YSM Issue 91.1

Yale Scientific
Established in 1894
THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION
MARCH 2018 VOL. 91 NO. 1 | $6.99
SNEAKING
ORGANS
PAST THE
IMMUNE SYSTEM
15
DELIVERING
18
A TALE OF ICE
20
BRAVING
THE INHIBITOR AND SNOW
THE COLD

Yale Scientific Magazine
VOL. 90 ISSUE NO. 5
CONTENTS
MARCH 2018
NEWS 6
FEATURES 25
ON THE COVER
12 SNEAKING
ORGANS PAST THE
IMMUNE SYSTEM
Current research done by Mark Saltzman
and Jordan Pober combines
techniques from multiple fields—
nanoparticle delivery and transplant
techniques—to improve long-term
results after transplant surgery.
15
DELIVERING THE
INHIBITOR
Cancer, diabetes, and many other
diseases involve dysregulation of
the same signaling pathway critical
for regulating protein function.
Researchers have developed a
drug delivery system facilitating the
inhibition of proteins implicated in
the disruption of this pathway.
18
A TALE OF ICE AND
SNOW
Why do clouds behave the way they
do, sometimes producing snow and
ice and rain? Yale professor Amir Haji-Akbari
investigates these processes
using computational techniques.
20
BRAVING THE
COLD
Yale researchers identify a genetic
adaptation in certain species of
rodents that reduces their sensitivity
to the cold, allowing them to hibernate
in temperatures just above
freezing.
22 DIVERGENCE
What makes the human brain so
unique? Although it is around three
times larger than the brains of our
closest living relatives, the complexity
in the connections between cells and
the differences between cells themselves
hint at a deeper explanation.
www.yalescientific.org
More articles available online at www.yalescientific.org
March 2018
Yale Scientific Magazine
3

Q&A
HOW COLD CAN WATER GET?
By Alice Tao
Way colder than you’d think! In fact, water
doesn’t always freeze when the temperature
reaches zero degrees Celsius, the
value regularly cited as the freezing point
of water. Under certain conditions, water
can undergo “supercooling” and exist in
a liquid state far below its usual freezing
point—at temperatures as low as -42.6 degrees
Celsius.
Previously, researchers encountered difficulties
determining the lowest possible
temperature of liquid water due to the rapid
rate of ice crystal formation. In Germany,
Robert Grisenti at the GSI Helmholtz Centre
for Heavy Ion Research is developing
new techniques for accurate measurement
of the temperature of supercooled water
with greater precision than ever before.
Grisenti’s team began by spraying microscopic
droplets of water into a vacuum. The
exceptionally low pressure in the vacuum
DO PENGUINS SNACK?
By Hannah Verma
Male emperor penguins have long
been thought to make the ultimate sacrifice:
fasting for almost three months
as they guard their eggs. As it turns out,
however, the penguins are not quite as
selfless as they’ve previously been portrayed.
Researchers from the Scripps
Institution of Oceanography discovered
that male emperor penguins sometimes
break their fast during the incubation
period.
Typically, females leave the egg with
the males for approximately for three or
four months; the male’s feet keep the egg
warm by cradling it with a fleshy layer
of skin. Scientists have long thought
that the male penguins stay by the
egg’s side at all times during this period.
They often spend these bone-chilling
Arctic months sleeping to preserve
their energy, but they still lose up to
IMAGE COURTESY OF PEXELS
Grisenti’s team supercooled water to -42.6 degrees
Celsius.
IMAGE COURTESY OF FLICKR
Two emperor penguins stand protectively over a young
chick.
causes fast evaporative cooling, where
evaporation cools the tiny water droplets
much faster than ice can form. With
the understanding that droplet size is
proportionally related to temperature,
the researchers determined the droplets’
temperature by measuring their size
with a laser that had 10-nanometer precision.
They calculated a record low for
liquid water, -42.6 degrees Celsius.
Supercooled water and its transformation
into atmospheric ice occur naturally
in the Earth’s upper atmosphere.
