YSM Issue 94.2
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Yale Scientific
THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION • ESTABLISHED IN 1894
MAY 2021
VOL. 94 NO. 2 • $6.99
16
A BREAKTHROUGH
THERAPY FOR DIABETES
2D SOLUTIONS FOR 3D
12
PROBLEMS
TRACKING DOWN LETHAL
14
MOSQUITOES
GENERATING
19
RANDOMNESS
THE RADIO STATION AT THE
22
END OF THE UNIVERSE
TABLE OF
VOL. 94 ISSUE NO. 2
COVER
16
A R T
I C L E
A Breakthrough Therapy for Diabetes
Alex Dong
There is no cure yet for type 1 diabetes, a disease that affects more than one million Americans. Hear
the story of a new FDA Breakthrough drug, Teplizumab, that could not only treat the symptoms of
type 1 diabetes, but also delay or prevent its onset.
12 2D Solutions for 3D Problems
Catherine Zheng
Yale researchers studied the electrical properties of different materials to solve challenges in the
design of electronic devices.
14 Tracking Down Lethal Mosquitoes
Elizabeth Wu
Climate changes is rapidly expanding the range of disease-carrying mosquitoes. Scientists at the
Yale School of Environment tackled the issue by using cutting-edge artificial intelligence techniques.
19 Generating Randomness
Alexa Jeanne Loste
Random numbers play an integral role in cybersecurity and scientific discovery. A Yale team
invented a new laser-based mechanism to generate randomness at ultrafast speeds.
22 The Radio Station at the End of the
Universe
Brianna Fernandez
Dark matter is one of the most elusive problems facing physicists today. But researchers at Yale’s
Wright Laboratory might have found a new method to detect it.
2 Yale Scientific Magazine May 2021 www.yalescientific.org
CONTENTS
More articles online at www.yalescientific.org & https://medium.com/the-scope-yale-scientific-magazines-online-blog
4
6
25
34
Q&A
NEWS
FEATURES
SPECIALS
Why do fragments spin after a nuclear fission split? • Meili Gupta
Identifying Deafness Mutations in the Iranian Population • Kelly
Chen
Stem Cell Therapy for Spinal Cord Injuries • Jerry Ruvalcaba
A Curious Salmonella Protein • Christopher Ye
"Like Dissolves Like": Updating Theories on Miscibility • Veronica
Brooks
Nanoscale Nucleation • Krishna Dasari
Stereochemistry Selection • Shudipto Wahed
Magnetism in Small Plants • Rayyan Darji
Racial Disparities in COVID-19 Mortality • Bella Xiong
ASIA: Assessing Social Identities • Tejita Agarwal
Memories of the Brainless Slime Mold • Malia Kuo
Bridging the Quantum Gap • Yu Jun Shen
Beauty is in the Eye of the Beholder • Lauren Chong
Gynecology for Guys: Male Birth Control • Angelica Lorenzo
Migratory Strategies: Past, Present, and Future • Madison Houck
Undergraduate Profile: Phyllis Mugadza (BS/MPH '22) • Eamon Goucher
Alumni Profile: Dr. C. Brandon Ogbunu (PhD '10) • Anna Calame
Science in the Spotlight: Vivek Murthy's Together: The Healing Power of
Human Connection in a Sometimes Lonely World • Hannah Huang
Science in the Spotlight: The Nocturnists • Ann-Marie Abunyewa
Counterpoint: Not-So-Identical Twins • Eva Syth
Into the Newsroom: A Conversation with Carl Zimmer • Sophia Li
www.yalescientific.org
May 2021 Yale Scientific Magazine 3
&
WHY DO FRAGMENTS SPIN AFTER
A NUCLEAR FISSION SPLIT?
By Meili Gupta
In 1938, chemists Otto Hahn and Fritz Strassmann
bombarded a uranium nucleus with a neutron. To their
surprise, they discovered that barium and krypton were
produced. This division of heavy nuclei was termed “fission,”
and since its discovery it has deeply intrigued physicists.
For decades, physicists have puzzled over why the resulting
fragments spin after nuclear fission. A recent collaboration
between scientists from France, Germany, the UK, and other
European countries offers clear answers.
At the IJC Laboratory in Orsay, France, scientists used highresolution
spectroscopy to inspect the fission of 232 Th, 238 U,
and 252 Cf. They specifically used a method from the University
of Manchester to measure the average spin of the fission
fragments. They discovered that the fragment spin appeared to
depend only on the fragment mass, not the mass of the original
nucleus or the mass or charge of its partner fragment. Their
results deny hypotheses that the spin is generated before the
nucleus splits (pre-scission), as these hypotheses predict equal
magnitude spins for partner fragments. The large asymmetries
in the angular momentum between the spins of heavy and
light partner fragments support a post-scission hypothesis and
the idea that the fragments should be treated as independent
quantal—discrete—systems.
Beyond deepening a fundamental understanding of fission,
these findings have important applications for nuclear
energy, since fragment spins influence the heating effects of
reactor gamma rays. This research may help unlock the full
potential of nuclear fission. ■
Wilson, J.N., Thisse, D., Lebois, M. et al. Angular momentum
generation in nuclear fission. Nature 590, 566–570 (2021).
https://doi.org/10.1038/s41586-021-03304-w
4 Yale Scientific Magazine May 2021 www.yalescientific.org
The Editor-in-Chief Speaks
FACING OUR CHALLENGES
It has been a challenging semester. Our Yale community, like much of the
rest of the world, has collectively grappled with burnout, isolation, and an
ongoing pandemic. For many of us, a small ounce of hope came towards the
end of the semester: vaccines, developed in record speeds using cutting edge
biomedical advances in mRNA and viral vector technology. Science provides us
a lot—a fundamental understanding of ourselves and our universe, an outlet for
human exploration. But these past few months, I’ve been particularly struck by
how science helps us respond to the challenges we face.
In this issue, we see science’s capacity to pose new solutions to persisting
problems—technical challenges in the fields of organic synthesis (pg. 9),
quantum computing (pg. 27), and dark matter detection (pg. 22); social
challenges such as gender inequity in birth control (pg. 30). This innovation can
come from both seasoned professors and new researchers: in our undergraduate
profile, we speak to a Yale mechanical engineering major who designed a device
to help those who menstruate manage their pain (pg. 34).
We also see how research can help us identify what problems we ought to
focus on at all, from public health studies that quantify racial disparities in the
COVID-19 pandemic (pg. 11) to ecological investigations that reveal to us the
threat that climate change poses to bird migration (pg. 32).
But I am perhaps most moved by scientists themselves and their ability to
persevere in the face of challenges inherent to the process of innovation. In this
issue’s cover story (pg. 16), we highlight the development of a groundbreaking
new drug that may be able to prevent type 1 diabetes. The treatment is the result
of thirty years of labor by a Yale researcher, who carried his work from the
cellular level to a nationwide clinical trial, even when disappointing preliminary
results and a lack of funding threatened his pursuits.
Science, of course, is not the end-all, be-all savior to all of humanity’s problems.
With every scientific innovation, from COVID-19 vaccines to rapidly advancing
AI technologies, comes a host of questions about trust, bias, injustice, inequality,
and more that we as a society must confront. Our Scope blog continues to
interrogate these ethical dimensions. But for this issue of Yale Scientific, after
such a dark year, I’d like to commend science for helping us see a bit of light.
To the Yale Scientific team, thank you for contributing your time and energy
despite the incredibly difficult semester. And to our readers, thank you for
continuing to support us despite all that the past few months have undoubtedly
brought upon you. Here’s to perseverance, hope, and innovation.
About the Art
Isabella Li, Editor-in-Chief
In this issue’s cover, I explore a
breakthrough therapy for diabetes
by illustrating its molecular
mechanism. I hope that the bright,
spring-like colors welcome this
treatment as one that will better
patients’ lives.
Sophia Zhao, Cover Artist
MASTHEAD
May 2021 VOL. 94 NO. 2
EDITORIAL BOARD
Editor-in-Chief
Managing Editors
News Editor
Features Editor
Special Sections Editor
Articles Editor
Online Editors
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PRODUCTION & DESIGN
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Publishers
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OUTREACH
Synapse Presidents
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WEB
Web Manager
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Web Designer
SENIOR STAFF WRITERS
Britt Bistis
Anavi Uppal
STAFF
Ann-Marie Abunyewa
Tejita Agarwal
Veronica Brooks
Dilge Buksur
Anna Calame
Kelly Chen
Frances Cheung
Mehana Daftary
Rayyan Darji
Krishna Dasari
Ivy Fan
Ellie Gabriel
Raquel Sequeria
Alex Dong
Eamon Goucher
Sydney Hirsch
Madison Houck
Malia Kuo
Cecilia Lee
Angelica Lorenzo
Alexa Loste Jeanne
Katherine Moon
Gonna Nwakudu
Emilia Oliva
Dhruv Patel
Rosie Rothschild
Isabella Li
James Han
Hannah Ro
Jenny Tan
Cindy Kuang
Nithyashri Baskaran
Maria Fernanda Pacheco
Meili Gupta
Cathleen Liang
Alex Dong
Brianna Fernandez
Hannah Huang
Christina Hijiya
Tai Michaels
Beatriz Horta
Ishani Singh
AnMei Little
Catherine Zheng
Elaine Cheng
Sophia Zhao
Crystal Xu
Blake Bridge
Jared Gould
Brian Li
Sophia Zhuang
Lauren Chong
Alice Zhang
Sophia Li
Blake Bridge
Jared Gould
Athena Stenor
Anavi Uppal
Sophie Edelstein
Matt Tu
Brett Jennings
Eten Uket
Megan He
Siena Cizdziel
Rayyan Darji
Jerry Ruvalcaba
Noora Said
Sydney Scott
Yu Shen Jun
Anasthasia Shilov
Eva Syth
Van Anh Tran
Shudipto Wahed
Elizabeth Wu
Bella Xiong
Christopher Ye
The Yale Scientific Magazine (YSM) is published four times a year by Yale
Scientific Publications, Inc. Third class postage paid in New Haven, CT
06520. Non-profit postage permit number 01106 paid for May 19, 1927
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NEWS
Genetics / Biomedical Engineering
IDENTIFYING
DEAFNESS
MUTATIONS IN
THE IRANIAN
POPULATION
BY KELLY CHEN
Hearing loss is a commonly overlooked sensory
disorder, even though it occurs all over the world.
One type of deafness is autosomal recessive
nonsyndromic deafness (ARNSD), a comparatively prevalent
type of deafness in Iran. Working with researchers from
Shiraz University of Medical Sciences, Emily Smith and Arya
Mani from Yale University used DNA sequencing techniques
to identify mutations that cause ARNSD.
The research established that causative mutations were
found in all ten Iranian families studied. Mutations were found
primarily within GJB2 genes, which code for gap junction
beta proteins. Novel mutations in the Iranian population were
found also within the TMC1, ESRRB and MYO15A genes.
These genes encode proteins involved in hearing. “These
mutations often impair the function of cochlear hair cells,”
Mani said. “For instance, TMC1[transmembrane channel
like] is a pore-forming component of mechanosensory
transduction channels in auditory and vestibular hair cells
with important function in hearing.”
Identification of common mutations allows for early
diagnosis of ARNSD. Earlier diagnosis, in turn, leads to
proactive treatment plans, such as cochlear implants or
speech therapy. “There are ongoing discussions in the media
about people [who are] affected by deafness but are afraid of
seeking help…[or] they try to deny their illness, so they are
not as stigmatized. But once they are treated or wear their
hearing aid, they catch up with challenges, and suddenly
they see the world changes for them,” Mani said. ■
Dianatpour, M., Smith, E., Hashemi, S., Farazifard, M.,
Nezafat, N., Razban, V., & Mani, A. (2021). Identification
of homozygous mutations for hearing loss. Gene, 778,
145464. doi:10.1016/j.gene.2021.145464
STEM CELL
THERAPY FOR
SPINAL CORD
INJURIES
BY JERRY RUVALCABA
IMAGE
COURTESY
OF PIXABAY
Spinal cord injury treatment without surgery—the work
of science fiction or a soon reality? Spinal cord injuries
continue to be a challenging medical issue: they commonly
cause disability yet have limited viable treatments. Discovering
such remedies has been one of the drivers behind the longstanding
relationship between researchers at the Sapporo
Medical University of Japan and the Yale School of Medicine.
Building on their focus on pre-clinical work with stem cells, this
collaboration has led to the implementation of a clinical trial
utilizing intravenous injection of stem cells.
In the study, patients’ stem cells were isolated from their bone
marrow and grown using their serum. “It’s a completely closed
system… it’s personalized medicine,” said Jeffery D. Kocsis,
professor of neurology and neuroscience at Yale. Following
the cells’ injection, the researchers monitored the patients and
reported neurologic improvements in twelve of the thirteen
patients under the ASIA Impairment Scale for sensory and motor
levels. Researchers did not detect adverse effects after injection.
“The studies are, I think, quite exciting and give us great hope
that we can push on with this,” Kocsis said.
While these results are promising, Kocsis notes that they
are only anecdotal. “The study that was done in Japan was not
blinded; it was observational and the paper [described the tests]
as case studies,” he said. With this, Kocsis is cautious to declare
the results conclusive and is looking forward to a future, blinded
study performed in New Haven for more definitive answers. ■
Honmou, O., Yamashita, T., Morita, T., Oshigiri, T., Hirota, R., Iyama,
S., Kato, J., Sasaki, Y., Ishiai, S., Ito, Y. M., Namioka, A., Namioka,
T., Nakazaki, M., Kataoka-Sasaki, Y., Onodera, R., Oka, S., Sasaki,
M., Waxman, S. G., & Kocsis, J. D. (2021). Intravenous infusion
of auto serum-expanded autologous mesenchymal stem cells
in spinal cord injury patients: 13 case series. Clinical Neurology
and Neurosurgery, 203, 106565. https://doi.org/10.1016/j.
clineuro.2021.106565
6 Yale Scientific Magazine May 2021 www.yalescientific.org
Microbiology / Chemistry
NEWS
A CURIOUS
SALMONELLA
PROTEIN
SOPD’S STIMULATION AND INHIBITION OF
INFLAMMATION
BY CHRISTOPHER YE
IMAGE COURTESY OF NIAID
The bacterial pathogen Salmonella typhimurium causes
intestinal inflammation. S. typhimurium injects effector
proteins such as SopD that stimulate a signaling cascade,
ultimately leading to inflammation. However, researchers from Yale
and Shandong University discovered that SopD is bifunctional and
can alternatively stimulate or inhibit inflammation. “It contains the
‘Yin and Yang’ elements of the Salmonella/host interaction within
the same protein… a remarkable piece of evolution,” said Jorge
Galán, lead researcher of the study and chair of the Department of
Microbial Pathogenesis at Yale School of Medicine.
“[Inflammation is] essential for [S. typhimurium] to colonize
the intestinal tract, since it allows Salmonella to [compete] with
the resident microbiota and secure nutrients that are otherwise
not accessible in the uninflamed intestine,” Galán said. Rab8
is a regulatory protein that is central for an anti-inflammatory
signaling pathway that helps the host recover homeostasis after
inflammation. Therefore, by inhibiting Rab8, SopD stimulates
inflammation and helps the pathogen replicate within the intestine.
When the researchers solved the SopD-Rab8 complex’s crystal
structure, they identified SopD’s unexpected second function: SopD
can activate Rab8 and stimulate an anti-inflammatory response. In
other words, opposing enzymatic activities are present within the
same protein. Rab8 normally binds to GDI2, an inhibitor that blocks
Rab8 activity. However, SopD can displace GDI2 to activate Rab8 and
inhibit inflammation. By doing so, S. typhimurium sacrifices virulence
to preserve host stability, maximizing its ability to continue replicating.
“[This research is] providing major insight into the pathogenesis
of chronic intestinal inflammatory diseases such as Crohn’s disease,”
Galán said. Understanding Salmonella has implications in the
development of novel therapeutic strategies. ■
Lian, H., Jiang, K., Tong, M. et al. The Salmonella effector protein
SopD targets Rab8 to positively and negatively modulate the
inflammatory response. Nat Microbiol (2021). https://doi.
org/10.1038/s41564-021-00866-3
www.yalescientific.org
“LIKE-DISSOLVES-
LIKE”
UPDATING THEORIES ON
MISCIBILITY
BY VERONICA BROOKS
IMAGE COURTESY OF WIKIMEDIA COMMONS
Miscibility, or the ability for liquids to mix, is often
determined by the “like-dissolves-like” rule, which is
largely qualitative. It remains difficult to quantitatively
determine how “alike” two substances are. But by using the
dielectric constant, Bilin Zhuang, an assistant professor at Yale-
NUS, developed a model that accurately predicts the miscibility
of two liquids using their permanent dipole moments, which
arise from differences in electronegativity across a molecule.
The dielectric constant is a number assigned to a substance
based on how polarized it becomes in an electric field. A molecule
with a high dielectric constant has higher polarity and a greater
ability to stabilize charges in an electric field. Materials with
similar dielectric constants often mix well. Zhuang’s model also
uses the free energy of mixing to predict miscibility of two liquids.
This model accurately fits experimental data when compared to
previous theories that use a similar number of parameters.
However, these new equations are unable to account for
hydrogen bonding, which leads certain liquids to adopt
conformations that the dielectric constant does not predict.
