 2 • $6.99
14
HOW TO MAKE A
HOT JUPITER
TORTOISES
12
THEN & NOW
SUPERCHARGED KILLER CELLS:
16
ADVANCES IN CAR-T CELL THERAPY
PUTTING ORDER
19
IN DISORDER
SCANNING DNA
22
BARCODES

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TABLE OF CONTENTS
VOL. 95 ISSUE NO. 2
More articles online at www.yalescientific.org
& https://medium.com/the-scope-yale-scientific-magazines-online-blog
COVER
14
A R T
I C L E
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.
www.yalescientific.org
May 2022 Yale Scientific Magazine 3

DECODING MACHINE
LEARNING MYSTERIES
USING ANTS
&
TIME TO MEET YOUR
GREAT NTH GRANDPARENTS
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
CHALLENGING THE
CONVENTIONAL
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
MASTHEAD
May 2022 VOL. 95 NO. 2
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NEWS
Psychology / Ecology & Evolutionary Biology, Archaeology
GROUP
DISCUSSIONS
WHEN WE DO AND
DON’T USE THEM
BY ELIZABETH LIN
STONE-AGE
SOCIAL
NETWORKS
WHEN SETTLING DOWN
BECAME THE STATUS QUO
BY DINARA BOLAT
IMAGE COURTESY OF PIXABAY
IMAGE COURTESY OF GETTY IMAGES
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
NEWS
WITH HIV, A
LITTLE GOES A
LONG WAY
TARGETING HIV PARTICLES
THAT HIDE FROM OUR
IMMUNE SYSTEM
BY BREANNA BROWNSON
A
CONTRASTING
CLIMATE
SHOULD WE TRUST
COMPUTERS OR FOSSILS?
BY CHLOE NIELD
IMAGE COURTESY OF NIAID FLICKR
IMAGE COURTESY OF DANIEL GASKELL
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. ■
www.yalescientific.org
May 2022 Yale Scientific Magazine 7

FOCUS
Psychology
A PERSONALIZED
BRAIN FINGERPRINT
FOR ATTENTION
How fMRI Scans and
Transformative Modeling Can
Predict Attentional Ability
BY CINDY KUANG
IMAGE COURTESY OF EMILY S. FINN FROM THECONVERSATION.COM
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
FOCUS
ELECTRONICALLY
CONDUCTIVE
PROTEIN
NANOWIRES
An Electrifying Discovery
for Healthcare Applications
BY YUSUF RASHEED
IMAGE COURTESY OF WIKIMEDIA COMMONS
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
www.yalescientific.org
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

FOCUS
Chemical Engineering
MAGNESIUM?
NO YOU’RE NOT
ON THE LIST
Mimicking Biology in
Wastewater Engineering
BY LUCAS LOMAN
IMAGE COURTESY OF FLICKR
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
FOCUS
I WANT YOU
Modeling Microbial
Recruitment and
Peer-Pressuring
Bacteria
BY PATRYK DABEK
IMAGE COURTESY OF FLICKR
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. ■
www.yalescientific.org
May 2022 Yale Scientific Magazine 11

FOCUS
Evolutionary Biology
TORTOISES
THEN
& NOW
DNA from tortoise bones
reveal an unknown lineage
of Galapagos giant tortoise
BY SOPHIA BURICK
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
decades,
researchers
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
estimated
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.”
ABOUT THE AUTHOR
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. ■
ART BY CATHERINE KWON
SOPHIA BURICK
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
research.
FURTHER READING
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.
FOCUS
www.yalescientific.org
May 2022 Yale Scientific Magazine 13

FOCUS
Astronomy
HOW TO MAKE A HOT JUPITER
Investigating the orbits of large
exoplanets to uncover the mysteries
behind solar system formation
BY BRIANNA FERNANDEZ
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
History
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.” ■
A R T B Y U R I E L T E A G U E
ABOUT THE AUTHOR
BRIANNA FERNANDEZ
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.
FURTHER READING
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.
Astronomy
FOCUS
www.yalescientific.org
May 2022 Yale Scientific Magazine 15

FOCUS
Immunology
SUPERCHARGED
KILLER CELLS:
Establishing a platform to discover
useful targets of CAR-T engineering
ADVANCES IN
CAR-T CELL THERAPY
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

Immunology
FOCUS
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
Landscape
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
www.yalescientific.org
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
Generation
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
Optimization
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