“Atmospheric climate models need an
accurate representation of such processes
for a realistic description of cloud formation
and precipitation,” Grisenti said.
The hope is that this research can ultimately
provide leading climate scientists
with better insight for developing more
reliable climate-predicting models.
half of their body weight. It is such a
challenging task that some emperor
penguins do not survive the winter.
Other males, however, have other
ideas. After tracking several emperor
penguins, the researchers observed
that these males snuck off
in the middle of the night to hunt
for fish in the open water. This phenomenon
is thought to be more
common among penguin colonies
based near the southern coast,
where the journey to the ocean is
much shorter. These “early feedings”
are significant because they
increase the male’s chance of survival
in the winter. By snacking, the
male makes it far more likely that
he will successfully incubate the egg
and ensures the chick’s chance at
life in the coming months.

Science belongs to everyone.
From doctors and biomedical engineers to astronomers and ecologists, science forms the
roots from which we grow. With science, we explore our planet and beyond, from modeling
the mysteries of the clouds in our sky (pg. 18) to imaging the galaxies that exist beyond the
scope of our sight (pg. 30). We attempt to describe the life that surrounds us, including bird
feather patterns (pg. 9), dog behavior (pg. 11), and butterfly evolution (pg. 34). We push the
limits of science to create new technologies and innovations such as quantum computers
(pg. 6), infrared imaging satellites (pg. 7), and dandelion lab tools (pg. 35).
But perhaps most importantly, science contributes to people. From exploring depression
(pg. 8), to inspiring young researchers (pg. 36), to challenging diabetes (pg. 32) and
attacking HIV (pg. 10), science drives our emotional, mental, and physical progress. Our
lives are supported and shaped by the scope of our scientific understanding and thus we
are defined by science and science is defined by us. This now brings us to you, the readers,
and the people that we hope to inspire.
Our cover article this issue gives hope towards a future of both improved organ transplant
outcomes and of increased transplant organ viability and thus availability (pg. 12).
This future is an encapsulation of the discoveries that mark years of progress in many
fields of research, where each breakthrough is built on the previous. But what are we
building towards?
The interconnected nature of science creates a pattern of progress that cannot begin to
be described as uniform. A step in one direction may lead to many in another, and thus the
nonlinearity of scientific discovery becomes increasingly evident. It is our responsibility
as scientific journalists to explore the direction of each scientific path and ultimately map
these fields of discovery. We attempt to guide you through what seems to be a labyrinth of
research and progress. We aim to understand science and share this understanding.
With our new 2018 masthead comes a new era of writing, editing, and design. We maintain
the same scientific excitement and curiosity that our predecessors celebrated and
shared with us. We cherish your continuing support and your high expectations, both of
which serve as inspirations for future improvement. I asked earlier what we are building
towards; the reality may be that we approach nothing in particular. Rather, we build towards
everything. Just as the universe expands, science reaches in all directions. It is driven
by the passions of people and thus represents the ideas of all. Science is shared and we are
lucky to be the ones to share it with you.
Yale Scientific
Established in 1894
THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION
MARCH 2018 VOL. 91 NO. 1 | $6.99
SNEAKING
ORGANS
PAST THE
IMMUNE SYSTEM
DELIVERING
A TALE OF ICE BRAVING
15THE INHIBITOR 18 20
AND SNOW
THE COLD
F R O M T H E E D I T O R
Sharing Science
A B O U T T H E A R T
Eileen Norris
Editor-in-Chief
I’m so excited to serve as arts editor this upcoming
year with YSM’s amazing board! For my
first cover piece, I wanted to capture the magnitude
of a new breakthrough in organ transplant
technology. I illustrated a surgeon’s hands
cradling a precious kidney, an organ that tens
of thousands of Americans are in desperate
need of, that has been treated by a nanoparticle
drug delivery system represented in glowing
green. By decreasing the frequency of organ
rejections, more patients will receive their vital
organs more quickly-making this a wonderful,
revolutionary development in medicine.