Zhuang’s next steps will focus on developing miscibility
predictors for hydrogen bonding liquids and polarizable
liquids, substances with no permanent dipoles.
Ultimately, these new equations will be particularly
useful for predicting the miscibility of newly synthesized
molecules. It also saves time at the bench when one studies
multi-component mixtures. “We can just plug in the number
and roughly see what the dielectric constant is [and] its
miscibility,” Zhuang said. ■
Zhuang, B., Ramanauskaite, G., Koa, Z. Y., & Wang, Z.-G. (2021).
Like dissolves like: A first-principles theory for predicting liquid
miscibility and mixture dielectric constant. Science Advances,
7(7), 1–7. https://doi.org/10.1126/sciadv.abe7275
May 2021 Yale Scientific Magazine 7
NEWS
Chemistry
NANOSCALE
NUCLEATION
Insight into the unusual
mechanism of contact
freezing
BY KRISHNA DASARI
IMAGE COURTESY OF FLICKR
Freezing: a simple phase transition with a surprisingly complex With these advancements, the researchers were able to
set of mechanisms. Researchers use freezing dynamics to study simulate the nanoscale dynamics of contact freezing for two
the crystallization of various materials, but not all kinds of mW-based liquids, one that had a surface freezing propensity
freezing are mechanistically understood. Graduate student Sarwar
Hussain and professor Amir Haji-Akbari in the Department of
Chemical and Environmental Engineering at Yale recently simulated
contact freezing to unravel its unique mechanism.
In contact freezing, a water droplet that is supercooled—below
freezing temperature but still liquid—collides with an external
particle that promotes nucleation, the initiating step in the process
of freezing. This results in unusually rapid ice formation. However,
why exactly freezing proceeds so quickly remains unclear. Previous
studies have suggested two key points. First, the rate of contact
freezing is related to the liquid’s tendency to surface freeze—that
is, to rapidly freeze its surface relative to the interior. Second, the
nucleating particle doesn’t necessarily have to directly disrupt the
liquid-vapor interface to increase the freezing (nucleation) rate.
The researchers’ results ruled out the prevailing theories on freezing
mechanism. “[These findings] were not necessarily explained by the
previous mechanisms which said that there has to be some sort of
mechanical disturbance in the free interface between the liquid and
the vapor for the increased freezing rate to take place,” Hussain said.
Further experiments into this nucleation mechanism are
hindered by the limits of technology. Freezing events occur on
the nanosecond timescale and create ice nuclei containing only
hundreds to thousands of molecules. They cannot be observed
with sufficient resolution, so the mystery of high nucleation rates
during contact freezing is difficult to approach experimentally.
What can’t yet be accomplished in a physical lab, though,
can now be done computationally. Two major advancements
allowed for the accurate simulation of contact freezing. The first
was the mW model, a water-like tetrahedral model liquid that
enables rapid simulation while still considering interactions
like hydrogen bonding. The second was the development of
jumpy forward flux sampling, a novel sampling technique
conceptualized by Haji-Akbari to address the shortcomings
of the original forward flux sampling method. The original
and one that did not. By simulating supported nanofilms of
the liquids, they were able to exclusively investigate the effect
of the proximity of the nucleating particle to the vapor-liquid
interface on the nucleation rate.
From their simulations, they observed that only the surface
freezing liquid’s nucleation rate was affected by proximity
to the nucleating particle, increasing the nucleation rate by
orders of magnitude. Moreover, they discovered that in such a
case, freezing proceeds through the formation of hourglassshaped
nuclei, a unique property that mechanistically explains
the increased nucleation rate. Compared to the spherical capshaped
nuclei of classical models, hourglass-shaped nuclei have a
smaller surface area exposed to the liquid. According to classical
nucleation theory, the smaller liquid-exposed surface area lowers
the nucleation barrier, allowing nucleation to proceed faster.
Their findings have implications for understanding contact
freezing of water in the atmosphere, a phenomenon important
for predicting weather patterns. These results support the
theory that water may be capable of surface freezing, giving it
access to rapid nucleation through contact freezing. However,
the authors also note that other agents in the atmosphere
may also contribute to nucleation rate, making it difficult to
conclude that the proximity effect of surface freezing liquids is
necessarily the main cause for atmospheric nucleation rates.
More broadly, their discovery of this non-classical nucleation
mechanism provides a roadmap to study other non-classical
processes. For example, scientists may investigate nucleation in
the vicinity of surfaces with different ice-forming properties,
such as a protein with hydrophilic and hydrophobic patches.
“The question is, if you put that protein inside supercooled
water, what will happen? How will the critical nucleus look like,
and how will the rate be sensitive to temperature, for example?
These are all questions that our work gives a good conceptual
framework to pursue,” Haji-Akbari said. ■
method could be used to estimate the likelihood of freezing
events progressing toward complete freezing, but Haji-Akbari’s
Hussain, S., & Haji-Akbari, A. (2021). Role of Nanoscale
version accounts for the jumpiness of freezing progression Interfacial Proximity in Contact Freezing in Water. Journal of
caused by the coagulation of ice particles. “If you do not take the American Chemical Society, 143(5), 2272–2284. https://
into account these jumps, you can underestimate the nucleation doi.org/10.1021/jacs.0c10663
rate by several orders of magnitude,” Haji-Akbari said.
8 Yale Scientific Magazine May 2021 www.yalescientific.org
Chemical Engineering
STEREOCHEMISTRY
SELECTION
The catalytic synthesis of
stereopure oligonucleotides
NEWS
IMAGE COURTESY OF PIXABAY
Nucleotides, the building blocks of DNA and RNA, can
be synthetically designed to mimic their biological
counterparts and interact with the cellular environment.
An important class of nucleotide molecules are cyclic dinucleotides
(CDNs), two single nucleotides that bind to form a ring. For example,
cGAMP is a naturally occurring CDN that can drive immune
response by activating the stimulator of interferon genes (STING)
protein. Because interferon genes are critically involved in immune
cell signaling, STING pathways are being extensively evaluated in
cancer immunotherapies, and CDNs such as cGAMP may serve as
promising new drugs. Synthetically manufacturing them represents
an important step in bringing these drugs to mass market.
A powerful method of increasing metabolic stability and therapeutic
potential of CDNs is to modify their native phosphodiester linkages into
phosphorothioate (PS) double-bonds. However, doing so introduces
an additional layer of complexity by rendering the central phosphorus
(P) atoms stereogenic (chiral), meaning different spatial orientations—
stereoisomers—of the same connected groups are possible. An analogy
for stereoisomers is a pair of baseball gloves in which one is left-handed
and the other is right-handed—although otherwise indistinguishable,
the right-handed glove will not fit on a left hand, and vice versa.
Each CDN stereoisomer, despite possessing identical atomic
connectivities, displays markedly different physical properties and
biological activities. The importance of stereochemistry is best
highlighted by the infamous case of thalidomide, a drug developed
in the 1950s that was marketed to treat morning sickness in pregnant
women. One of its stereoisomers has sedative effects, whereas the
other caused birth defects. As a result, thousands of children whose
mothers took thalidomide during pregnancy had severe birth
defects, since both stereoisomers were present in the medicine.
Most synthetic methods for preparing PS-derived CDNs are
nonselective in stereochemical outcome, relying on intensive purification
techniques or large quantities of auxiliary reagents to produce stereopure
products. In a recent study published in Science, the Scott Miller lab
at Yale’s Department of Chemistry, in collaboration with Takeda
Pharmaceutical Company, reported the first catalytic, stereocontrolled
synthesis of dinucleotides. Lead author Aaron Featherston, along with
a team of academic and industrial researchers, sought to address the
aforementioned problem using asymmetric catalysis. Catalysts, which are
regenerated throughout the course of a reaction, could ideally be used in
small amounts to facilitate the stereoselective assembly of PS compounds.
The first step of oligonucleotide synthesis is often achieved using
excess amounts of an acid activator. Symmetric chiral phosphoric acids
www.yalescientific.org
BY SHUDIPTO N. WAHED
(CPAs) have proven to be powerful catalysts in several asymmetric
transformations that isolate one stereoisomer. Recently, the Miller lab
developed an additional class of CPAs containing a modified amino
acid, phosphothreonine (pThr). Their rationale was that the amino acid,
a building block of proteins, could conceivably help impart selectivity on
par with enzymes, the ultra-specific protein catalysts of nature.
Accordingly, Featherston and the team assessed the ability of
these two classes of CPAs to asymmetrically couple two select
nucleotides, guanosine and adenosine. They found that several
pThr-derived catalysts greatly biased coupling towards one product
stereoisomer. Alternatively, the symmetric CPA catalysts were
highly selective for the other stereoisomer. The researchers thus
demonstrated two distinct, complementary catalyst frameworks,
allowing for the synthesis of either stereopure isomer.
The researchers then evaluated the ability of these catalysts
to asymmetrically couple a broader range of representative
nucleotides, finding that their stereoselective catalyses could
be applied to other base pairs beyond the guanosine-adenosine
coupling initially tested. Although selectivity decreased for
certain nucleotide couplings, the chemists demonstrated that their
approach is generalizable and can potentially yield a universal
catalyst. Finally, the group applied their method to the synthesis of
PS-modified cGAMP, showing that the pThr and symmetric CPA
catalysts could allow for an efficient, stereocontrolled preparation.
The researchers found, for the first time, a stereocontrolled
synthesis of dinucleotides using two catalyst frameworks.
Oligonucleotide syntheses have long struggled with controlling
P-stereogenicity, which reduces the efficacy of nucleotide-based
therapeutics. This new approach both provides efficient access to a
dinucleotide P-stereoisomer and enables preparation of stereopure
analogs of cGAMP, a CDN of great biological significance.
In the future, the Miller lab may dive deeper into the catalysts’
mechanism of action. A longer-term ambition would be to develop a
more universal catalyst framework that can facilitate the asymmetric
synthesis of all possible nucleotide couplings. Their current findings
will prove vital to the field of oligonucleotide chemistry, as synthetically
modified nucleotides continue to grow in importance. “It was a great
collaboration, and I think we were able to make a significant impact by
developing some really cool chemistry,” Featherston said. ■
Featherston, A. L., Kwon, Y., Pompeo, M. M., Engl, O. D., Leahy, D. K.,
& Miller, S. J. (2021). Catalytic asymmetric and stereodivergent
oligonucleotide synthesis. Science, 371(6530), 702–707.
May 2021 Yale Scientific Magazine 9
NEWS
Astrophysics
MAGNETISM
IN SMALL
PLANETS
BY RAYYAN DARJI
IMAGE COURTESY OF FLICKR
Within the expansive solar system, there are bodies of
numerous types and sizes, and our understanding
of them is far from complete. A key tool toward
furthering our understanding of our own planet Earth and
other bodies in the solar system is the study of magnetic fields.
In general, the magnetization of a body in space can tell us
about how it formed, what it is made of, and how it has cooled
and evolved over time.
Larger bodies like planets are believed to have been formed
from the collisions and eventual conglomeration of smaller
bodies called planetesimals. By studying planetesimals,
scientists can apply those findings to larger planets, which
are far more difficult to directly study. Building upon existing
models, researchers from Yale’s Department of Earth and
Planetary Sciences developed a new model to understand
magnetism in planetesimals.
Evidence that planetesimals are magnetized comes from the
analysis of meteorites, which are fragments of planetesimals
that have made it to the Earth’s surface. Magnetization of
planetesimals implies they were already segregated like miniplanets
into a metallic core (in which the magnetic field is
generated) and rocky mantle and crust, even before they
accreted to make bigger planets.
Certain conditions must be present for a body to be able
to generate a magnetic field. “To get a magnetized body, you
need an electrically conductive fluid—like molten iron in
the core—and the fluid needs to be moving at a fast enough
rate to generate a magnetic field,” said Elvira Mulyukova, a
co-author of the paper published in Physics of the Earth and
Planetary Interiors. This motion is referred to as dynamo
activity. “There also needs to be a solidifying, cooling crust
at the surface that can record that induced magnetic field,”
Mulyukova said.
The top of metallic cores in planets and planetesimals will
crystallize over time to a solid material, making that region
heavier and causing it to sink downward—a process known as
delamination. When the solid material drops off, it tends to do
so in big blobs, and when these blobs disconnect, they form
geological intrusions known as diapirs. That delamination
can cause the fluid in the core to stir fast enough to generate
dynamo activity and ultimately a magnetic field.
In deducing how magnetization occurs in small planetesimal
cores, a primary obstacle is the inability of the smaller bodies
to sustain sufficient dynamo activity. “When the solid outer
shell delaminates, the falling of those solid bodies is so fast
and sporadic that it would require a lot of them to be falling
at the same time to induce vigorous motion of the fluid and
thus generate a dynamo; moreover, they need to be falling over
a long period of time for the induced magnetic field to get
recorded,” Mulyukova said.
Instead, by analyzing various factors influencing dynamo
activity, the researchers proposed the nature of planetesimal
cores may be the cause of their magnetism. Because
planetesimal cores are not pure iron, the diapirs formed are
probably porous, like iron snowballs. “For a sinking porous
diapir, the motion of the liquid in the surroundings and the
motion of the liquid through the pores will generate enough
velocity of the liquid to induce a magnetic field,” said David
Bercovici, the another co-author of the paper.
More research must be done to fully understand magnetism
in planetesimals and how it relates to larger planets. “The
presence of magnetization in an object tells us something
about its differentiation history and composition, which
in turn allows us to understand the types of planetesimals
that likely have created our own planet,” Mulyukova said.
Although bound by certain limitations and assumptions, the
theoretical model produced from this study paves the way for
promising future research, including developing a model for
multiple diapirs, and ultimately understanding the magnetic
and thermal histories of planetesimals—the building blocks
of our planet. ■
Bercovici, D., & Mulyukova, E. (2021) Magnetization of
sinking porous diapirs in planetesimal cores. Physics of
the Earth and Planetary Interiors, 313, 106678. https://
doi.org/10.1016/j.pepi.2021.106678
10 Yale Scientific Magazine May 2021 www.yalescientific.org
Public Health
NEWS
RACIAL
DISPARITIES
IN COVID-19
MORTALITY
BY BELLA XIONG
IMAGE COURTESY OF GETTY IMAGES
It has been frequently reported that racial disparities persist
in COVID-19 mortality rates, but how large are these
disparities, and what factors create them? Exactly one
year after the World Health Organization (WHO) declared
COVID-19 a pandemic, a team of researchers from the Yale
School of Public Health, led by graduate student Alyssa Parpia,
published a study evaluating how the pandemic has reflected
systemic racism in the United States. The study looked at the
disproportionate burden borne by Black Michiganians in the
COVID-19 pandemic relative to their White counterparts.
Specifically, the team studied mortality attributable to
COVID-19. While only 14.1 percent of the Michigan population is
Black, Black Michiganians experienced about thirty-five percent
of COVID-19 deaths in the entire state as of November 2020.
The researchers compared the demographic characteristics—
such as age, sex, and total number of comorbidities (presence of
more than one illness or disease in one patient)—of White and
Black individuals. Even after accounting for these factors, Black
individuals were still at higher risk of COVID-19 mortality than
their White counterparts, indicating that race is a driving factor
behind the disproportionate mortality burden in Michigan.
These results shine a light on systemic racism in the United
States. The team’s research demonstrated that chronic conditions
alone are not responsible for the increased mortality rate among
Black individuals, especially for those who are younger. Systemic
racism, for one, has created racial disparities in socioeconomic
status. And even when socioeconomic status is not a factor,
biases and stereotypes have a serious impact on how doctors
treat people of color, especially Black individuals. For example,
a study conducted by the National Institutes of Health reported
that between 2005 and 2016, the admission rate into hospitals was
ten percent lower for Black individuals compared to their White
counterparts. This can lead to misdiagnosis of illnesses, a lack of
proper pain management, and increased health risks in general.
Histories of systemic racism have created a lack of trust between
medical personnel and racialized populations.
Parpia’s study helps us quantitatively identify racial disparities
in the United States, a crucial step toward addressing systemic
racism. Stopping the pandemic will not stop the inequalities built
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by hundreds of years of racially discriminatory and oppressive
policies. Parpia noted that there are many other important factors
linked with systemic racism that we should continue to explore.
Racial inequality in employment presents one such example. As
“essential workers,” grocery store or transit employees—positions
disproportionately held by Black Americans—have less access to
personal protective equipment compared to hospital employees.
Many who do not have access to higher paid positions are also
excluded from health insurance. In addition, essential workers
might not have access to paid sick leave and are less likely to socially
distance because of the nature of their jobs.
Race-based socioeconomic inequities and inaccessibility of
healthcare have heightened chances of COVID-19 exposure and
lowered overall survival rate. “The pandemic magnified many existing
issues we had in the U.S., and we should use it as an impetus to change
our entire healthcare structure,” Parpia said. Even as the spread of the
COVID-19 dies down, it is imperative to examine underlying reasons
why certain populations are more at risk of contracting and dying
from COVID-19 than others. These communities will continue to be
more at risk if we maintain the status quo.
Parpia suggested solutions such as providing paid sick leaves, living
wages, and universal healthcare, as well as restructuring the U.S.
prison system. These supports would help ensure that people are able
to adhere to the stay-at-home guidelines put in place to control disease
transmission. This, in turn, could have compounding effects. For
example, providing paid sick leaves would allow for people to avoid
exposure to others when sick, thus decreasing the spread of the virus.