FOCUS
Immunology
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
IMAGE COURTESY OF FLICKR
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.
ABOUT THE AUTHOR
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
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.
FURTHER READING
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.
org/timeline/car-t-timeline-progress.
18 Yale Scientific Magazine May 2022 www.yalescientific.org

Wave Physics
FOCUS
PUTTING
ORDER IN
DISORDER
Focusing delivery
of energy into
diffusive systems
for applications in
neuronal control
and tissue imaging
BY
EUNSOO
HYUN
www.yalescientific.org
ART BY NOORA SAID
“
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

FOCUS
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
manipulation.
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
FOCUS
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
www.yalescientific.org
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.
ABOUT THE AUTHOR
Controlling Randomness
IMAGE COURTESY OF HUI CAO
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
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
team.
THE AUTHOR WOULD LIKE TO THANK Professor Hui Cao and Dr. Nicholas Bender for their time
and enthusiasm about their research.
FURTHER READING
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-
021-01475-x.
May 2022 Yale Scientific Magazine 21

FOCUS
Spatial Transcriptomics / Chemistry
SCANNING DNA
BARCODES
Profiling epigenetic mechanisms on a genome-wide
level using spatial-CUT&Tag
BY HANNAH HAN
ART BY SOPHIA ZHAO
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
FOCUS
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
[formation],”
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
www.yalescientific.org
May 2022 Yale Scientific Magazine 23

FOCUS
Spatial Transcriptomics / Chemistry
PHOTO COURTESY OF JAMES HAN
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
system.
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.
ABOUT THE AUTHOR
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
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.
FURTHER READING
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
TRICKING THE BRAIN TO PERCEIVE A PHANTOM FINGER
Cognition / Neuroscience
FEATURE
is real, and the truth is not.” So said the wife
of the late Philippine dictator in The Kingmaker, a 2019
“Perception
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
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BY ZEKI
TAN
ART BY
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TEAGUE
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

FEATURE
Artificial Intelligence
A LEGO ROBOT’S
ORGANIC BRAIN
USING NEUROMORPHIC CIRCUITS TO SOLVE MAZES
BY MALIA KUO
ART BY LANA ZHENG
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

HOW TO TRICK
Material Science
FEATURE
A TOOTH FAIRY
BY KAYLA YUP
ENGINEERING SYNTHETIC TOOTH ENAMEL
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
www.yalescientific.org
ART BY
MALIA KUO
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

FEATURE
Quantum Physics / Optics
A Real-Life Infinity Stone
THE TIME CRYSTAL
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
FEATURE
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
experi-
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
www.yalescientific.org
May 2022 Yale Scientific Magazine 29

FEATURE
Neuroscience
The
How an unexpected
part of the cerebellum
regulates food intake
BY CONNIE TIAN
ART BY SOPHIA ZHAO
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
environment.
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

Neuroscience
FEATURE
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. ■
www.yalescientific.org
May 2022 Yale Scientific Magazine 31

FEATURE
Nuclear Energy
FUTURE
FOR FUSION?
Producing a
self-heating
plasma
BY KRISHNA DASARI
ART BY ALEX DONG
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
IMAGE COURTESY OF WOOLSEY, 2022
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
FEATURE
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
milestone.
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. ■
www.yalescientific.org
May 2022 Yale Scientific Magazine 33

JENNIFER
MIAO
UNDERGRADUATE
PROFILE
BY EMILY SHANG
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.
PHOTO COURTESY OF ALEX DONG VIA JENNIFER MIAO
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

DANIEL
SPIELMAN
ALUMNI PROFILE
BY RISHA CHAKRABORTY
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,
www.yalescientific.org
IMAGE COURTESY OF DANIEL SPIELMAN
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

THE MAN WHO TASTED WORDS
BY ELISA HOWARD
SCIENCE
IN T
S
IMAGE COURTESY OF THE STORY COLLIDER
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

INTO THE METAVERSE
BY KELLY CHEN
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. ■
THE
SPOTLIGHT
IMAGE COURTESY OF PIXABAY
www.yalescientific.org
May 2022 Yale Scientific Magazine 37

COUNTERPOINT
The Future of Prosthetics
Can Be Found On Venus...
FLYTRAPS
By Hannah Shi
IMAGE COURTESY OF PIXABAY
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

HIDDEN
HISTORIES
BY ANN-MARIE ABUNYEWA
ART BY CATHERINE KWON
EUNICE NEWTON FOOTE:
THE WOMAN WHO DISCOVERED THE
GREENHOUSE EFFECT
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
reported
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. ■
www.yalescientific.org
May 2022 Yale Scientific Magazine 39

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