Editor-in-Chief
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NEWS
in brief
THE ROLE OF ERROR IN QUANTUM
COMPUTING
By Victoria Dombrowik
COURTESY OF QUATRONICS LABORATORY
An image of a mother board, the most
important piece of a binary computer.
The future of information technology may
be in the qubit. The term, a combination of
quantum and bit, is used to refer to an electronic
circuit that functions as the basis of
quantum computing. It relies on the principle
of superposition, which holds that a physical
system may exist simultaneously in two different
states. While the computer bits of today
can store information in either a 0 or 1
state, qubits are capable of storing a 0 and 1 at
the same time, expanding the ability to cache
data exponentially. Such a device could function
with unimaginable speed and precision,
making considerable advancements in fields
like medicine and cyber security.
The next step is to build a quantum computer
that is capable of using qubits. The
foremost problem facing developers today is
the extreme sensitivity of quantum systems.
Even a slight interaction of the qubit with
the surroundings could lead to decoherence,
or a slow collapse of the quantum mechanical
properties of the system, which would
in turn lead to errors in calculations. Michel
Devoret, the F. W. Beinecke Professor of Applied
Physics at Yale University, and his team
at the Quantronics Laboratory are investigating
a method to improve coherence through
the use of quantum error correction, which
protects the integrity of the qubit. Quantum
error correction does this correcting for both
decoherence and quantum noise, which is the
uncertainty in the original quantum system.
They believe that mastering this technique
will lead to the design of systems that remain
coherent indefinitely. Devoret was also optimistic
about the future of the quantum computer.
“There is no roadblock, no physics that
would prevent it. If it is possible, then humans
will find a way to create it.”
TRIGGERING THE RESPONSE
By Alice Li
PHOTOGRAPHY BY WIKIMEDIA COMMONS
An image of a healthy human T-cell.
You probably had a sore deltoid muscle
after your flu vaccine this year. This is because
this standard shot is delivered straight into
muscle. But there’s another problem besides
you getting a sore shoulder: by injecting the
vaccine into the muscle, the vaccine bypasses
most of the potent cells needed to initiate
an immune response, meaning high vaccine
doses must be given to stimulate immunity.
In an epidemic, however, there might not be
enough vaccine to immunize everyone with
the high doses needed for muscle injection.
To find a better injection site, a team
of scientists led by professor Stephanie
Eisenbarth from the Yale School of Medicine
investigated immune cells responsible for
generating an effective vaccine response.
The team knew that antigens in the vaccine
activate immune cells called T-follicular
helper cells (Tfh), which in turn enable a
second type of immune cell, the B-cells, to
make antibodies. However, the scientists
found that another type of immune cell,
called Type 2 dendritic cell, recognizes the
antigens from vaccines and presents them to
Tfh cells, which then activate B-cells in an
immune cell relay race.
Vaccinating into muscle misses most of the
dendritic cells needed to initiate the response
chain. Instead, the findings, published in
Science Immunology, suggest a new injection
site for your next flu shot: the skin. “If we
deliver the vaccine through the skin, then
we are presenting the vaccine directly to the
dendritic cells,” said Eisenbarth. This means
that existing vaccine stores less likely to run
out in the case of an epidemic, and that the
vaccine can be more widely available.
This new delivery method creates a more
effective immune response and requires
only one-tenth of the original dose. While
injecting into the skin is more painful, the
10-fold increase in efficiency outweighs the
additional discomfort.
6 Yale Scientific Magazine March 2018 www.yalescientific.org

in brief
NEWS
UNDER THE SEA: UNUSUAL MANTLE
BEHAVIOR
By Tiger Zhang
Though hidden, Earth’s interior is full of
activity. Heat from Earth’s interior drives
plate tectonics, the movement of giant slabs
of the Earth’s crust. At certain areas, such
as along the coast of Chile, one plate slides
under another, sinking into the mantle in
a process called subduction. New research
by Yale geoscientists Kanani Lee, associate
professor of geology and geophysics, and
graduate student Jie Deng helps explains why
subducting plates do not sink directly down,
but stagnate at around 1000 km in the lower
mantle.