“These should be seen as basic rights, and for some reason,
they are not,” Parpia said. And while the proposed solutions
center on just one aspect of systemic racism, according to
Parpia, they “will have wide-reaching implications on the ability
of racialized populations to be able to approach a semblance of
equity with White populations in the United States.” ■
Parpia, A. S., Martinez, I., El-Sayed, A. M., Wells, C. R., Myers,
L., Duncan, J., ... & Pandey, A. (2021). Racial disparities
in COVID-19 mortality across Michigan, United States.
EClinicalMedicine, 33, 100761.
May 2021 Yale Scientific Magazine 11
FOCUS
Material Science
3D
2D SOLUTIONS
TO
PROBLEMS
Studying the electrical properties of
altered 2D materials
BY CATHERINE ZHENG
Electronics are ubiquitous in our
everyday lives—they are in the cars
we drive, the microwaves that heat
up our food, and the computers we use.
This omnipresence is due to technology’s
constant evolution. Currently, unbelievably
complex technologies can be found in even
common devices, such as our cell phones.
The creation of materials that are elaborate
in their complexity but simple in their
design—and can thus be implemented
into many technological devices—sits at
the intersection of electrical engineering
and materials science.
Judy Cha, Yale Professor of Mechanical
Engineering and Materials Science, has
led her lab in important work within these
fields. Her team focuses on discovering
new layered materials that can be used
in electronics. Through manipulating
their electrical properties, they seek to
understand more about the materials
themselves and how they can be used. The
team hopes to elucidate which materials
might be particularly ideal for a certain
electronic device, as well as how the
materials’ performance can be improved by
altering electrical properties.
In the beginning of 2021, Cha’s group and
its collaborators published two studies: one
focusing on the mechanical properties of
graphene with lithium between its layers,
and the other on molecular doping—the
addition of small molecules to materials to
activate them for use in electronics.
ART BY SOPHIA ZHAO
Lithium-Ion Batteries
2D materials are usually approximately one
to three atoms thick. They come from layered
materials that are exfoliated down to a single
layer. The properties of 2D materials normally
change when their layers are isolated.
Graphite, commonly found in pencil lead,
is a classic example of this: graphite consists
of layers of graphene, and the individual
graphene layers have properties that differ
substantially from those of graphite as a
whole. To harness such materials for device
applications, it is important to understand
these thickness-dependent changes.
Lithium intercalation into graphite—or,
the insertion of lithium between layers
of graphene that are held together by
van der Waals (vdW) forces—is essential
to create lithium-ion batteries, which
power many of our modern electronics.
Staging, or structural ordering, minimizes
electrostatic repulsions within graphite’s
crystal lattice, allowing lithium to order
itself between the van der Waals gaps of
graphene. Initially, lithium is randomly
distributed throughout the graphite, but as
the lithium concentration increases, there’s
a phase transition where lithium moves
laterally to form intercalated regions that
are vertically separated by unintercalated
regions. The kinetics of lithium moving
between the sheets of graphene are directly
related to how well the battery performs.
This staging process is well understood
for bulk graphite, which is thick. But on a
nanoscale, the way lithium and graphene are
confined so closely together affects the overall
structure. As lithium makes its way between
vdW gaps, these gaps expand to accommodate
the new atoms. However, anchoring graphene
sheets by clamping the edges down changes
the way lithium interacts with the graphene.
This constrains how much the graphene is able
to open, and it requires more work for lithium
to squeeze into those gaps. The kinetics of
lithium diffusion are also slowed down, since
it becomes more difficult for lithium to move
between the graphene sheets.
The effect of this mechanical strain sparked
the interest of Cha’s group. To investigate it
further, they used thin sheets of graphene—
between four and fifteen layers thick—with
gold electrodes on top that acted as a clamp.
Although these electrodes were only onehundred
nanometers thick, each layer of
graphene was even thinner: one-third of a
nanometer. The difference in size allowed the
gold to act as a source of pressure and hold
down the ends of the graphene sheets.
But as they observed this configuration,
the group realized that, while the edges of
the graphene sheets stayed still, the center
would expand freely, stretching in both the
x and y directions and causing strain in the
graphene. “Interestingly, what we found is
this strain can delay the lithiation kinetics
of graphene,” said Josh Pondick, a PhD
candidate in Cha’s lab and one of the lead
researchers for this experiment—lithiation
12 Yale Scientific Magazine May 2021
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Material Science
FOCUS
referring to the process by which a lithium
ion replaces hydrogen atoms.
The team looked at these properties
in different thicknesses of graphene
with in situ Raman spectroscopy, a
method that provides molecularlevel
information about material
surface structures based on light
scattering. They found that,
as the thickness of graphene
increases, staging is delayed,
requiring more electrochemical
voltage to be induced.
A major obstacle in this study
arose while dealing with lithium,
since it is a rather flammable
chemical. Lithium-ion batteries are
typically assembled in glove boxes filled
with an inert, unreactive gas. However,
to experimentally monitor things like
electrical properties, the lithium had to be
taken out of the glovebox. “We spent quite a bit
of time trying to devise device geometry and
architecture that would allow us to contain all
of these volatile chemicals inside a small pouch
while we could still safely take it out and do the
types of measurements that we wanted to do,”
Cha said. But even with these tricky chemical
properties under control, simply handling
these materials was a challenge due to their
small size. The flakes of graphene are on the
order of ten to thirty microns—about the reallife
size of a white blood cell. Thus, techniques
in lithography, a special form of printing, were
required to add the gold electrodes.
With the push for new kinds of batteries
that use metals like magnesium and sodium
rather than lithium, there are plans to see
the results of these different kinds of atoms
being intercalated in graphene. These atoms
are bigger and will undoubtedly provide a
larger mechanical strain. Given how strong
graphene is, researchers are also considering
looking into new materials—notably
heterostructures that consist of multiple
layers of different 2D materials. Adding
intercalants could allow scientists to tune
the electrical and chemical properties of
these structures to be used in many different
devices, from optoelectronic to logic devices.
Molecular Doping
Alongside the research on lithium-ion
batteries and graphene, Cha’s group also
published a study on molecular doping.
An example of molecular doping is
adding boron or phosphorus to silicon,
which activates silicon so that it can be
used in electronics. This is particularly
Professor Judy Cha attempts to measure a device on the probe station.
useful for transistors, which are an
important component of computers.
Adding impurity atoms to a 2D material
like molybdenum sulfide (MoS 2
) is not as
simple as doing so to a single layer of inactive
atoms. The method used in this study involved
sprinkling molecules on top of the 2D material.
The molecules readily gave electrons to the
material, slightly altering its properties. For this
particular study, a synthetic organic molecule
known as DMAP-OED was added to MoS 2
.
To evaluate the effect of this compound on the
2D material, the number of electrons donated
from it to the material was investigated.
Finding the proper technique to do this
proved to be an arduous process. Given
the small size of the molecules, optical
microscopes would be useless. Although
electron microscopes have higher resolution,
they would also be ineffective, since they
would burn through all the molecules.
Alternative spectroscopy techniques were
also considered, but they were too crude to
ABOUT THE AUTHOR
PHOTO COURTESY OF LAUREN CHONG
properly count the number of molecules.
In the end, Cha’s group landed on atomic
force microscopy. This method, which uses
a sharp tip to scan a surface by interacting
with it and tracing its topography, allows for
high resolution of small objects.
Ultimately, Cha’s group found that
DMAP-OED donates 0.63 to 1.26
electrons per molecule to MoS 2
—record
molecular doping levels.
This work represents one of the first
experiments of such a nature done with an
organic electron donor. Thus, it will likely lead
to the development of more organic electron
donors beyond DMAP-OED for this purpose.
Moving ahead, Nilay Hizari, Yale Professor of
Chemistry and the collaborator involved in
the making of DMAP-OED, looks forward to
better understanding molecular doping levels
in the context of other molecules and materials.
“Now, there’s a whole range of small molecules
we could try on [those] 2D materials to get
some kind of desired property,” he said. ■
CATHERINE ZHENG
CATHERINE ZHENG is a sophomore BME major in Pauli Murray College. In addition to writing for YSM,
she’s involved in research and other organizations on campus like WGiCS.
THE AUTHOR WOULD LIKE TO THANK Professors Judy Cha, Nilay Hizari, and Josh Pondick for their
time and enthusiasm in sharing their research.
FURTHER READING
Pondick, J. V., Yazdani, S., Yarali, M., Reed, S. N., Hynek, D. J., & Cha, J. J. (2021). The Effect of Mechanical
Strain on Lithium Staging in Graphene. Advanced Electronic Materials, 7(3), 2000981. doi:10.1002/
aelm.202000981
Yarali, M., Zhong, Y., Reed, S. N., Wang, J., Ulman, K. A., Charboneau, D. J., . . . Cha, J. J. (2020). Near‐
Unity Molecular Doping Efficiency in Monolayer MoS 2. Advanced Electronic Materials, 7(2), 2000873.
doi:10.1002/aelm.202000873
www.yalescientific.org
May 2021 Yale Scientific Magazine 13
FOCUS
Ecology
TRACKING DOWN
LETHAL MOSQUITOES
Machine learning to map the
genetic connectivity of A. aegypti
in the southern United States
BY ELIZABETH WU
With global temperatures
reaching record highs over the
last few years, climate change
has expanded the ranges of diseasecarrying
animals. Even tiny insects,
such as Aedes aegypti mosquitoes, which
are native to Africa, are not exempt
from this trend. Because of their highly
invasive nature, recent increases in global
temperatures have allowed the range of A.
aegypti to continue expanding worldwide,
throughout tropical and temperate
regions. In the United States, they can be
found in the southern states, most notably
in Texas, Florida, and California. They
prefer warm, humid areas close to humans
who can serve as sources of bloodmeals for
female mosquitoes. Feasting on our blood
provides not only a means for A. aegypti to
nourish themselves, but also allows them
to transmit infectious diseases like yellow
fever, Zika, dengue, and chikungunya.
Current climate trends could result in
the exposure of one billion additional
people to these diseases. The fact that, with
the exception of yellow fever, there are
no reliable and widely used vaccines for
these diseases creates an urgent need for
improved tracking and management of A.
aegypti populations. Two scientists at the
Yale School of the Environment—Evlyn
Pless, a postdoctoral researcher at UC Davis
who completed her graduate studies in
ecology and evolutionary biology at Yale,
and Giuseppe Amatulli, a research scientist
in geocomputation and spatial science—
collaborated on a recent study to tackle this
pressing environmental issue. Their goal
was to map North American landscape
connectivity for A. aegyti mosquitoes.
Old Limitations in Landscape Genetics
Landscape genetics, which is the study of
organisms’ population genetic data alongside
landscape data from their habitats, provides
scientists with helpful information that could
be used to control invasive species, such as
A. aegypti. Classical models of population
genetics relate increased genetic differentiation
to increased geographical distance, but these
models do not account for environmental
limitations on dispersal, such as geographic
barriers, or for landscape variables that
facilitate connectivity, like favorable climate.
A common approach to incorporate
environmental data into a model of genetic
connectivity is “resistance surface mapping.”
In this technique, a map of pixels is created
where each pixel represents the hypothesized
resistance of an organism’s movement.
These hypotheses consider environmental
variables. But although the resulting map of
resistance surfaces allows for extrapolation
of genetic distributions across the region,
this method involves substantial subjectivity,
as it relies on the hypothesized effect of an
environmental factor on population mobility.
Prior studies attempted to circumvent the
subjectivity of resistance surface mapping
by modelling genetic connectivity directly
from environmental data and iteratively
refining the model using least cost path
analysis, a mathematical technique that
estimates the least resource-intensive route
along which an organism could travel.
However, according to Amatulli and Pless,
this model was limited because it employed a
mathematical method known as maximum
likelihood estimation, which establishes
a relationship between environmental
variables and genetic distances before the
model is built. The model produced by
this methodology can therefore “overfit”
the data: while it may have been optimized
to match the data, it does not necessarily
make accurate ecological estimations.
14 Yale Scientific Magazine May 2021
www.yalescientific.org
Ecology
FOCUS
A New Approach to Modeling
To improve upon these previous models,
Pless and Amatulli took a groundbreaking
approach towards determining the
relationship between landscape variables
and genetic distance. First, they sampled
mosquitos from thirty-eight sites across
North America and calculated the genetic
differences between mosquitoes in each of
those sites. Open-source data for twenty-nine
different environmental factors, such as daily
temperature ranges and accessibility to major
cities, served as variables meant to explain
and predict genetic distances. For every pair
of sites in the set of thirty-eight sampling
sites, the researchers calculated average
values describing each of the twenty-nine
environmental factors that lay in between.
Using those values on genetic distances and
environmental factors, Pless and Amatulli
employed a fascinating strategy to predict
the effects of landscape conditions on genetic
connectivity: they used a machine learning
method called a random forest (RF)—a
predictive model based on aggregations of
possible effects of different factors—to create
landscape resistance maps. In doing so, they
generated a map representing landscape
resistance, which measured the difficulty
of mosquito migration at any particular
point based on all of the twenty-nine
environmental factors combined.
Using the resistance map built by RF, least
cost paths were drawn between each pair
of thirty-eight sampling sites. These paths
describe the least energetically expensive
routes between sites that could be taken
by mosquitoes over a particular landscape.
Then, multiple iterations of this process were
conducted by generating more resistance maps
via RF and subsequently re-calculating least
cost paths. As a result, the model refined itself
with each subsequent iteration, producing
increasingly accurate predictions of mosquito
genetic connectivity based on landscape data.
Compared to previous landscape genetic
models, one distinct advantage of RF is
its resistance to overfitting—the model
produced by RF is not overly sensitive to
noise in the data that it was trained on. To
test if their model overfit the data, Pless and
Amatulli conducted “leave-one-out crossvalidation,”
meaning that the model was run
thirty-eight times, each time leaving out one
of the thirty-eight genetic data points.
Results generated by this cross-validation
process were comparable to the results from a
www.yalescientific.org
model based on a full data set, demonstrating
that the model was not overfitting the data. In
fact, leave-two-out cross-validation was also
conducted, which further demonstrated that
the model did not overfit the data and could
accurately predict genetic distances.
But while this novel iterative approach
combined with RF did, in fact, prove to be
effective, it was initially time-consuming. To
address this, the researchers decided to use
GRASS—a geographic information system
software—in addition to R, a statistical
computing environment. “We wrote
everything first in R, but it was not fast enough
to do all the iterations, so then we used GRASS
to build cost paths analysis… and we conducted
the machine learning part in R, allowing us to
speed up the process from twenty-four hours
to one or two,” Amatulli said.
The researchers had successfully
constructed a model that predicted genetic
distances based on landscape data more
accurately than previous models. This
meant that they could track the movements
of A. aegypti mosquitoes based on the idea
that landscapes facilitating the animal’s
movements allow for greater genetic
connectivity. Inversely, they could also
consider the possibility that landscape
barriers result in greater genetic distances
due to lower movement. Interestingly, of the
twenty-nine environmental variables tested,
the researchers discovered that maximum
temperature was the most important in
predicting genetic connectivity, followed by
slope, barren land cover, and human density.
ABOUT THE AUTHOR
A Tool for Ecological Intervention
and Protection
The novel model of A. aegypti
landscape genetics is important because
it accurately predicts the genetic
connectivity—and thus the mobility—
of mosquitoes in regions where samples
were not taken and genotyped.
The broader implications of tracking
mosquitos with such accuracy involve
recently developed methods of disease
control. A prime example of this is releasing
genetically modified mosquitos that will
prevent wild mosquito populations from
reproducing. This kind of model provides
valuable knowledge about where the
mosquitoes should be released and how
far the intervention will spread. Another
potential application is demonstrating
the effects of pesticide application,
which would cause natural selection of
mosquitoes with pesticide-resistant genes.
In theory, the model could be used to
predict where those genes would prevail.
Beyond mosquitoes, this study—
with its iterative RF methods—is an
innovative step forward in the field of
landscape genetics. The novel strategies
that were employed could help protect
corridors for vulnerable animal
populations. “We hope this paper will be
inspiring to people, more broadly, who
are trying to control invasive species or
who are trying to protect endangered
species,” Pless said. ■
A R T B Y N O O R A S A I D
ELIZABETH WU
ELIZABETH WU is a first-year in Saybrook College. In addition to YSM, she is an intern for the New Haven
Public School Advocates through Yale's First Years in Support of New Haven.
THE AUTHOR WOULD LIKE TO THANK Evlyn Pless and Giuseppe Amatulli for their time and
enthusiasm about their research
FURTHER READING
Pless, E., Saarman, N. P., Powell, J. R., Caccone, A., & Amatulli, G. (2021). A machine-learning approach
to map landscape connectivity in A. aegypti with genetic and environmental data. Proceedings of
the National Academy of Sciences of the United States of America, 118(9), e2003201118. https://doi.
org/10.1073/pnas.2003201118
Bishop, A., Amatulli, G., Hyseni, C., Pless, E., Bateta, R., Okeyo, W. A., ... & Saarman, N. P. A machine learning
approach to integrating genetic and ecological data in tsetse flies (Glossina pallidipes) for spatially
explicit vector control planning. Evolutionary Applications. https://doi.org/10.1111/eva.13237
Zhao N, Charland K, Carabali M, Nsoesie EO, Maheu-Giroux M, Rees E, et al. (2020) Machine learning
and dengue forecasting: Comparing random forests and artificial neural networks for predicting
dengue burden at national and sub-national scales in Colombia. PLoS Negl Trop Dis 14(9): e0008056.
https://doi.org/10.1371/journal.pntd.0008056
May 2021 Yale Scientific Magazine 15
FOCUS
Medicine
A BREAKTHROUGH TH
Could teplizumab lead us to a cure for typ
Before insulin was discovered in 1922
by Sir Frederick Banting and Charles
Best, type 1 diabetes—an autoimmune
disease that renders the body unable to
convert blood sugars to energy—was often a
death sentence. Patients with diabetes rarely
lived for more than two years after disease
onset. This discovery of the insulin treatment
was revolutionary: for the first time, patients
could survive and manage their illness.
Nearly a century later, a new
breakthrough in the field of type 1
diabetes has been achieved. A clinical
trial analysis published in Science
Translational Medicine, co-authored by
Kevan Herold, C.N.H. Long Professor of
Immunology and of Internal Medicine
at Yale University, and Emily Sims,
Assistant Professor of Pediatrics at
Indiana University, reported compelling
evidence for teplizumab—a drug granted
FDA ‘Breakthrough’ status in January
2021. The breakthrough aspect comes
from the fact that this drug doesn’t
simply address symptoms; it could be
able to preemptively delay, or even
prevent, type 1 diabetes altogether.
The journey towards teplizumab has
been a long and arduous one. “Literally
for the past thirty years I’ve been working
on this, from doing the pre-clinical mouse
work, to doing the early investigatorinitiated
clinical trials, to eventually
leading clinical trials that were done by
NIH consortia like the Immune Tolerance
Network or TrialNet,” Herold said.
A Long and Winding Road
Even after insulin started to be used as
treatment, Herold witnessed the drastic
effects that the disease had on the quality
of life of patients. “Diabetes is with you
twenty-four-seven,” he said. “There’s literally
nothing that you do that is not impacted by
having the disease, whether it’s deciding to
eat or not, whether it’s exercise, whether it’s
sleep, whether it’s going to class.”
For Herold, the prospect of conducting
research had been appealing since his
undergraduate years. Throughout his
research trajectory, he has always strived to
understand the basic mechanisms, causes,
and treatments of type 1 diabetes. Herold’s
decades-long commitment to the pursuit
of scientific advancement in this area began
even before the invention of many essential
research techniques scientists often rely on
today, such as polymerase chain reaction. “At
that time, a lot of what we take for granted now
hadn’t even been discovered,” he explained.
“Immunology was still in its infancy.”
The research leading up to this
breakthrough drug began in 1990
for Herold and his colleague, Jeffrey
Bluestone, Professor of Metabolism and
Endocrinology at UCSF. In his earlier
research, Herold had studied autoreactive
T cells—a group of immune white blood
cells that turn against our own cells and
tissues. By looking at them in mouse
models with diabetes, he was led to believe
that they could cause type 1 diabetes in
humans. With researchers at Johnson
& Johnson, Bluestone then developed a
human drug, teplizumab, that modifies
a certain population of autoreactive T
cells that play an important role in killing
beta cells—the cells that produce insulin
in the pancreas. CD3, a T cell receptor, is
involved in activating this population of
autoreactive T cells. Teplizumab is an anti-
CD3 antibody that binds competitively to
CD3—an action thought to prevent the
receptor from binding to and activating the
autoreactive T cells. Teplizumab thus serves
as a regulatory immunosuppressant for an
overactive immune system, protecting
against the depletion of beta-cells that is
characteristically seen in type 1 diabetes.
From Gold, to Dirt, and Back
Teplizumab showed early success in
Herold’s first clinical trial in 2002 and was
later acquired by biotechnology company
MacroGenics. It was also supported by
the pharmaceutical company Eli Lilly
in phase III clinical trials to evaluate its
safety and efficacy. However, this large-
PHOTOS COURTESY OF ALEX DONG
16 Yale Scientific Magazine May 2021 www.yalescientific.org
Medicine
FOCUS
ERAPY FOR DIABETES
e 1 diabetes?
BY ALEX DONG
scale trial did not end up meeting its
target efficacy endpoint, the necessary
threshold to move forward. “When
that happens in the pharma field, it’s
a disaster,” Herold explained. “You’ve
basically turned gold into dirt.”
MacroGenics and Eli Lilly both
abandoned the project in 2010, and
teplizumab was considered a failure.
“There was nobody willing to pick it up,
and we had no support,” Herold said.
Knowing that the drug development
process requires substantial resources,
Herold and his colleagues traveled across
the country and even flew internationally
to Germany in pursuit of funding and
support. Despite teplizumab having
favorable mouse and human trial data,
every company, foundation, or potential
investor declined—for eight years.
Finally, in 2018, Provention, a
biotechnology company founded just
two years prior, decided to take on
teplizumab anew. Herold cites his belief
in the promising science behind the
mechanisms of the drug in humans as a
large motivating factor in his persistence
over the eight long years. “This was
literally dead,” he said. “It just goes to
show you that if you think something
is really worth doing, you [have] got to
stick with it no matter how bad it seems,
because one turn of the tide could make
all the difference in the world.”
In 2019, Herold led a phase II clinical
trial, sponsored by TrialNet, testing the
effectiveness of teplizumab. He found
that it successfully delayed the onset of
type 1 diabetes in high-risk patients by
approximately two years. Herold then
proposed a new question: how does
www.yalescientific.org
teplizumab affect beta-cell function?
“We ask this question all the time in
people who have diabetes, but we really
never had the opportunity to answer it in
people at risk for diabetes,” he explained.
“They don’t yet have the disease, but we
know that they’re going to develop it.”
Delaying the Onset of Diabetes
For Sims, conducting research was not
always a priority. “I always thought I wanted
to be a doctor, and I always loved kids, so I
thought I was going to be a pediatrician,”
Sims said. She found the physiology of
endocrinology interesting and intuitive,
so she decided to specialize in pediatric
endocrinology. She was first exposed to
basic science research during these years.
Almost immediately, the inherent crossapplications
of research and medicine
became apparent. “Working in the lab
gave me this really cool opportunity to
ask questions that were relevant to what
you see in the patients you’re treating,” she
said. Referencing a line from Aaron Burr in
the musical Hamilton, she explained that
research is like “being in the room where it
happens.” In Sims’ many interactions with
children diagnosed with type 1 diabetes,
she witnessed the toll of this disease on her
patients and their families. “When you get
that diagnosis, your life changes,” she said.
Herold and Sims are both involved in the
NIH consortium TrialNet. Sims’ expertise
studying beta-cells and analyzing metabolic
data drew her to join Herold in pursuit
of a better understanding of the effects of
teplizumab on beta-cell function.
In their 2021 study, published in Science
Translational Medicine this March,
Sims and Herold suggested that there
is progressive depletion of beta-cells
in the years preceding type 1 diabetes
diagnosis. During this period, the level
of metabolic dysfunction, which is a sign
of autoimmunity, defines the stages of
the disease. Stage 1 consists of the period
before glucose abnormalities arise; stage 2
makes these abnormalities more evident;
and stage 3 is the typical definition of
diabetes—the phase defined by clinical
presentation of high blood sugar.
Sims and Herold investigated whether
teplizumab would delay stage 3 clinical
diagnosis in seventy-six individuals at
stage 2 of the disease. They found that a
single fourteen-day teplizumab treatment
program could have enduring effects: the
teplizumab group had a median time of
May 2021 Yale Scientific Magazine 17
FOCUS
Medicine
five years before stage 3 onset compared to
just two for the placebo group. Moreover,
eighteen percent of teplizumab-treated
individuals treated were not diagnosed
with stage 3 at all in more than five years,
which is the time during which followup
data was being collected, compared to
just six percent for the placebo group. The
study also found that teplizumab improved
beta-cell function, even in individuals who
did not develop diabetes. The drug could
also reverse declines in insulin secretion.
Sims and Herold’s paper outlined
that teplizumab led to an improvement
in metabolic responses and delay of
diabetes. It is the first drug of its kind
to ever do so. “If you’re eight years old
and get treated for the disease, you’re
not going to develop it for five years
until you’re thirteen,” Herold said. “The
maturation of a child during that period
of time is extensive, and you’re probably
better able to manage the disease when
[you’re] older. Same thing if you’re going
into middle school and you’re not going
to get it until after graduating high
school. That’s a big deal!”
A Game-Changer
The Food and Drug Administration
(FDA) has recently granted teplizumab
“Breakthrough Therapy Designation,”
which bodes well for its approval this
summer. If the drug is approved, an
important next step is to identify those
who are eligible for and could benefit
from the treatment. Sims explained that
TrialNet screens the relatives of patients
with diabetes, but most people who
develop diabetes do not actually have
family members with the disease. “We
have to think big: now we have a reason
to screen people at risk for diabetes,
because there is something we can do
about it,” Herold stated.
Current insulin treatments act as
retroactive “band-aids,” making it
possible for diabetes patients to manage
their symptoms and survive. Teplizumab,
on the other hand, targets the underlying
mechanisms of type 1 diabetes before its
onset. This means that it could modify
the disease’s trajectory. With teplizumab,
the playing field for type 1 diabetes has
completely shifted—what was once a
waiting game now holds options for
delay, or even prevention, of the disease. ■
A R T B Y S O P H I A Z H A O
ABOUT THE AUTHOR
ALEX DONG
ALEX DONG is a first-year student from Canada in Benjamin Franklin college interested in studying
Biomedical Engineering on the pre-med track. On YSM, Alex is a copy editor, staff writer, layout designer,
photographer, and artist. Outside of YSM, Alex is a Senator for the Yale College Council and a poet for
the Yale Layer.
THE AUTHOR WOULD LIKE TO THANK Dr. Kevan Herold and Dr. Emily Sims for taking the time to
discuss their experiences and research with him.
FURTHER READING
Herold, K. C., Bundy, B. N., Long, S. A., Bluestone, J. A., DiMeglio, L. A., Dufort, M. J., ... & Greenbaum, C. J.
(2019). An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. New England Journal
of Medicine, 381(7), 603-613.
Sims, E. K., Bundy, B. N., Stier, K., Serti, E., Lim, N., Long, S. A., ... & Type 1 Diabetes TrialNet Study Group.
(2021). Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals.
Science Translational Medicine, 13(583).
18 Yale Scientific Magazine May 2021 www.yalescientific.org
Electrical Engineering
FOCUS
GENERATING
RANDOMNESS
A Laser-Based Scramble
for Random Numbers
Introducing a new mechanism, a hundred times faster than before
BY ALEXA JEANNE LOSTE
ART BY ELAINE CHENG
When you play the violin, you can trace back its sound to the vibration of its
strings. These energy vibrations—the sound waves—transfer from the strings
to the violin’s bridge, and then to its body, eventually vibrating the air before
reaching our ears as sound. The hollow wooden body serves as a resonator for acoustic
waves. Its shape is tailored to resonate with many acoustic frequencies, producing the rich,
resonant quality of sound that we appreciate as music.
This is how Hui Cao, John C. Malone Professor of Applied Physics and of Physics at
Yale, explained the design of a new laser developed in her lab. Her team is leveraging this
innovative technology to generate random numbers at revolutionary speeds.
In an article published in Science on February 26, Cao and her collaborators wrote about
their new laser design with a random bit generation (RBG) rate of two hundred fifty terabits
per second—faster than existing versions by more than a hundredfold. Functioning by
a completely different mechanism, their laser uses many different channels to generate
random numbers in parallel, while increasing the RBG rate of each individual channel.
www.yalescientific.org
May 2021 Yale Scientific Magazine 19
FOCUS
Electrical Engineering
IMAGE COURTESY OF FLICKR
The potential of their basic research to be leveraged into concrete applications inspires the team to continue studying the complex physics of laser dynamics, Cao said.
Like the sound waves produced by a violin
string that are amplified in the wooden
body, the laser produces light waves that
are amplified in an optical resonator, which
Cao designed in a bow-tie shape. This shape
allows the laser to resonate with many optical
modes of different frequencies, analogous to
the multiple tones of a violin string. “The
breakthrough is a different mechanism,” Cao
said. Whereas conventional lasers only have
one or a few modes, the many modes of this
new laser can interfere with each other to
create complex spatio-temporal patterns—
which is where the randomness originates.
Leveraging Lasers for Cybersecurity
Doing basic research in understanding
complex laser behaviors opens up the
possibility for a multitude of applications,
some of which come in unexpected forms.
“The original goal was not generating
random numbers, but just changing the
shape of the cavity and studying the laser
dynamics,” said Kyungduk Kim, a graduate
student in Cao’s group. Cao explained
that by working with more complex laser
designs, her lab is tapping into potential new
functions of lasers. “Lasers are probably one
of the most important inventions in science
and technology in the last century,” Cao said.
Among all the potential applications
of lasers, random number generation
represents a particularly important one. In
a world increasingly dependent on digital
communication and exchange, random
number generation is integral to ensuring
online security. One ubiquitous example is
in the creation of encryption keys—used
to scramble private information such as
passwords, banking information, or messages
to prevent them from being intercepted
when sent through online channels, like
emails. The random quality of the selected
key is integral to preventing potential
attackers from breaking into messages and
stealing information. Predictable keys, or
even keys based on sophisticated algorithms
whose pattern can be uncovered, could leave
sensitive private data vulnerable.
Additionally, random numbers have
a variety of applications in scientific
research. The modelling of stochastic
processes that involve random
probabilities, such as the spreading of
viruses or fluctuations in the stock market,
relies on streams of random numbers that
can simulate the unpredictability of these
systems. Statistical analysis also relies on
random number generation to choose
random samples from a population in
order to prevent biases that may make
the analysis less reliable.
20 Yale Scientific Magazine May 2021 www.yalescientific.org
Electrical Engineering
FOCUS
Laser-to-Randomness Fundamentals
Not even the most powerful supercomputer
can generate true random numbers on its
own. This is because computers run on
algorithms, and any finite algorithm will
eventually loop back and repeat itself, yielding
a specific pattern of outputs. To generate true
randomness, one has to rely on external
physical sources of entropy, or naturally
occurring disorder in the universe. Through
monitoring systems that have dynamics that
cannot be predicted, they can be used as a
source of randomness. One way that scientists
have done this is by using lasers.
Light waves in the lasers that the researchers
work with, called broad-area semiconductor
lasers, often naturally experience irregular
fluctuations from the interaction of light with
the lasing medium. Previously, researchers
leveraged this property of light as a source
of randomness, translating fluctuations
of light intensity into zeros and ones. The
randomness comes from the chaotic pattern
of the stream of bits generated. However,
there is a limit on how quickly those lasers
can generate random number streams. This
depends entirely on how fast the fluctuations
occur. To increase the RBG rate of a laser
beyond that limit, one would need to either
increase the number of bit streams generated
in parallel or use a new mechanism as a source
of randomness that has faster dynamics. The
Yale team’s new laser does both.
Improvements in Quantity and Quality
Previously implemented lasers had flat
edges. With this conventional shape, laser
intensity fluctuations were correlated
with both time and space, limiting the
lasers’ effectiveness: correlations over time
decrease the quality of the randomness
sampled from a single location, and
correlations over space decrease the
number of different locations one could
measure to get random numbers.
By curving the edges of the laser cavity,
Cao and her collaborators were able to
substantially increase the number of lasing
modes (think: violin string tones). “When
you have this curved edge, the light can
come out at many different spatial locations,”
Cao said. “When you measure the intensity
at each spatial location, these intensities
will fluctuate in time.” By recording output
from multiple positions simultaneously,
they could use the laser to generate multiple
random number streams in parallel.
www.yalescientific.org
In addition to inducing multiple
RBG streams at once, the new laser also
enhances the random bit generation rate
of every individual stream by using a new
mechanism. Whereas conventional chaotic
lasers rely on the irregular fluctuations on
a time scale set by their response time to
extract randomness, the research team’s laser
uses a different source of randomness: the
interference of the multiple lasing modes.
Since the light waves in each mode have
different frequencies, by summing them up
at different points in space and time—that
is, their spatio-temporal interference—
the researchers could use the variation
in interference intensity as a source of
randomness. Because the interference
pattern fluctuates much faster than the
emission from chaotic lasers, it can generate
random numbers at a much faster rate.
Breaking into a New Field
Cao mentioned that this project was her
lab’s first venture into the field of random
number generation, and they did not have
any previous experience or connections to
other researchers in the field. Having realized
that her work could be applied to a new
mechanism for random number generation,
she assembled an interdisciplinary team
to study techniques including translating
measured intensities into digital bits and
quality testing random numbers. “We
learned a lot through this adventure, and I
think that is how scientific research gives us
a lot of surprises. And sometimes, we also
get some reward,” Cao said.
To get published in a scientific journal,
every article must undergo a thorough
review process in which peer researchers
in the field must provide feedback on the
work. “The reviewers of our papers …
were very critical and made sure we did
everything right,” Cao said. “On the other
ABOUT THE AUTHOR
hand, they really helped us by suggesting the
additional tasks we need to do to convince
people our method works.” Cao cited the
support received from the random number
generation community, which was helpful to
her team as they broke into the field.