The researchers studied ferropericlase, the
second most abundant mineral in Earth’s
mantle, under high temperature and pressure
conditions simulating Earth’s interior. By
looking at how ferropericlase’s melting
behavior affects its viscosity, or its resistance to
flow, the researchers hypothesized that around
1000 km below Earth’s crust, ferropericlase
helps create a region in the mantle a hundred
times more viscous than the surrounding
rock.
This layer would hinder the sinking of
tectonic slabs, causing the slabs to buckle
and stagnate. In the other direction, the layer
would affect mantle plumes, such as those
beneath Hawaii and Iceland, that contribute
to volcanic activity. The layer’s high viscosity
would slow down and deflect plumes of hot
rock rising from Earth’s core, causing the
plumes to bend sideways.
“There have been other ways to explain
the stagnation of subducting slabs, however
this mechanism also explains the deflection
of rising plumes,” Lee said. This new theory
is the first to account for both stagnation of
subducting plates and deflection of mantle
plumes.
COURTESY OF WIKIMEDIA COMMONS
Volcanic activity in hot spots such as the
Hawaiian Islands is fed by rising plumes
of hot rock. The upward movement
of the plume is altered by the high
viscosity rock present around 1000 km
below the Earth’s surface.
NIGHTTIME LIGHTS, DATA, ACTION
By Erica Lin
Close your eyes and imagine yourself on
the moon. It is night, and before you, the
glow of cities, sprawl, and human activity
illuminate Earth.
Yale Professor of Geography and
Urbanization Karen Seto and Ph.D.
Candidate Eleanor Stokes spend their time
marveling at these lights—but not with their
bare eyes. Instead, they see through the eyes
of Visible Infrared Imaging Radiometer
Suite (VIIRS), a real-time sensor on the
NASA/NOAA Suomi-NPP satellite that
collects high-resolution nighttime imagery
of Earth.
The Seto Lab processed raw VIIRS
imagery and analyzed nighttime light
intensity patterns for cities across the globe.
They discovered that after accounting for
confounding factors like light pollution or
moon reflectance, VIIRS data acts as a proxy
for electricity usage within individual cities.
The connection between nighttime lights
and electricity usage may seem intuitive,
but previous metrics have typically relied on
national rather than localized data, leading
to misgeneralizations about individual cities’
energy usages. Thus, VIIRS provides more
precise energy usage analyses. “I’m very
excited about the scope, that it’s global, yet
we also look at the within-urban scale to
assess the world,” Stokes said.
Cities can use the new data to tackle
local sustainability issues. Potential VIIRS
applications include facilitating disaster relief
planning, foreign urbanization development,
and transportation sustainability. For
example, tracking road connectivity via
lights could pinpoint traffic-congested
zones in need of redesign, and tracing light
usage after earthquakes may reveal areas
with limited resource access. Indeed, VIIRS
can drive sustainability efforts by using
data relevant to each glowing city in our
illuminated world.
PHOTOGRAPHY BY NASA EARTH OBSERVATORY
Nighttime lights map of the United
States
www.yalescientific.org
March 2018
Yale Scientific Magazine
7

NEWS
psychology
KNOW TOO MUCH?
The downside of genetic testing for depression
BY SUNNIE LIU
Picture yourself as a participant in a study: you receive a kit
containing mouthwash and a color-changing strip of paper.
Sleek text on the professional label reads “Saliva Self-Testing Kit
for 5-Hydroxylindoleacetic Acid.” Following the instructions,
you rinse your mouth and hold the test strip to your tongue,
immediately transforming the test strip from blue to brownish
green. While this kit may appear to be a saliva-based genetic
test, it is actually a placebo test. However, you were not the only
person fooled; 786 participants in the study also believed that
the kit was a real genetic test.
In this study, Yale psychologist Woo-Kyong Ahn and Columbia
University postdoctoral research fellow Matthew S. Lebowitz explored
the negative effects of genetic testing for depression, which
had been mostly overlooked during the growing popularization
of personalized genetic testing for explaining and predicting
health issues in the twenty-first century. Public opinion is shifting
to believe that depression and other mental disorders, like physical
diseases, stem from biological causes, leading to higher interest
in genetic testing for mental disorders.