Kim also attested to the important role
of collaboration in the project. “It was
very lucky that I met good collaborators,”
Kim said. Researchers from Nanyang
Technological University in Singapore
built the lasers that the Yale team designed,
which are cutting-edge chip-scale lasers
fabricated on a semiconductor wafer. Kim
also emphasized that his work directly built
upon the work of previous researchers in
the lab, highlighting the cumulative process
of building knowledge in the scientific field.
Scaling Down to Scale Up
Looking forward, the next challenge facing
this new laser is integrating the system into a
smaller medium, such as a chip. In this study,
to measure the spatiotemporal interference of
the light waves (the source of randomness), a
special camera was used. This streak camera
measured the light emission at an extremely
rapid rate, recording an image of the emission
every picosecond, resulting in one image
produced per every trillionth of a second. A
resolution this high comes with a steep cost,
so the camera is primarily used by researchers.
Additionally, its bulkiness presents a hurdle
to wide-scale adoption. Taking the new laser
forward would require engineering laser
chips with integrated photodetectors.
Nevertheless, the work done by the Yale
researchers takes the field of random number
generation a step forward—or in this case,
two whole orders of magnitude forward.
For Cao, the potential of basic research to be
leveraged into concrete applications inspires
the team to continue studying the complex
physics of laser dynamics. ■
ALEXA JEANNE LOSTE
ALEXA JEANNE LOSTE is a first-year prospective Molecular Biophysics & Biochemistry major in Ezra
Stiles College. In addition to writing for YSM, she is a project head for GREEN at Yale, a member of the
Environmental Education Collaborative, the STEM Panel Chair for the Conference Committee of the
Women’s Leadership Initiative, and a copy desk staffer at the Yale Daily News.
THE AUTHOR WOULD LIKE TO THANK Kyungduk Kim and Dr. Hui Cao for their time and enthusiasm
in sharing their research.
FURTHER READING
Kim, K., Bittner, S., Zeng, Y., Guazzotti, S., Hess, O., Wang, Q. J., & Cao, H. (2021). Massively parallel
ultrafast random bit generation with a chip-scale laser. Science, 371(6532), 948-952.
May 2021 Yale Scientific Magazine 21
FOCUS
Physics
BY BRIANNA FERNANDEZ
ART BY ALEX DONG
THE RADIO
STATION AT
THE END OF
THE UNIVERSE
Chasing the axion to unravel the
mystery of dark matter
22 Yale Scientific Magazine May 2021
www.yalescientific.org
Physics
FOCUS
The matter we interact with on
a daily basis is known as normal
matter. Counterintuitively, this
normal matter makes up only about
five percent of the universe. Physicists
think the rest is composed of two other
constituents: dark energy, the force
thought to be speeding up the expansion
of the universe, and dark matter, an
unknown type of matter that only
interacts strongly with gravity. Though
neither of them can be detected directly,
the role that dark energy plays in the rate
of the universe’s expansion, as well as the
effect that dark matter has on galactic
structure, make physicists confident in
these hypothesized substances.
Some people wonder how galaxies
rotate at a seemingly impossible rate; in
theory, they simply could not maintain
such high speeds given the masses we
detect from Earth. From the perspective
of astronomers, galaxies’ low masses
could not generate enough gravity to hold
them together. Something is giving them
extra mass—something undetectable.
This is what we have designated dark
matter. But what is dark matter, really?
What is it made of? Enter the axion.
Researchers at the Yale Department of
Physics’s Wright Laboratory have come
together in pursuit of the axion. By looking
for this hypothetical particle—which is
thought to comprise dark matter—they
think it could be possible to find dark
matter. Led by fifth-year graduate student
Kelly Backes, this group recently published
a paper in Nature that reports the use of
vacuum squeezing to double the search
rate for axions. This process enabled them
to circumvent the quantum limit that many
dark matter searches can barely approach.
By breaking through this limit, rather than
merely approaching it, they are ushering in
an age in which searches for fundamental
physics are less hindered by noise, bettering
the chances of the axion’s discovery.
Hiding in Plain Sight
This question of missing galactic mass
has been pondered by physicists since the
1930s, resulting in a variety of potential
candidates
for what dark matter
could be. “Because there are so many
different options for what could be
dark matter, a lot of the well-motivated
theories are particles or theories that
solve multiple problems,” Backes said.
“There are very few things in physics that
just exist for one weird purpose.” One
promising dark matter candidate is the
axion—a hypothetical particle that was
first proposed in 1977 by Roberto Peccei
and Helen Quinn. Named after a laundry
detergent, the axion was theorized to solve
the strong charge-parity (CP) problem of
quantum chromodynamics—a problem
within the Standard Model of particle
physics in which two fundamental
nuclear forces act differently. Later,
researchers Steven Weinberg and Frank
Wilczek suggested that the axion could
also be what makes up dark matter.
Although axions are theorized to be
infinitesimally small and extraordinarily
light, they completely pervade the space
which they occupy, existing everywhere
and all the time. Their omnipresence
makes it more convenient to imagine
each axion as a sea of particles that
oscillate together rather than as
individual ones. With this knowledge in
hand, the detectors searching for axions
aim to sense them as waves.
While we generally think of dark matter
in the context of its interactions with gravity,
since this is the only way in which we know
it exists, dark matter seems to have feeble
interactions with other fundamental forces.
As a result, some scientists looking for
axions do so by detecting their extremely
weak interactions with electromagnetism.
“If you supply a magnetic field, the axion
field and this magnetic field interact and
produce a tiny [bit of] excess electric field
that is actually then detectable, and that's
the interaction that we center our detector
around,” Backes said. Essentially, axions
are detected as excess power in
a detector. They react with
magnetic
f i e l d s ,
yielding small traces of electric field. It is
Backes’s job to amplify this electric signal
and, from there, detect these evasive axions.
The Great Cosmic Radio
Backes’s research group has spent years
searching for this dark matter candidate,
analyzing excess power that could be
produced by axion waves and a large
magnetic field in the hopes of finding
the answer to this long-held mystery.
“Essentially what we’re doing is operating a
really, really, really sensitive radio,” Backes
said. The interactions they measure occur
inside of a microwave cavity, or a resonator,
and when the resonator frequency matches
that of the axion field, the interaction is
enhanced, amplifying the signal.
When you’re flipping through radio
stations in the car, you’ll tune to a station,
listen to hear if that’s what you want, and
tune to the next station until you find what
you’re looking for. However, your radio
will only pick up a station if it is tuned to
the same frequency as the incoming radio
waves. In this case, the detector functions
similarly to the car radio, and the axion is
the station to be detected.
But where exactly is the axion station
located? As it turns out, it is hard to tell.
“You’re tuning through frequency space, and
you’re looking for the only station in the
universe, and you have no
idea where it is,”
Backes said.
For now,
www.yalescientific.org
May 2021 Yale Scientific Magazine 23
FOCUS
Physics
Backes’s
group is searching
for axion frequencies at around
four or five gigahertz, but the axion
could be hiding anywhere on the range
of hertz to terahertz—where a frequency of
one hertz is one cycle per second, and one
terahertz is a trillion times that.
Though the range Backes and her
colleagues are investigating is small relative
to the orders of magnitude of potential
frequencies that surround it, it is strongly
grounded in theory. Some groups of
theorists have done large-scale calculations
that indicate that the axion’s location is
likely around the range they are exploring.
Experimentally, this range is favorable
because the low gigahertz range makes
for a nicely sized detector: resonator size
is proportional to desired frequency, so a
much lower frequency would require an
inconveniently large detector. A higher
frequency, conversely, would necessitate an
exceptionally smaller one.
The Coolest Part: Vacuum Squeezing
The vacuums physicists use are nothing
like the loud cleaning appliances with
which most people are familiar. In physics,
a vacuum is the absence of matter and
energy. It is the ground state of all fields
in quantum mechanics, and its energy
fluctuates in quantum fluctuations, creating
temporary random changes of energy
in a point in space. Vacuum squeezing
redistributes these fluctuations, enhancing
or repressing them along different time
intervals. “I think I’m biased, but this is the
coolest part of what I’ve done,” Backes said.
When conducting any experiment,
data is likely to come with noise, which
is a result of random variations that
interfere with the signal. Like radio
static, the electronic noise in axion
experiments
doesn’t
h a v e
any specific frequency or phase
preference. Since that noise is made of
components with different phases, one
could mathematically decompose it into
terms of more traditional sine and cosine
wave patterns. The amplitudes of these
sine- and cosine-like components of these
fluctuations don’t commute, which is why
the noise exists in the first place. “Like
the traditional uncertainty relationship
between position and momentum, you
can't measure all fluctuations at once
without adding noise to your system,”
Backes explained. “That's where these
quantum vacuum fluctuations come in.”
However, it does not matter whether all
the phases can be precisely measured in the
detector—the way that axion signals are
measured does not necessitate it. Instead,
physicists squeeze the noise into one
“quadrature,” like position and momentum
in the previous example, meaning that the
sine- and cosine-like fluctuations would be
two measurement quadratures.
If we were to think of noise as a malleable
ball, squeezing it would involve taking a
round noise state that lacks phase preference
and processing it with an amplifier so that
it is squeezed into an oblong blob of a noise
state—one that has a phase preference. The
resonator’s power has no phase preference,
so when the newly squeezed state is guided
into its cavity, the axion is measured until
it no longer has a phase preference either.
Essentially, one axion arrives, displacing
the squeezed state in one direction, and
another follows, displacing it in a different
direction. This process molds the squeezed
state, and the pattern continues until it is
broadened by the displacement.
Once the squeezed state is slightly
fattened, it is read out of the microwave
cavity and squeezed in the opposite
direction. Flattening the squeezed state
amplifies the hypothetical axion signal
IMAGE COURTESY OF LAUREN CHONG
The upper plates of the experiment's dilution
refrigerator at the Lamoreaux Group.
along the newly shaped quadrature,
which is the same quadrature that
originally had the squeezed noise.
Ultimately, this allows Backes and her
team to measure an amplified signal
against subquantum limited noise,
making it easier to detect axions.
This work is revolutionizing the field,
which should make the search for axions
more efficient. “I think the big impact of
this specific paper and this work is it shows
for the first time that quantum squeezing
can be used as a tool to speed up a fullscale
fundamental particle search,” Backes
said. As the first experiment to show that
one can look for new fundamental particles
against a noise background that is below
the standard quantum limit, this work is at
the forefront of the search for dark matter.
Dark matter has eluded physicists for
decades, but Backes and her team might
have unearthed a faster path to find it
with their novel approach to detecting
the axion. They have not had luck
yet, but their research takes time.
For now, they can only continue
flipping through galactic radio
channels, hoping to find the
station at the end of the
universe. ■
ABOUT THE AUTHOR BRIANNA FERNANDEZ
BRIANNA FERNANDEZ is a sophomore in Pierson College studying astrophysics. In addition
to writing for YSM, she is one of the magazine’s copy editors. Outside of YSM, she researches
exoplanets with Professor Debra Fischer and advocates for free prison phone calls with the
Yale Undergraduate Prison Project.
THE AUTHOR WOULD LIKE TO THANK Kelly Backes for her time and enthusiasm to share her research.
FURTHER READING
Backes, K. M., Palken, D. A., Al Kenany, S., Brubaker, B. M., Cahn, S. B., Droster, A., ... & Wang, H. (2021). A
quantum enhanced search for dark matter axions. Nature, 590(7845), 238-242.e
24 Yale Scientific Magazine May 2021 www.yalescientific.org
ASIA
ASSESSING SOCIAL IDENTITIES
T
he various groups we belong to are at the heart of our human
identities. These social identities shape who we are and
influence everything from our individual actions to our shared
interactions. We behave in accordance with the norms of the groups we
identify with, with group memberships that are dynamic. This means
that our social identities are context-dependent; at any moment, the
group membership that is psychologically salient for a person can
change. In other words, our actions and interactions often conform to
the norms of the group we identify with at a particular instance.
This prompts questions about our social identities: what factors
determine which groups we identify with? How do we switch between
our different identities, and how do we deal with competing identities?
The major roadblock to studying these concepts is that social identity
salience is difficult to assess, especially in a natural setting. Researchers
face obstacles and uncertainties in determining which identity is guiding
someone’s actions and interactions at a given moment.
In a creative attempt to address this, researchers from the
University of Exeter in the United Kingdom recently developed
an analytical protocol, ASIA (Automated Social Identity
Assessment), that uses linguistic indicators in text to infer salient
group membership at a particular moment.
“Salience is a very dynamic thing, so it can switch very quickly,”
said Miriam Koschate-Reis, the lead researcher for this project. “If
my little girl runs through here, then I can very quickly switch to
being a parent and back to being an academic. It’s very fast switching,
and we haven’t really looked much at these switches.” (Ironically,
seconds after she said this, her little girl did run through the room.)
In the past, researchers have attempted to use self-reporting as a way
of assessing salient social identity. However, self-report measures are not
very useful for studying temporal dynamics of social identities in natural
settings, nor are they reliable for studying long periods of time, because
they provide relatively limited datasets. Additionally, if someone is
asked to self-report their “main” social identity at a particular moment,
they may lack the introspection to actually answer the question. For
example, take a moment now to try to identify your salient social
identity—student, feminist, daughter, etc. It is quite difficult.
In contrast, ASIA relies on computational linguistics and uses a
binary classification model in order to determine which of two
social identities is salient in a person at a particular moment. ASIA
makes use of linguistic indicators, because sociolinguistic theories
assert that both vocabulary and stylistic choices are affected by social
variables and groups. Linguistic information has been established as
a reliable way to determine group classification and identification.
Additionally, there is a wide availability of useful data in the form
of written text in online forums, which makes models that focus on
linguistic styles convenient and desirable.
However, this data use doesn’t come free of concerns. While
developing the ASIA protocol, the researchers made sure to
center ethical considerations—mainly the ethical implications
of assessing specific social identities in the first place, as well as
of using online data to train and validate the model.
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Psychology
BY TEJITA AGARWAL
ART BY MALIA KUO
FEATURE
“It’s quite tricky when you’re almost looking into people’s
minds. . . . that’s why we really felt strong about writing and
putting ethics first to say, if you want to develop this tool, please
think carefully about the ethics of it,” Koschate-Reis said.
Koschate-Reis and colleagues concluded that researchers have
a responsibility to consider any foreseeable harm to individuals,
especially those whose identities may expose them to discrimination
and ostracism. They explained that public online forums are perhaps
a more ethical source of data than social media platforms where
users face difficulty or confusion in selecting appropriate privacy
settings. Public online platforms generally have anonymous users
with little personal identifying information.
After training and testing their program, the researchers concluded
that ASIA provides a mechanism to assess salient social identities using
naturally occurring data at a scale large enough to investigate salience
within a person over time. This step is essential in investigating how
people switch between different identities and when those identities
come about. For example, consider: when does someone start to
identify themselves as a parent? Is it when they become aware of
pregnancy, when they are buying child-raising materials, or when the
baby is actually born? The ASIA protocol gives researchers a reliable
way to seek answers to these questions, furthering the general effort
to learn about our social identities in natural social settings. ■
Koschate, M., Naserian, E., Dickens, L., Stuart, A., Russo, A.,
& Levine, M. (2021). ASIA: Automated social identity
Assessment using linguistic style. Behavior Research
Methods. doi:10.3758/s13428-020-01511-3
May 2021 Yale Scientific Magazine 25
FEATURE
Microbiology
MEMORIES OF A BRAINLESS
SLIME MOLD
THE LITTLE SLIME THAT COULD
Let’s talk about slime.
And no, not the kind that went viral on ASMR TikTok.
Today, we’re diving deep into the world of Physarum
polycephalum, an intelligent unicellular eukaryote with the
ability to solve complex problems, and how it is changing our
perception of memory one tube at a time.
The concept of memory is often associated with complex
organisms: humans reminiscing about failed family picnics or
those heartfelt videos of dogs jumping into the arms of their
owners after years of separation. We love to see it. But it turns
out that the conceptualization of memory may be different from
what most expect. Researchers Mirna Kramar and Karen Alim
at the Max Planck Institute for Dynamics and Self-Organization
and the Technical University of Munich recently investigated
Physarum and the way it encodes memory of food sources
through rapid communication between its tube systems.
Spoiler alert—and apologies to the viral military dog reuniting
clips—Physarum is coming for your brand.
Physarum is a network-shaped organism that explores its
environment with a vast array of tubes, rapidly and constantly
reorganizing its body plan to pin down a food source, all while
maintaining the ability to find the shortest possible path between
nutrients. Yet, even though Physarum seems like just another slime
mold, Kramar chuckles at the memory of working with the organism.
“Physarum is extremely dynamic and very, very moody. It
really doesn’t like being under the microscope. It will run away,
actually physically run away. It’s hilarious,” Kramar said.
Kramar began working with Physarum years ago at the
beginning of her PhD, carrying out various exploratory
projects and recording observations about this capricious
creature. During one of these observatory studies, she noticed
that Physarum was running to the edge of the petri dish.
Not wanting the experiment to conclude with Physarum
committing scientific death through a heroic escape, Kramar
attempted to lure it back down with a food source.
It worked. After Physarum consumed the food source and
began moseying elsewhere, Kramar noticed that a circular
arrangement of big tubes had formed exactly where the
food source was. And this tube imprint didn’t fade, even
after Physarum continued its journey around the petri dish.
“Observing this I had two questions: how does this imprint
come around in the first place, and is it useful?” Kramar said.
The researchers began observing the changes in tube diameter
before and after the addition of a food stimulus, finding that
there was an internal redistribution of mass: tubes closer to the
food got much larger, whereas peripheral tubes became smaller.
BY MALIA KUO
ART BY ANASTHASIA SHILOV
And even long after the stimulus had been consumed, the larger
tubes remained enlarged. But how did this happen?
They found that the propagation of tube dilation across the
network was mediated through a cytoplasmic flow, which
carried a chemical agent that softened the tube walls. This
cytoplasmic flow is critical to Physarum, transmitting both
nutrients and information through chemical signaling.
After determining that the propagation was due to cytoplasmic
flow, the researchers asked the second main question: does the
observed imprint constitute memory?
Hypothesizing that the tubes could represent Physarum’s
memory, given that they remained as an imprint even after
the stimulus disappeared, the researchers analyzed three
large tubes in a sample of Physarum. One tube was directly
connected to a group of tubes arranged in fan shape to forage
towards the bottom of the microscopic window. When Kramar
placed a food stimulus towards the top of the sample, that
tube attached to the fan got increasingly small whereas the
two tubes closer to the stimulus increased in size. This was
critical evidence for the memory of Physarum. “The selection
of which big tubes are important shows something more than
just an imprint or a remnant of the stimulus,” Kramar said.
Ruminating on the impact of this discovery, Kramar
discussed the potential implications of Physarum on primitive
memory. “This reminded us of synaptic plasticity and synaptic
facilitation, creating long-term memories from short-term
memories. That’s very interesting because Physarum has some
kind of very primitive membrane potential going on that we
don’t know much about,” Kramar said.
Of course, the implications of Physarum’s memory don’t
end with this project. Kramar predicts potential impacts on
fields such as soft robotics. Although the concept is still in its
beginning stages, she proposes that Physarum’s self-navigation
based on attraction to chemical stimuli could be used to guide
technological advances in arterial surgeries. For example, robots
could be designed to crawl and adapt to the arterial environment,
following a chemical stimulus that the condition creates.
So yes, maybe we can all have a little bit of Physarum within
us someday. ■
Kramar, M., & Alim, K. (2021). Encoding memory in tube
diameter hierarchy of living flow network. Proceedings of
the National Academy of Sciences of the United States of
America, 118(10), e2007815118. https://doi.org/10.1073/
pnas.2007815118
26 Yale Scientific Magazine May 2021
www.yalescientific.org
Physics
FEATURE
BRIDGING THE QUANTUM GAP
A NONLOCAL QUANTUM GATE CLOSES THE GAP
TO DISTRIBUTED QUANTUM COMPUTERS
BY YU JUN SHEN
ART BY TAI MICHAELS
Quantum computers may one day solve difficult problems, but
currently they still face many hardware limitations. Quantum
physics—the science of the very small, such as electrons and
photons— allows for “qubits” that can represent “0” and “1” at the same
time, a concept known as superposition. This gives them exponentially
faster processing speeds than traditional computers, which use binary
electrical bits assigned a fixed value of either “0” or “1.”
However, today’s quantum processors can only work with a few
qubits, compared to the billions of transistor bits in traditional
computers. To increase the number of qubits involved, researchers
from the Max Planck Institute of Quantum Optics in Germany have
demonstrated a distributed quantum logic gate that can connect
multiple quantum processors. Severin Daiss, Gerhard Rempe, and
colleagues set up two qubits, located sixty meters apart in two labs,
to interact using an additional photon sent between them. Quantum
logic gates like this are the quantum version of classical logic gates,
performing specific operations to input qubits. Researchers hope
having a distributed setup—where the quantum logic gate is not
necessarily in one location only—provides a more flexible, modular
approach towards achieving larger quantum computing power.
Using the distributed gate, the German researchers produced pairs
of maximally entangled qubits known as Bell states. Entangled qubits
can be highly correlated even though they are physically apart. Such
“spooky action at a distance,” as Einstein remarked, actually provides
quantum computers with their potential power. If one element in a
pair of Bell state qubits is measured, the other qubit’s condition is also
fixed, no matter how
far away.
In an ordinary
computer, billions of
transistors work in
unison to perform
logical operations—
such as addition,
multiplication
and information
processing—on
electrical bits.
Quantum researchers
have adopted a
similar approach to
quantum computing
(among other
methods) to design
“quantum circuits.”
IMAGE COURTESY OF WIKIMEDIA COMMONS
IQM Quantum Computer in Finland. A large
part of quantum computers is the cooling
system, in order to minimize thermal noise.
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Quantum circuits
manipulate qubits,
which, in contrast to
electrical bits, are not
a fixed “0” or “1.” The circuits therefore require quantum logic
gates instead of the silicon chips found in ordinary computers.
As an example of a nonlocal operation, Daiss and Rempe performed
a quantum controlled-NOT (CNOT) gate in their experiments. The
CNOT gate uses the input of one qubit to determine whether or not
to invert the input of a second qubit. In many quantum circuits,
CNOT gates are used to achieve the superposition necessary for any
potential quantum advantage over classical computing.
Daiss and his colleagues placed two optical cavities containing a
rubidium atom in two separate rooms within a building at the Max
Planck Institute. In order to perform a quantum logic gate between
the two devices, the researchers first launched a photon towards the
first optical cavity along an optical fiber, then directed the reflection
to the second cavity (in the other room). The reflection caused an
interaction between the photon state and each atomic qubit state.
Following the photon measurement, with the addition of a Z-gate—a
type of quantum logic gate—on the first cavity controlled by a classical
communication channel, Daiss and his team completed a CNOT gate.
“Our experiment is the first that does such a gate between qubits
residing in completely independent laboratories,” Daiss said.
The team reported results of up to eighty-five percent accuracy
for the CNOT operation, at a computation rate of one kHz. While
this is low compared to current state-of-the-art quantum hardware,
the approach holds promise for a modular approach to scaling up
quantum computers. Qubits are much more fragile than electrical
bits; the slightest measurement by environmental disturbances
(dust, air, stray light) could break the trance. As qubits typically
reside in dilution fridges or vacuum chambers—which have limited
space—increasing qubit number requires denser packing. This
can cause problems like crosstalk noise and limited access to each
individual qubit, complicating manipulation and measurement.
Thus, in the future, instead of just increasing just the number of
qubits in a single processor, researchers may connect multiple
quantum devices using distributed quantum gates to improve
computational power. “Such a modular approach might open a new
development path for larger quantum computers,” Daiss said.
The researchers think that their protocol with the use of a
separate photon may be applied to other quantum operations
and gates between distant qubit modules. In a future quantum
computer, it is likely that many quantum gates—such as the
CNOT—will be involved, each with its own chance of failure.
Thus, the photon’s ultimate arrival would signal a successful
quantum operation, before subsequent operations proceed. ■
Daiss, S., Langenfeld, S., Welte, S., Distante, E., Thomas, P.,
Hartung, L., Morin, O., Rempe, G. (2021). A quantum-logic
gate between distant quantum-network modules. Science,
371(6529), 614-617. doi:10.1126/science.abe3150
May 2021 Yale Scientific Magazine 27
FEATURE
Artificial Intelligence
BEAUTY IS IN THE EYE OF THE BEHOLDER
BY LAUREN CHONG
ART BY CECILIA LEE
Left. Right. Left. Right. We’re
swiping on Tinder, a social
network dating app where
users swipe left on users they find
unattractive and right on users they
find attractive. During these splitsecond
glances at pictures, we know
instantly when we find someone goodlooking.
Generally, when we make these
judgements about others, we do not
28 Yale Scientific Magazine May 2021
think about the specific attributes that
make them attractive. Our individual
preferences for beauty all come down
to subtle subconscious preferences in
our minds shaped by sociocultural
influence, background, age, and gender.
How, then, do we define beauty?
Researchers at the University of
Helsinki designed an innovative method
at the intersection of computer science
and psychology to investigate the
human brain and its interpretation of
attractiveness. With novel generative
brain-computer interfaces (GBCI)
technology, psychologist Michiel Spape
and computer scientist Tuukka Ruotsalo
studied the computer’s potential to
identify facial features that participants
consistently found attractive, as
measured by spikes in brain signals. With
this data, the computer then generated
new images of faces that the participant
was likely to find attractive, thus
interpreting each individual’s personal
preference based on brain signals.
“The point is that most of computer
vision and AI is busy with the question
of detecting what is in a picture: who’s
the person, what kind of person is it,
and so on. Our work is focused on
how humans respond to the picture,
what feelings are evoked in them, and
what kind of subjective perceptions do
different individuals get from looking
at the picture. So, by feeding this
information back into the AI, we teach
the machine about what it is like being
human, while at the same time, we gain
a unique insight into what being human
even means,” Spape said.
In a session with thirty participants,
the researchers formulated a setup
similar to Tinder, in which the
participants were shown a series of
images derived from a generative
adversarial neural network (GAN) that
used a dataset to create zillions and
zillions of different images that looked
like they could be of celebrities. These
images were artificially engineered from
real celebrity images. Instead of having
participants swipe right as Tinder users
normally would when faced with an
attractive image, researchers simply
used brain activity measuring caps to
track brain activity, which was then
analyzed by electroencephalography
(EEG). The EEG was connected to the
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Artificial Intelligence
FEATURE
GAN: every time the participants’
brains demonstrated a positive
reaction towards a specific image, the
GAN generated more images that the
participant was likely to find attractive.
In the second half of the experiment,
the participants were invited back
for a double-blinded controlled
experiment and instructed to rate
their GAN-generated photos in terms
of attractiveness. The participants
found that around eighty percent of the
photos generated suited their personal
preferences, significantly far above
control conditions.
Interestingly enough, the participants
would not be explicitly rude about the
faces generated when asked about their
attractiveness, despite knowing they
were AI-generated images and not real
ones. Generally,
the negative
responses fell
into one of three
categories: blamed
their personal
preference for their
lack of attraction to
the face (clarifying
that they might not
find it attractive
but others might),
associated the
face with negative
personality traits
(for example, stating, “His smile… too
bossy”), or blamed the source material for
their lack of attraction. These interviews
were conducted after the big reveal,
ensuring its blind procedure.
Nevertheless, while the participants
downplayed their unattraction towards
certain images during the second half of
the experiment, they generally reacted
positively to the GBCI-generated images.
Overall trends showed a general preference
for blonde hair and youthful faces for
male participants. Female participants
often linked age with facial features. For
example, a lack of a beard was associated
with a youthful appearance and a lack of
hair was associated with age.
“The interview tells us that while
obviously they explain their attractiveness
decisions first as a pretty objective
process of checking against readily
identifiable [physical] features, like hair
color, age, and so on, they continue in
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more psychological explanations of their
preference—‘This person looks kind.’
This ascribing of humanity continues
all the way to the extent that they even
expressed resistance in saying anything
rude to an image,” Spape said.
The ability of the GAN to recognize
implicit preferences within the human
brain demonstrates the advances
of computer technology. AI can
potentially model individual human
behavior, including latent mental
functions, meaning those that do not
require conscious thinking. In this way,
computer technology can potentially
decode the inner workings of the human
brain, diving deep into our deepest
thoughts and perceptions.
Spape hopes to move the study beyond
its current application to reveal insights
We teach the machine about what
it is like being human, while at the
same time, we gain a unique insight
into what being human even means.
into other core human behaviors, such
as implicit biases or stereotypes. Since
the computer has shown the capability
to “decode” attractiveness, a mental
process people themselves do not fully
understand, its potential to analyze
implicit biases and stereotypes—other
mental processes we do not explicitly
think about—is huge.
From the computer science perspective,
Ruotsalo strongly believes that the ability
of the computer to recognize human
perspectives can be used to add a touch
of creativity to technology.
“It’s very exciting to see that computers
can actually capture something much
more complex than a command. We can
make them understand something that
is subjectively important for people, and
allowing this generative loop takes this
[technology] towards something that
could support creativity, rather than just
transmitting a command,” Ruotsalo said.
However, there are some limitations to
the study that may not exactly replicate
results in real life. Ruotsalo recognizes
the limitations of using a database of
celebrities for generating the images.
“I think it has both pros and cons. The
training data is made up of supposedly
generally attractive-looking people,
which makes it more challenging to
personalize. . . . it's not representing
the overall population,” Ruotsalo said.
Additionally, the celebrity dataset
does not account for a diverse array of
ethnicities due to its inherent limitations.
Since the study focuses on the
intersection
between human
thinking and
c o m p u t e r
science, Spape
also recognizes
the limitations
of applying
computer-based
thinking to reallife
applications.
“As a psychologist,
it would be great
if we could say
that [what] we are
finding is actually a perfect match for
a mental model. We know that to some
extent we are finding something certainly
related to a mental 'picture,' but that
might also be some sort of local optimum.
Another question is, of course, whether
we can get further than just attractiveness,
and study also other aspects of social
perception as well,” Spape said.
Nevertheless, with the potential
to decipher other aspects of human
preference, the GBCI technology reveals
more about the human psyche than ever.
In the future, the technology could lead
to the advent of other new innovations,
including artificial intelligence to find
implicit biases behind behavior and
psychology. ■
Spape, M., Davis, K. M., Kangassalo, L. K., Ravaja, N., Sovijärvi-Spape, Z., & Ruotsalo, T. (2021).
Brain-computer interface for generating personally attractive images. IEEE Transactions on
Affective Computing, 1-13. https://doi.org/10.1109/taffc.2021.3059043
May 2021 Yale Scientific Magazine 29
FEATURE
Medicine
GYNECOLOGY FOR GUYS:
MALE BIRTH CONTROL
HOW AN ANCIENT CHINESE HERB MAY BRING US
CLOSER TO CONTRACEPTIVE EQUITY
Oral birth control, commonly
referred to as “the pill,” is
prescribed to millions of women
in the United States as a convenient and
effective way to prevent pregnancy,
treat acne, regulate periods, and more.
While the pill in the 1950s marked
a triumph for women’s reproductive
rights, the history of birth control is
one deeply rooted in injustice. From
the propagation of eugenics ideology
to the mass sterilization of Puerto
Rican women during the Rio Piedras
clinical trials, the development of
oral contraception directly targeted
impoverished Black and Brown
communities in the United States.
Even today, the economic and
health-related burdens associated
with preventing pregnancy fall
predominantly on women. This has
long been due to the lack of birth
control options available to men. While
women have over ten birth control
options including barrier (condoms,
diaphragms, and sponges), hormonal
(pills, patches, shots, and rings), and
long acting, reversible contraceptive
methods (IUDs and implants), men only
have two: condoms and vasectomies.
After twenty years of studying sperm
formation, researchers at the Lundquist
Institute at Harbor-UCLA Medical Center
have recently discovered that triptonide,
a compound purified from the Chinese
herb Tripterygium wilfordii Hook F, can
demonstrate reversible contraceptive
abilities in men. With this finding, a
reversible non-hormonal male contraceptive
may be on the horizon, making equitable
reproductive health a possibility.
For over five decades, researchers
have tried to develop contraceptive pills
for men with no success. Previously, the
mainstream approach for developing
male contraceptives involved blocking
sperm production. The belief was that
if sperm counts were reduced to zero,
there would be no sperm available to
fertilize eggs and, therefore, pregnancy
would be prevented. The problem
with this approach, however, is that it
requires depletion of sperm precursor
cells, which is hard to achieve and tends
to cause significant side effects.
Wei Yan, principal investigator of
the study, explored a new, innovative
approach for developing male
contraceptives. Instead of depleting
all sperm cells, Yan sought to disable
sperm by causing deformation during
spermiogenesis, the maturation process
of spermatids (immature male germ
cells) into sperm. By disrupting the final
steps of sperm assembly, Yan theorized
that sperm would become incompetent,
or unable to fertilize eggs, due to their
malformation, while sperm count and
testis size would be largely preserved.
Towards this goal, the researchers
combed databases containing thousands
of drug candidates with documented
side effects in search of a compound with
sperm deforming effects. Tripterygium
wilfordii Hook F, sometimes called
thunder god vine, has long been used
in traditional Chinese medicine to
treat autoimmune and inflammatory
diseases like rheumatoid arthritis and
lupus. Ever since the first reported cases
of infertility in men after taking this
herbal medicine, researchers have spent
years isolating and purifying different
compounds of this herb in an effort
to identify which specific compound
caused deformed sperm. However, many
of these purified compounds caused
severe liver toxicity or had limited
reversibility of contraceptive ability. In
hopes of isolating a compound of the
herb that demonstrated reversibility
in male fertility without serious side
effects, the researchers persisted in
their testing and ultimately observed
that triptonide displayed the desired
contraceptive properties.
After administering triptonide at
different doses to adult male mice, the
researchers found that between three
and four weeks, daily oral consumption
of triptonide at a dose of 0.8mg/kg
body weight (BW) induced deformed
sperm with limited forward motility,
successfully causing infertility.
Repeating this experiment with
cynomolgus monkeys, the researchers
similarly observed that daily intake of
triptonide at 0.1mg/kg BW for five to
six weeks led to male infertility due
to disabled sperm. In both mice and
monkeys, the induced infertility was
found to be fully reversible, meaning
that fertility was regained between four
to six weeks after stopping consumption
of the contraceptive. This reversibility
in contraceptive effects is essential in
granting the consumer more flexibility
over his own fertility.