“There was hope that genetic testing would further decrease
the stigma around mental health issues,” Lebowitz explained.
However, only recognizing the benefits of genetic testing leaves
out details about potentially adverse consequences, resulting in a
dangerously overoptimistic view of genetic testing. This recently
published Yale Thinking Lab study helped show the emotional
downside of genetic testing that so often gets ignored.
The researchers divided the participants into three groups: a
depression gene-absent group and two depression gene-present
groups. The test strip turned brown for all three groups, so all
the participants received the same placebo test results, but the researchers
randomly assigned different meaning to the results. The
gene-absent group was told they did not carry the gene that would
make them more susceptible to depression, while both gene-present
groups were told that they carried the gene.
One of the two gene-present groups watched a short intervention
video explaining that genes alone cannot make a person depressed
because complicated factors—such as epigenetics, which
turn genes on or off, the interactions between many different
genes, and environmental and experiential factors—also play important
roles in the development of depression. The other group
did not. Finally, all three groups completed a Negative Mood Regulation
(NMR) scale, which measures how well one expects to be
able to control one’s negative emotions in the future.
The gene-absent group reported higher NMR scores than the
two gene-present groups, suggesting that the gene-present groups
felt less confident in their ability to cope with depressive symptoms
than the gene-absent group. In other words, the people who
thought they were genetically predisposed to depression felt more
helpless and hopeless in regulating their mood, and thus, viewed
themselves as more susceptible to depression. “We basically created
depression in three minutes,” said Ahn.
Adding further complexity, the gene-present group shown
the educational video scored significantly higher on the NMR
scale than the gene-present group who did not watch the video.
This difference in NMR scores demonstrates that the educational
video effectively mitigated the negative effects of the genetic
testing on the people who believed that they were genetically
disposed to depression.
Personalized genetic testing for susceptibility to depression and
other mental disorders is already common among the general
public and will most likely become even more prevalent in the
future. Ahn thinks the popularity of genetic testing keeps growing
because it promises easy answers, even if they may be misleading.
“Genetic testing is a way for people to simplify this complicated
world, but problems arise with oversimplifying,” said Ahn.
Celebrating only the beneficial aspects of genetic testing overlooks
its negative implications, potentially leading to tragic clinical
effects. For example, this study showed that genetic testing for
depression could actually increase one’s risk for depression, because
test results showing genetic predisposition to depression exacerbate
people’s pessimism in their ability to cope with and overcome
depressive symptoms. This negative consequence of genetic
testing is especially concerning because faith in one’s own possibility
of overcoming depression can be a self-fulfilling prophecy,
so abandoning self-confidence can prevent improvement.
The researchers hope their results will spark thoughtful consideration
of genetic testing. “I would like for people who are otherwise
gung-ho about rolling out genetic testing in all fields to be
more cautious,” said Lebowitz.
COURTESY OF DR. AHN
Photograph shows closed container of “Saliva Self-Testing Kit for
5-Hydroxylindoleacetic Acid,” the fake genetic testing kit used in
the study.
8 Yale Scientific Magazine March 2018 www.yalescientific.org

ecology
NEWS
THE SINGLE BIRDS’ BAR
The evolution of super-black feathers in birds-of-paradise
BY MIRIAM ROSS
IMAGE COURTESY OF WIKIPEDIA
The feathers of the superblack bird of paradise trap all of the light.
Just like a teenager before a first date, male birds-of-paradise
spend hours checking their looks and practicing their dance
moves. But unlike a teenager, who might change clothes five
times before leaving the house, male birds-of-paradise wear the
same outfit their whole life, so they make it as flashy as possible.
Their plumage is astonishingly black, much more so than any tuxedo.
A new study by Yale researchers Todd Harvey and Richard
Prum examined what causes the velvety, super-black quality in
the feathers of these birds.