The testes of both mice and monkeys
maintained normal morphology without
any severe cell depletion, meaning
sperm counts remained relatively
normal during triptonide treatment. The
30 Yale Scientific Magazine May 2021 www.yalescientific.org
Medicine
FEATURE
BY ANGELICA LORENZO | ART BY NOORA SAID
difference between triptonide-treated
and control animals was that the former
displayed deformed sperm, particularly
a “head-bent-back” phenotype with
complete inability of forward motility.
To understand what this looks like,
picture sperm as a tadpole, containing
both a head and a tail. Spermatids, the
precursors to sperm, are round and
do not have a tail. In order to mature
into sperm, spermatids undergo an
elongation process in which the head
becomes compacted and the tail forms
through gradual elongation. This
coordinated process is controlled by the
gene SPEM1, which allows the tail and
head to grow proportionally.
Normally, SPEM1 interacts with a
protein called junction plakoglobin;
however, in the presence of triptonide,
this interaction is blocked due to
junction plakoglobin’s higher binding
affinity to triptonide. When SPEM1 and
junction plakoglobin are unable to bind,
the elongation process of spermatids
is disrupted. “The consequence [of
inhibiting the SPEM1 gene] is that you’re
going to have a head that is all bent back
and sometimes the tail actually starts
wrapping around the head,” Yan said.
Deformed sperm are unable to
fertilize eggs because of their inability
to swim vigorously to meet the egg
and because defective sperm tails are
not strong enough to penetrate the egg
during fertilization. With the inhibition
of SPEM1, spermiogenesis lacks a
checkpoint mechanism to eliminate
deformed spermatids. Importantly, this
missing “quality control” is advantageous
to birth control safety because normal
sperm counts are preserved.
Because two abundant compounds
of the Chinese herb—triptolide and
triptochloride—are known for causing
liver toxicity, many grant reviewers
rejected Yan’s applications because of the
herb’s notorious reputation.
“At a certain point, I wanted to give up
because [the project] just didn’t go anywhere
without funding,” Yan said. “I was lucky
enough to secure private funding.”
Now that triptonide has successfully
displayed reversible contraceptive effects
in both male mice and monkeys without
side effects, when can it be used by human
men? Before any clinical trials, the
Food and Drug Administration (FDA)
must approve the drug’s Investigational
New Drug (IND) status. Before that,
pharmacokinetics and toxicology
studies must be conducted to further
assess safety and metabolism of the drug
in the body. Ultimately, securing further
funding is the prerequisite to move this
project forward.
So why has it taken so long to
make progress in developing male
contraceptives? While funding poses a
challenge, Yan believes the underlying
reason is because of lack of success with
popular methodologies. As described
previously, the standard research
approach for inducing male infertility
has historically been sperm depletion.
Finding a chemical that can deplete all
sperm cells without causing adverse
effects has proven difficult.
“A popular joke in the field is that
male contraceptives have been five
years away for fifty years,” Yan said.
With the success of treating animals
with triptonide, Yan hopes that he can
find enough financial support to bring
triptonide drugs onto the market. Not
only will this achievement allow for
shared contraceptive responsibility
between men and women, but it will
also provide men with more autonomy
over their reproductive health. After all,
according to Yan, “to control your own
fertility is a basic human right.” ■
Chang, Z., Qin, W., Zheng, H., Schegg, K., Han, L., Liu, X., ... & Yan, W. (2021). Triptonide is a
reversible non-hormonal male contraceptive agent in mice and non-human primates.
Nature communications, 12(1), 1-14.
www.yalescientific.org
May 2021 Yale Scientific Magazine 31
FEATURE
Ecology
MIGRATORY STRATEGIES
PAST, PRESENT, AND FUTURE BY MADISON HOUCK
ART BY ANMEI LITTLE
In the coldest depths of winter, many of us spend our
hours wishing we could move somewhere warmer.
Luckily for them, many species of birds have perfected
this process. Birds' seemingly intrinsic ability to navigate has
always left us with more questions than answers, especially
now as climate change threatens the migration routes and
survival of many avian species. To investigate the formation
of migratory patterns across thousands of years, and to
demystify the relationship between climate and migration,
a research team from the Chinese Academy of Sciences
collected migratory data to model the effects of rising global
temperatures on migratory strategies in years to come.
The peregrine falcons studied here typically live and
breed in the Arctic, but every September they embark
on a month-long journey to find solace (and warmth)
during the winter. These “wintering locations”
are mostly located in tropical or temperate areas.
In order to study current migration patterns of these
falcons, the team strapped satellite trackers to the backs
of forty-one peregrine falcons and sent them on their way,
monitoring their locations for an entire year. Birds that
were tracked for more than this one-year period
returned to the same migratory route year
after year, settling in the same
32 Yale Scientific Magazine May 2021
location each October.
Additionally, it was
determined that birds from the
same population migrated using
s i m i l a r pathways, but not all peregrine
falcons wound up in the same wintering
areas. This is referred to as “individual
migration”—different populations of
peregrine falcons have their own unique
migration strategies that depend on a variety
of factors. Such behavior offers valuable insight
into the influence of seemingly tiny changes in
climate on overall migration behavior.
Scott Yanco, an incoming postdoctoral researcher
at the Max Planck Yale Center for Biodiversity,
Movement, and Global Change, praised the methods that
the research team used, citing that the transmitters had a
spatial error of only a few meters. “We really know where that
bird was,” he said, laughing. “We’re in a golden age for that.”
“One of the big holy grails, at least in my opinion for
migration, is: why does it happen? There's all these different
adaptations that organisms show to seasonality, and migration
is just one of them,” Yanco said.
Towards this question, the team also studied the intrinsic,
genetic component of migration. After studying a wide variety
of falcon populations with observably different migration
patterns (long versus short migratory paths), it was suggested
www.yalescientific.org
Ecology
FEATURE
that the ADCY8 gene had a large effect in
directing migration of peregrine falcons.
An epigenetic modification actually
results in over-expression of the ADCY8
gene in falcons that must travel long
distances, leading the research team to
believe that the gene is directly related
to long-term memory. This indicates
that migration is a combination of
intrinsic ability to remember pathways
and learned behavior from other falcons
or previous experience. This is also
supported by the fact that the level of
expression of the ADCY8 gene correlates
with the length of the migratory journey.
Yanco thinks this kind of research
touches on a question that has been everpresent
in the field of migration. “What
they've been able to do here,” he said,
“that is relatively new and I think very
few authors are working on, is the sort of
ultimate drivers. Why do it? How does it
happen? How does something like this
emerge in the first place in deep
evolutionary time? How is it
maintained?” These questions
will propel the field forward to
looking at the underlying why in
migratory patterns.
The research team then set
out to determine the history
of migration and how it was
impacted by large scale climate
changes in history, such as the melting
of the ice caps. By modelling historical
migration paths, they were able to
determine that as the ice caps melted,
northern falcon populations decreased
due to disruptions to their breeding
grounds. Breeding grounds shifted north
in order to maintain a similar temperature
environment for the falcons, lengthening
the falcons’ migratory path. As discussed
above, the length that a falcon can
travel is at least partially genetically
determined, meaning that only birds that
were genetically predisposed to remember
and travel long distances were likely to
survive long journeys. This particularly
brutal bout of natural selection resulted
in a dramatic decrease in the population
of peregrine falcons.
In addition to impacting the duration
of the migratory journey, changing
temperatures and melting glaciers also
impacted the directional orientation
of migration routes. During the last
Ice Age, or the Last Glacial Maximum,
there were many more accessible
wintering locations to the west, whereas
now, there are a relatively equal number
of western and eastern locations.
Both of these changes demonstrate
that global climate can have a marked
impact on migratory routes and relative
survival of the peregrine falcon species,
and likely other species of Arctic birds as
well. The findings offer a grave perspective
on the impact of current rising global
temperatures on Arctic avian populations.
Having studied how climate change has
impacted migration in the past, as well
as migratory routes in the present, the
research team then directed their attention
towards the future. To study how presentday
climate change would impact future
survival of the peregrine falcon species,
“Some groups of peregrine falcons
”
could lose between ninety and one
hundred percent of all suitable
breeding grounds.
they used ecological niche modelling
simulations to predict how rising global
temperatures would affect potential
breeding grounds and wintering areas.
The results were striking. Some
groups of peregrine falcons could lose
between ninety and one hundred percent
of all suitable breeding grounds, a
development that would be devastating
to those populations. As a result,
populations with short migratory routes
would see a decrease in migration
distance, eventually reaching the point
where they wouldn’t migrate at all,
while populations with long migratory
journeys would see further increases in
distance. Longer migration routes are
more closely correlated with mortality,
so lengthening an already long and
harrowing journey could devastate the
population size substantially.
IMAGE COURTESY OF WBUR
Melting ice caps in the Arctic reflect rising
temperatures and changes to Arctic climates that
threaten the breeding grounds and migration
routes of peregrine falcons.
According to data from the team, these
shifts have already begun. Retroactive
analysis of peregrine populations
found that population numbers have
been declining for the past twenty-five
generations: the future doesn't look
bright for peregrines.
What does this mean for the rest of us?
While some might hesitate to
understand how a peregrine falcon
can represent the world, this work
has done nothing if not convey how
interconnected our planet is. The
same climate changes that impact
these falcons will undoubtedly
have similarly intricate impacts
on our ways of life, especially if
no steps are taken to slow rising
temperatures in the coming years.
The Chinese team’s study is unique in
that it focused heavily on one species,
using a wide variety of tools and research
methods to create a complete and almost
definitive picture of the migration
patterns of peregrine falcons.
“One of the cool things in this study
was that they integrated approaches
that are often quite siloed. And I think
that this makes a compelling case
for putting together teams that can
do that stuff—that you're looking at
things behaviorally, environmentally,
ecologically, and [with] molecular tools,”
Yanco said. “I mean, I think there’s a
broad trend in science, that it’s becoming
more interdisciplinary and [with] larger
teams. As we reach the limits of what we
can infer with any given tool, it becomes
important to start expanding out.” ■
Gu, Z., Pan, S., Lin, Z., Hu, L., Dai, X., Chang, J., ... & Zhan, X. (2021). Climate-driven flyway changes and memory-based long-distance
migration. Nature, 591(7849), 259-264.
www.yalescientific.org
May 2021 Yale Scientific Magazine 33
PHYLLIS MUGADZA
(BS/MPH ’22)
BY EAMON GOUCHER ART BY ELLIE GABRIEL
UNDERGRADUATE PROFILE
In a normal year, you can find Phyllis Mugadza (’22 BS/
MPH) hanging out in the Silliman courtyard, giving tours
of Yale’s campus, or working as a recruitment coordinator
in the admissions office. In between classes and work,
Mugadza, a mechanical engineering major, spends her free
time innovating the world around her.
This past winter, Mugadza was selected as one of the winners of the
2020 Reimagine Challenge, a scholarship competition that aims to
identify innovative solutions that will help spark global movements
and build back from COVID-19. For her proposal, Mugadza
focused on the growing waste mismanagement crisis in several
developing nations. Despite the serious public health problems
they pose, waste sites have become unique spaces of creation in
which grassroots innovators repurpose discarded materials into art
and commodities. Mugadza, inspired by the creative superpower
of these creators, proposed a novel method of addressing the waste
mismanagement crisis: opening makerspaces to support grassroots
creators, bolster local economies, and repurpose waste.
Mugadza’s passion for innovation first blossomed out of a desire
to help her home community in Harare, Zimbabwe. “The biggest
challenge I found was that a lot of women around me were missing
school—my friends would miss work when they were on their
period because of dysmenorrhea, or menstrual pains,” she said. The
inaccessibility of medicine, sanitary products, hygienic facilities,
and education on menstruation created ubiquitous barriers to
everyday life. “When I committed to Yale, I wanted to commit my
entire engineering journey to finding a solution for this problem,”
she said. Over the past four years, Mugadza has collaborated
with OB-GYNs at the medical school, conducted surveys with
menstruators of all identities, and iteratively designed a device that
can effectively collect menstrual blood and treat dysmenorrhea.
Listening to Mugadza feels liberating; her passion is palpable.
Over the course of our conversation, I realized that Mugadza’s
unique perspective comes from a belief in the potentiality of objects
and people to build a happier, safer, and more equitable world. For
her Reimagine Challenge proposal, Mugadza emphasized breaking
out of a functional fixedness mindset—using everyday materials
in new and exciting ways. Mugadza is inspired by the work of
architects Kevin Kimwelle and Ashis Paul, who have built plastic
bottles in their designs as storage hooks and as naturally cooling
air filters. Mugadza wanted to center this kind of ingenuity in her
project proposal. She believes that in order to solve this problem,
we must empower local creators: “They possess a gift and a talent
that the world needs right now,” Mugadza said.
As she described the process of designing a menstrual device, I
started to understand Mugadza’s experience in reimagining a better
world. “I would say that a lot of my inspiration and motivation come
from studying engineering at a university that is rooted in the liberal
arts,” she said. Especially at first, Mugadza leaned heavily on Tsai
City and her mentors for both guidance and support. She points to
Alyssa Siefert, Christina Mainero, and Anjelica Gonzalez as some
of the people who have helped her get to this place. “Mentorship
has been extremely important, especially being a woman of color
in engineering at Yale and all that comes with that,” she said. “My
mentors have really uplifted me, connected me to resources, have
pushed me to take up space, and always push me constantly to
achieve.” Still, Mugadza is very transparent about her experiences
being a woman of color in engineering and entrepreneurship: “I’ve
had to put in a lot of extra work to make my voice heard in a lot
of spaces. I felt like I was constantly being sheltered and limited by
what I could achieve,” she said. In times like these, Mugadza turns
to her mentors—particularly her female mentors of color—to help
her get back to doing what she loves: building a better world.
Mugadza will graduate from Yale College in May, before
moving to the School of Public Health full-time to complete
her MPH. She hopes to launch her menstrual device startup
Sprxng by the end of the year and plans to resume work on
her makerspace project within five years. I
walked away from our conversation
feeling inspired and excited
about the future. We
often tend to
feel like very
small cogs
in a very big
machine—
everything
we do is a
drop in the
bucket. But
Mugadza has
demonstrated
the power that
each person
has in creating
a happier, safer,
and more equitable
world. ■
34 Yale Scientific Magazine May 2021 www.yalescientific.org
DR. C. BRANDON OGBUNU
(PHD ’10)
BY ANNA CALAME ART BY ELLIE GABRIEL
ALUMNI PROFILE
Ten minutes into my conversation with Dr. C. Brandon
Ogbunu (PhD ’10), I knew that no 750-word profile could
fully do him justice. Throughout his life, Ogbunu has
consistently pushed boundaries and rejected dichotomy, making
for an impressive career that resists abridgement. Ogbunu is
a scientist, yes, but he is also a prolific writer, storyteller, and
educator. His nontraditional, interdisciplinary path has led him
to the Ecology & Evolutionary Biology Department at Yale,
where he is an assistant professor and the principal investigator
for the Ogbunu Lab for Genetics, Ecology, Evolution, and
Quantitative Science (GEEQs) research.
Despite being a self-described “late bloomer” academically,
Ogbunu emphasizes that he has always harbored a deep love
of learning. He credits his mother, a teacher, with imparting to
him this proclivity for scholarship, which blossomed during his
undergraduate years at Howard University. There, Ogbunu studied
chemistry, explored the intersections between various scientific
disciplines, and developed an interest in disease. After graduating
from Howard in 2002, Ogbunu studied malaria in Kenya on a
Fulbright scholarship, an experience that confirmed his preference
for research over clinical practice. “It was when I got to Kenya that
I said, if I can be doing this kind of work as a grown-up, this is
the career that I want: the producing and engaging of scholarship,”
Ogbunu said. “Science is a type of scholarship; it’s a manner through
which a person creates knowledge and offers it to the world.”
Upon returning to the US, Ogbunu
followed his curiosity to Yale,
where he worked in Paul Turner’s
virology lab. He completed
his PhD in microbiology
in 2010 and, subsequently,
a postdoctoral fellowship
at Harvard. Ogbunu spent
two years working at Brown
University before returning
to Yale in the fall of 2020, this
time as a faculty member.
Ogbunu, a computational
biologist trained in chemistry,
mathematics, genetics, evolution,
and microbiology, approaches research
in a way that reflects the diversity
of his interests and abilities. His
GEEQs lab conducts “remix
science,” drawing on concepts from various scientific fields to gain
insight into disease. Ogbunu considers research questions on two
levels: the molecular scale, comprising technical knowledge of
genetics and biology, and the population scale, involving modeling
and data analysis. Together, they have brought him great success and
an enduring love for his work. “[The multidisciplinary approach] is
just more fun—I can talk to more people, I can engage more people,”
Ogbunu said. “On one end, these two lenses allow me to comment
on and think about very practical things. On the other, they let me
ask broad questions about society or evolution or ecology.”
Ogbunu is a staunch believer in the importance of collaboration.
Throughout our discussion, Ogbunu was quick to credit the
positive influences that others, particularly his mother, his college
friends, and Turner, have had on his life and career. When asked
how his passion for community informs his approach to teaching,
Ogbunu described the ability to craft an engaging and supportive
lab environment as an “incredibly exciting” aspect of being a
principal investigator. “I do a self-care symposium in my lab,
where every year you have to present on the ways you’re going to
take care of yourself, and answer questions,” Ogbunu said. “I can
work my value system into the ways my lab interacts.”
Consistent with his lifelong love of learning and creating
scholarship, Ogbunu is also an impressive communicator,
having written numerous blog posts, contributed to WIRED,
and appeared on podcasts. “I’ve always been connected to
writing—I’ve read comics all my life. Writing and art and being
creative have always been a part of my identity,” he said. Rather
than seeing his creative pursuits as separate from his dedication
to science, Ogbunu considers his writing, his scientific process,
and his teaching to be complementary. Through his writing,
Ogbunu skillfully explores questions at the intersection of
science and society: the limitations of analogizing infectious
disease and white nationalism, the potential of network science
to make sense of our increasingly interconnected world, and
the insidiousness of scientific racism and the legacy of James
Watson. Moreover, he presents his thoughts on these complex
and technical topics in ways accessible to the average reader.
Ogbunu’s success serves as a reassuring reminder to my
fellow students, anxious over seemingly binary decisions
between disciplines and unsure of how to appropriately
navigate the professional world. Prioritizing a dedication to
one’s values—in Ogbunu’s case: community, scholarship, and
creativity—over an adherence to previously-trodden paths is
not only possible, but highly rewarding. ■
www.yalescientific.org
May 2021 Yale Scientific Magazine 35
VIVEK MURTHY’S TOGETHER: THE HEALING POWER OF
HUMAN CONNECTION IN A SOMETIMES LONELY WORLD
BY HANNAH HUANG
Whether it be walking into a room of strangers or standing alone at recess,
everyone has felt lonely at some point. Vivek Murthy (SOM ’03), the
nineteenth and twenty-first Surgeon General of the US, built his platform
on combating loneliness after realizing how insidious its long-term effects are. In his
book Together: The Healing Power of Human Connection in a Sometimes Lonely World,
Murthy explains that because loneliness is the root cause of many societal problems,
combating loneliness ultimately bolsters our collective health.
Murthy’s childhood role models were his parents. Physicians themselves, they built
relationships with their patients by taking time to listen to their needs. When Murthy
began his first stint as Surgeon General, he took his parents’ example to heart and
embarked on a listening tour across America to identify the most pressing health
issues Americans were facing. Between those listed—addiction, violence, anxiety, and
depression—there was a common connector. “To be at home is to share a sense of
common ground, common interests, pursuits, and values with others who truly care
about you. In community after community, I met lonely people who felt homeless
even though they had a roof over their heads,” Murthy said.
The link between loneliness and physical health, though surprising when first
discovered, is nonetheless an established one. Psychologist Julianne Holt-Lunstad
found that loneliness is a stronger risk factor for reduced life span than obesity,
alcoholism, and lack of exercise. In fact, lack of social connection is as detrimental
to one’s health as smoking fifteen cigarettes a day. “If neglected, loneliness can
have long-term health implications, yet it is not a state that can be fixed with a pill
or a procedure. It is a human condition that reminds us of our need for the love,
compassion, and companionship of fellow human beings,” Murthy said.
Given the current state of social distancing and mandated isolation, it’s likely
that loneliness is more prevalent than ever. However, Murthy insists that physical
solitude doesn’t necessarily translate to loneliness. “Loneliness is the subjective
feeling that you’re lacking the social connections you need. Solitude, by contrast,
is a state of peaceful aloneness or voluntary isolation. It is an opportunity for selfreflection
and a chance to connect with ourselves without distraction,” Murthy said.
Murthy believes that even in the current pandemic, we can find ways to
combat loneliness while finding peace in solitude. He lays out four strategies: 1)
spending time each day with those you love, even if it’s fifteen minutes on a video
call; 2) giving other people your full, undivided attention when conversing; 3)
performing acts of service to be reminded of how we can support each other; and
4) embracing solitude through nature, meditation, and art.
“Developing comfort with solitude is an essential part of strengthening our
connection to ourselves, and by extension, enabling our connection with others.
Solitude, paradoxically, protects against loneliness,” Murthy said. Even in the despair
of this past year, there may be a hidden blessing if one ascribes to Murthy’s teachings. ■
IMAGE COURTESY OF THE ACCREDITATION COUNCIL FOR
GRADUATE MEDICAL EDUCATION
Dr. Vivek Murthy participates in a fireside chat at the 2019 Annual
Educational Conference.
SCIENCE IN TH
36 Yale Scientific Magazine May 2021
www.yalescientific.org
THE NOCTURNISTS
BY ANN-MARIE ABUNYEWA
IMAGE COURTESY OF
CANVA
Medical professionals “pull back the curtain on medicine,” as host Emily
Silverman describes her show.
Just as Charon ferried souls post-death across the River Styx to receive their
fate, death too propelled Jenny Tiskus into her journey with medicine.
In “The River Styx,” an appropriately named episode of the podcast The
Nocturnists, Tiskus explores gallows humor and how physicians process death.
She reflects on the deaths of her father and grandmother and her initial hesitance
to go into medicine. Her wandering back between a life with and without
medicine feels reminiscent of the wandering souls of the Greek Underworld
river, who anticipate the moment when their afterlife fates become clear.
The Nocturnists is a podcast in which healthcare workers share their experiences
in the field. Integral to each episode is the art of storytelling. The anecdotes that
each guest shares are raw: listeners feel as though they have a special insight into
healthcare without having to enter the hospital or clinic themselves. They learn
about healthcare professionals’ joys and vulnerabilities while working in the field.
March 2020 marked the beginning of The Nocturnists’ “Stories from a
Pandemic” series. This season is particularly moving; though our one-year
anniversary since the beginning of the COVID-19 pandemic has passed, all the
initial emotions and reactions are still incredibly tangible. The hope, exhaustion,
and cynicism that listeners have in common with storytellers grounds the
healthcare workers as people like us, rather than sacrificial heroes the media
glorifies. “It’s not bad yet. It's a whole lot of unknown,” recounts a trauma nurse
as she marvels at her colleagues’ smiles despite their surging anxious emotions.
“[The hospital] sent me home early today because I'm getting too much
overtime. Apparently being willing to make sure that our patients get their stuff
is too expensive,” reports a Durable Medical Equipment truck driver.
This season, the producers have expanded the podcast to make it a nationwide,
collaborative effort. They created an interactive map where each destination
features a story from a healthcare worker into which listeners can tune. Usually,
the podcast uses music by composer Yosef Munro to open and close episodes.
However, the only music featured this season is that provided by the diarists. At
the end of “Stories from a Pandemic: New World,” an internal medicine resident
details that she picked up music again because it gives her the comfort that
uncertainty has often taken away; she closes out the episode playing Dvorak’s New
World Symphony on her violin. By incorporating these collaborative components,
the producers have elevated this season’s storytelling power, authenticity, and
connectedness—an important mission now that we have been so apart.
Looking back on her journey into medicine, Tiskus worries about the “emotional
desiccation” that could ensue as her profession exposes her to more death. To combat
this, she says it’s important to discuss how to stay in touch with her humanity when
gallows humor seems to strip it away. Storytelling through The Nocturnists is how she
can more fully emphasize the gravity of the deaths that shaped her path to medicine. ■
E SPOTLIGHT
www.yalescientific.org
May 2021 Yale Scientific Magazine 37
COUNTERPOINT
NOT-SO-IDENTICAL
TWINS
BY EVA SYTH
The classic scientific debate on “nature vs. nurture” asks:
to what extent do genetics shape our characteristics,
and to what extent do our environments shape our
characteristics? In pursuit of the answer, scientists historically
studied identical twins, or monozygotic twins, who were widely
believed to share the same DNA. To isolate differences associated
with nature as opposed to nurture, these studies assumed that
any differences in identical twins must have been due to the
environment, as their genetic material would be the same.
However, new research from Hakon Jonsson and Erna
Magnusdottir, as well as collaborators at deCODE genetics, the
University of Iceland, and Reykjavik University, suggests otherwise.
The team recently found that identical twins on average differ by
5.2 mutations from early in the life cycle. The study, which involved
the genetic sequencing of almost fifty thousand people, further
showed that, in fifteen percent of identical twins, one of the twins
has a substantial number of mutations that the other does not have.
Beyond quantifying the average mutation differences
between monozygotic twins, this study also looked into when
the mutations occurred during development. Jonsson and the
research team cleverly used information on early development,
coupled with genetic sequencing of identical twins along
with their parents, spouses, and children, to draw inferences
surrounding the timing of mutations during development.
So, how exactly can researchers use the genetic sequences
of these close contacts to decipher when mutations occurred?
The answer relies on the very beginnings of the human life
cycle. When an egg cell is fertilized, it becomes a single-celled
zygote, composed of genetic material from both parents. Over
time, the zygote divides and embeds itself into the uterine
lining to form the blastocyst. After several weeks, some of the
cells are designated to be germ cells, or sex cells. Sex cells are
involved in passing genetic material on to offspring.
Twinning occurs when the single mass of developing cells
splits into two identical masses, which eventually become the
two twins. This process generally occurs early in development,
much before the designation of germ cells.
The researchers used the development process coupled with
genetic information from relatives of identical twins to determine
at what point mutations occurred in development. For example,
IMAGE COURTESY OF PIXABAY
the researchers identified mutations in an identical twin and
their offspring, but not in the twin’s spouse or twin counterpart.
Of these mutations, the researchers then found that some were
also present in somatic body cells of the twin. From the life cycle,
the researchers could extrapolate that the mutation occurred
after twinning, because the twin’s monozygotic counterpart
didn’t have the mutation. Additionally, because the mutation
was present in both somatic cells and germ cells, investigators
inferred that the mutation likely occurred before the germ line
cells were designated. If this wasn’t the case, the mutation would
have been found in either somatic cells or germ cells, not both.
The researchers used similar logic to identify at what point in
development a variety of mutations likely occurred.
In addition to identical twins, the researchers also investigated
a family with identical triplets in order to learn more about
genetic variation. Specifically, this case study proved crucial
in exploring cell allocation. Cell allocation is concerned with
the designation of different cell types. For example, twinning
may occur when a group of cells is designated and begins
developing independently of existing cells. In the case of the
triplets, researchers found that two of the triplets shared more
mutations with each other than the third. The study pointed to
cell lineage as a potential explanation: two of the triplets were
likely “descended” from the same cell whereas the third triplet
came from another set of cells that was allocated separately.
So where does this leave identical twin studies, which assume
that these mutations are insignificant compared to environmental
factors? Jonsson and the research team caution that the effects of
these mutations have likely been underestimated when it comes
to the development of certain diseases. However, even if nature
vs. nurture identical twin studies are eventually retired from the
field, studies involving twins still have their place: further work
can be done with identical twin genetics to better understand
early stages of human development. ■
Jonsson, H., Magnusdottir, E., Eggertsson, H.P. et al. (2021). Differences
between germline genomes of monozygotic twins. Nat Genet, 53,
27–34. https://doi.org/10.1038/s41588-020-00755-1
38 Yale Scientific Magazine May 2021 www.yalescientific.org
IMAGE COURTESY OF CARL ZIMMER
INTO THE
NEWSROOM
A CONVERSATION WITH
CARL ZIMMER
By Sophia Li
Carl Zimmer’s award-winning science journalism regularly
features in the New York Times. A Yale alum (’87) and
professor adjunct, Zimmer has also authored fourteen
books. His most recent, Life’s Edge: The Search For What It Means
To Be Alive, was published in March of this year.
This is an abridged version of YSM’s recent conversation with
Zimmer. For a full version, visit https://www.yalescientific.org/.
How did you get into covering for the New York Times?
I really loved to write and graduated from Yale as an English major. I
worked at Discover for ten years before deciding I just wanted to work
on my own projects and started writing for National Geographic and
Wired. In 2004, I pitched the idea of a science column to the NYT. The
editor who read my pitch was happy to talk about ideas and we started
off with a story on why leaves change color in the fall. And after that, I
started contributing stories to them until it became a weekly column.
How do you make scientific information understandable to a
broader audience?
When I start working on a story, I will get familiar with the research
that was important to make the new discoveries possible. Then I
just have long conversations. I’ll talk to scientists about their work.
I might talk to outside scientists to get an expert opinion. If it’s the
kind of research that affects people’s lives, I will talk to those people.
When writing, I always remind myself that I have spent several
days or weeks immersed in this subject, whereas my readers are
coming to it completely fresh. You have to tell a story that’s clear
and compelling enough that people who aren’t experts will want
to read and understand it.
You recently published your book, Life’s Edge. Where did the
idea for it come from?
A lot of people, even when they’re kids, wonder, “Well, what is
life exactly, and what does it mean that we’re alive?” If you ask your
parents you might not get a satisfying answer, and it turns out if
you ask scientists you might also not be satisfied, because everyone
seems to have a different definition of it. I talked with researchers
www.yalescientific.org
and philosophers, spending time to look at particularly weird and
amazing forms of life, whether it’s hibernating bats or slime mold
or just a maple tree. I start the book in the familiar heartland of
life, thinking about things no one would really argue are alive (like
ourselves) and then move out to the borderlands where it suddenly
gets much harder to decide whether things are alive or not.
You write, “All life gives way to half-life and then to no life at
all.” Through your investigation, do you have a different way of
characterizing life?
Something like a virus shows you how shaky the whole edifice of the
definition of life is. Definitions, as we think of them, are kind of arbitrary
hallmarks. You don’t really get at something fundamental about nature.
We can have some sort of rough and ready definition, but in Life’s Edge, I
compare it to asking an alchemist in the 1500s to define water.
They would probably say: It’s wet, it’s transparent, it’s liquid,
and if I make it cold it gets hard. But then you say: Then, the stuff
it becomes, is that water too? Then they would say: No, that’s ice,
because water as I just told you is liquid.
So, it’s kind of a meaningless exercise to ask an alchemist to
define water. What you really want is a theory of chemistry. You
can say: According to your theory you call that stuff water. What’s in
it are these molecules, and I can tell you what molecules are, and I
can tell you how this particular substance has molecules that contain
oxygen and hydrogen. It’s still water when it freezes because the
molecules just arrange in different shapes. So suddenly I’ve told you
something deep and profound about water because I have a theory
of it. However, we don’t have a theory of life that everyone agrees
on yet.
Do you have advice for Yalies who want to engage with scientific
writing?
It takes a lot of practice, so nobody should expect to do a
spectacular job their first time out. It’s a big challenge to learn
about complicated things and write about them in an exciting and
comprehensible way that’s as close to the truth as you can make it.
Try to write it the way you actually talk. Tell us a good story about
science and we’ll want to read it! ■
May 2021 Yale Scientific Magazine 39
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learn more at
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YSEA’s 2021 Awardees for
Outstanding Academic Achievement
YSEA’s 2021 Awardees for Outstanding Academic Achievement
Your achievements inspire all of us in the Yale STEM community.
Your achievements inspire all of us in the Yale STEM community
YSEA Award for Meritorious Class of 2021 Service to Yale University:
Amer Al-Hiyasat
Claire Lamarre
Joseph Cerro, Yale MB&B ’89, Technologist & Life Sciences Consultant and
Molecular Biophysics and Biochemistry / Physics Engineering Sciences (Chemical)
Elie Track, Yale PhD Physics '88, CEO of nVizix LLC
Joe and Elie are receiving Justin Cheong this year's award for their decades of commitment Sally Ma to the Yale-alumni STEM
connection. By managing Molecular, the Cellular, organization and Developmental and solidifying Biology our partnership Computer with Science Yale administration, they
have jointly established and maintained the pre-eminence of our centenarian institution.
Athena Flint
Anna Sun
Joesph Cerro
Elie Track
Chemistry (Int.)
Molecular, Cellular, and
Developmental Biology (Int.)
Class of 2022
YSEA Award for Advancement of Basic
YSEA Award for Distinguished Service to
Franklin Bertellotti and Applied Science: Matt King
Industry, Commerce or Education: Ecology and Evolutionary Biology Gary Chanan, Yale Mathematics Physics (Int.) / Mathematics and Physics (Int.) '70,
Eileen Pollack, Yale Physics '78, Jocelyn Chau
Professor Emeritus Steven of Physics Ma & Astronomy,
Professor, Writer
Molecular Biophysics and Biochemistry
University of California, Mathematics Irvine
Eileen is receiving this award for raising our Avi Cohen
Gary is a pioneer and Joy innovator Ma in telescope optics who
nation's consciousness about the continued Molecular, Cellular, and Developmental Biology
is receiving this year's Psychology award for / Ecology his fundamental and Evolutionary and Biology
under-representation of women and minorities Alexandra Galls
transformative contributions to the design and operation
Eileen Pollack
in science, and for tirelessly advocating Chemistry
Fiona O’Brien
Gary Chanan of segmented mirror telescopes, particularly the Keck
solutions across spheres of society.
Environmental Engineering
Rohit Giridharan
telescopes in Hawaii.
Electrical Engineering / Computer Science
Faiaz Rahman
Thank you for continuing Yale's rich tradition in STEM.
Eamon Awards Goucher shall be presented at the YSEA Annual Computer Dinner, Science Friday, April 17th 2020
For more information visit: ysea.org
Molecular Biophysics and Biochemistry
Graham Hardcastle
Computer Science / Economics
Alden Tan Ming Yang
Computer Science and Economics