Understanding the processes behind bird coloration is important
to understand evolution, sexual selection, and speciation.
Birds-of-paradise have some of the most intricate courtship
dances and feather coloration in the world, making them
ideal to study. The researchers hypothesized that the birds’ super-black
feathers evolved to intensify the perceived brightness
of neighboring colorful feather patches, appealing more to females
during the courtship dance.
Two processes contribute to bird feather coloration. Molecular
pigments absorb light only at specific wavelengths, reflecting
the rest to produce color. The second process, known as structural
absorption, generates color by scattering light at multiple
angles. In both cases, we see the reflected light as color. A material
that reflects all light will appear white, and a material that
absorbs all light will look black.
The researchers discovered that the birds’ super-black color
comes from this second process of structural absorption. When
light is scattered, the feather absorbs some of that scattered light.
By causing more scattering, structurally absorbent objects like
bird feathers can take in more light and appear much darker.
Bird-of-paradise feathers look so black because they are essentially
trapping all the light.
The researchers studied the function of this structural absorption
in feathers from seven different bird-of-paradise species.
They discovered that super-black feathers structurally absorbed
99.95% of incoming light, the most efficient rate of any natural
material. The shape, position, and texture of feather barbs and
barbules, hook-like structures holding the feather together, all
affect the coloration. The experimenters found that the barbule
arrays of super-black feathers tilted vertically, forming deep and
curved structural cavities.
The scientists hypothesized that the tilted feather microstructure,
combined with the courtship dance, evolved to elevate vibrant
feathers to their maximal brilliance. In both butterflies and
birds-of-paradise, super-black areas are located next to structurally
colorful feathers. The super-black feathers make other colors
appear brighter by eliminating the environmental signals females
typically use to judge color intensity. Specifically, they override
specular highlights, the spots of light that show up on illuminated
shiny objects, and define physical boundaries. The feathers absorb
all the incident light, making the neighboring colors seem so radiant
they lose their boundaries and hover in space.
The researchers also found that super-black feathers have a
strong directional reflectance bias, making them look darkest
when facing a viewer head on. Male birds-of-paradise strut their
stuff at a particular angle relative to watchful females, consistent
with the optimal angle for a super-black appearance.
However, only feathers used in the courtship dance were super-black.
Other feathers, such as those on the birds’ backs, reflected
more light. The difference in structure and color between
feathers involved in the courtship dance and those that are not
was striking, suggesting a highly specialized purpose. “Other organisms
that evolved super-black, a West African viper, or a butterfly...in
both cases they evolve this super-black material for a
different purpose than our birds-of-paradise,” said Harvey. “Our
birds-of-paradise are not developing it for camouflage...they’re developing
it because it makes them shockingly beautiful to a mate.”
But much research remains to understand in what ways structural
absorption and multiple scattering of light affect the female
birds’ color correction. Moving forward, Prum’s lab will likely focus
on how female birds-of-paradise perceive a male’s plumage
during a courtship dance. Furthermore, the researchers hope that
super-black feathers will inspire new biomimetic materials. Structural
absorption has major potential for a variety of mechanical,
thermal, and solar technologies, like the lining inside space telescopes.
Perhaps, like a male bird-of-paradise, the next batch of
space photography will blind us with its beauty.
www.yalescientific.org
March 2018
Yale Scientific Magazine
9

NEWS
medicine
ERADICATING HIV
Targeting latently-infected T-cells
BY GRACE CHEN
IMAGE COURTESY OF NIH
Scanning electron micrograph of a T cell infected infected with HIV.
One of the most pressing problems today in the effort to
eradicate HIV is latency. Infected T cells may harbor the virus
but lie dormant for years, making up a latent reservoir
that evades the drugs, which effectively kill only active cells
replicating the virus. Researchers have recently discovered
a new way to uncover cells harboring latent forms of the virus,
opening the door to a new approach to extinguishing
reservoirs of infected T cells inside a patient’s body.
Recently published in Nature Scientific Reports, the
project was headed by Linda Fong, a graduate student in
the laboratory of Kathryn Miller-Jensen, Associate Professor
of Biomedical Engineering at Yale University. Her
team studied five cell-signaling pathways in an attempt
to distinguish infected cells from healthy ones. Signaling
pathways are essential in multicellular organisms, since
they facilitate how external and internal stimuli trigger
changes in cells. These changes include events like releasing
a hormone or expressing a gene. Before Fong’s team
could study these pathways, however, they needed to reactivate
the latently infected T cells.
To do this, several classes of latency reversing agents
(LRAs) were used to stimulate the cells. One type of LRA
functions by opening up the cell’s chromatin, where the
virus’s genetic information is found, to allow for the transcription
and expression of the HIV genome; others are
able to activate specific proteins leading to expression of
the HIV genome. These agents are currently of great interest
to HIV researchers looking to “activate-and-kill” the latent
reservoir.
Once the T cells were treated with LRAs, researchers
compared levels of kinase phosphorylation in infected cells
and healthy ones. Kinases are enzymes that play an essential
role in cell signaling pathways by transferring a phosphate
from ATP, a molecule in which energy is stored, to another
molecular substrate—usually a key protein in a cell signaling
pathway—effectively activating or deactivating the
protein. This transfer releases energy so that the signaling
pathway can continue. The researchers realized that infected
cells exhibit a significantly higher level of kinase phosphorylation
than do healthy cells. Mathematical analyses
further confirmed that the extent of variation in phosphorylation
between infected and healthy cells was sufficient to
differentiate them. This increased level of phosphorylation
in infected cells indicates that the virus has managed to deregulate
crucial cell processes, shedding light into one of
the many ways the virus impacts the cells harboring it.
“You can imagine that if scores of scientists were working
on this, you could find so many other pathways that are
dysregulated,” Fong said. “That comes back to pathway engineering
and the idea that you can get a cell to do what you
want if you understand its circuitry.”
Previous research has compared latently infected and
healthy T cells in a state prior to reactivation by LRAs.
These studies were unable to find an accurate, specific way
to distinguish latently infected T cells from healthy cells.
These findings could have meaningful clinical implications,
and Fong is working towards eventually conducting
trials in HIV patients. For now, she has transitioned from
testing healthy cells that are manually infected with HIV to
working with cells extracted from the blood of HIV-positive
patients. Ultimately, Fong and her team hope that their
work will enable more selective and specific eradication
strategies that target only infected T cells while leaving the
healthy ones intact in patients with HIV.
IMAGE COURTESY OF LINDA FONG
Linda Fong pipettes her samples in the Miller-Jensen Lab.
10 Yale Scientific Magazine March 2018 www.yalescientific.org

evolutionary biology
NEWS
THINKING ON FOUR FEET
Peering into the mystery of canine eye contact
BY GRACE NIEWIJK
PHOTO BY LINDA CHANG
Eye contact may have facillitated the healthy relationship between
humans and dogs.
Humans use eye contact all the time, from bonding with
our babies to sharing an awkward glance with someone
during an embarrassing situation. Eye contact isn’t just
for humans though—dogs use it too. Man’s best friend has
learned to use eye contact to connect and communicate
with humans extraordinarily well. Researchers at Yale’s Canine
Cognition Center (CCC) set out to learn more about
how this behavior developed over the course of the domestication
process by comparing dogs, wolves, and dingoes.
We can learn a lot about ourselves by observing the
behavior of animals that spend a lot of time around us.
“Across domestication, dogs have come to learn from humans
in much the same way as human children learn from
adults, so dogs and dingoes offer us the unique opportunity
to examine how these human-like abilities may have
evolved,” said Yale graduate student Angie Johnston. Johnston
works in the CCC alongside Laurie Santos, Ph.D.,
who directs the center, observing canine behavior to answer
these types of questions.
Back in 2015, a Japanese group found that both dogs and
humans experience a rush of oxytocin—a hormone associated
with bonding and warm fuzzy feelings—when they
make eye contact with each other. In contrast, wolves that
underwent the same experiments rarely made eye contact
with their handlers and didn’t show similar oxytocin
spikes even when their eyes did meet.
For dogs, eye contact has practical uses that extend beyond
warm fuzzy feelings. When dogs were given a difficult
puzzle to solve, they looked at their owners more
frequently, seeking help or looking for solutions based on
where the human’s gaze is directed. On the other hand,
labs that compared dogs’ problem-solving behavior to
wolves’ found that the wolves tackled the puzzle independently
and mostly ignored the humans.
The CCC added nuance to these previous studies by collecting
observations from Australian dingoes that underwent
the same experiments. Wolves are considered the standard
undomesticated ancestor; in contrast, dingoes associate frequently
with humans but have never been selectively bred
like dogs. The last shared ancestor between dingoes and
modern dogs existed roughly 5000 years ago. As a result, dingoes
represent an intermediate step in canine domestication.
By studying dingoes, researchers can notice subtle effects
of complete domestication that may be overlooked
when comparing dogs to wolves. “If we see differences in
dogs and dingoes, it’s coming from a really tiny window
of domestication,” said Santos. The dingoes in this recent
study made eye contact with humans less often than dogs,
but more often than wolves, indicating that some motivation
to make eye contact developed even before the tiny
window separating dingoes and dogs.
“Our study in particular suggests that eye contact between
humans and canids may have evolved relatively early
in the domestication process, before humans began actively
breeding dogs,” said Johnston. “This is significant
because it suggests that one of the most foundational aspects
of canine social cognition was already being shaped
very early in domestication.”
The results led researchers to hypothesize that the
bond between humans and dogs may have developed in
two stages. Early efforts at domestication might have favored
dogs that showed some tendency to make eye contact,
since that would have elicited some of the same warm
fuzzy feelings as parent-child eye contact. Once some
bond was established, humans probably started treating
dogs as social partners, which would have prompted dogs
to start learning eye contact as a form of communication.
Looking ahead, Johnston expresses enthusiasm about
how she expects this research to move forward. She’s especially
interested in diving deeper into social cognition
and the communicative aspects of eye contact. She
points out that understanding domestication and canine
cognition not only helps unravel history but can also
have practical implications for our day-to-day interactions
with the canines in our lives. “Understanding more
about how the bond between our two species develops
may help promote healthy relationships between people
and their pet dogs, therapy dogs, service dogs, and emotional
support dogs,” she said.
www.yalescientific.org
March 2018
Yale Scientific Magazine
11

FOCUS
biotechnology
Sneaking Organs
Past the Immune
System
By SONIA WANG
Art by SUNNIE LIU
12 Yale Scientific Magazine April 2015 www.yalescientific.org

The diagnosis comes in: patient X has end-stage
renal failure. His kidneys no longer work, and he has
the choice of either staying hooked up to a machine
for dialysis treatment a few times each week, or
obtaining a transplant organ. Luckily, he is able to
receive a donated kidney—hard to come by.
biomedical engineering
FOCUS
But a new diagnosis comes in three
months after the surgery: his new kidney
is failing. His body has rejected the new organ,
and his immune system is slowly eating
away at it. Once again, he is forced to begin
dialysis treatment, depending on a blinking
machine to carry out the same function that
his kidneys used to do.
This story is not uncommon: around fifteen
to twenty percent of kidney transplants
fail within five years of transplantation. Currently,
the main way physicians attempt to
decrease the rejection rate is by giving patients
drugs that suppress the immune system,
thereby reducing the body’s ability to
attack and reject the transplant.
But Yale researchers are seeking to develop
a new way to reduce immune rejection. A
long-standing study done by Yale professors
Mark Saltzman and Jordan Pober in collaboration
with researchers at Cambridge University
seeks to use carefully designed, tiny
nanoparticles to deliver drugs to transplant
organs before they are placed in the body.
They hope their process will improve longterm
outcomes for transplant patients.
America’s transplant problem
The organ transplant waiting list is a national
list compiled by the United Network
for Organ Sharing (UNOS), a non-profit established
to manage the federal organ transplant
system and to objectify the complex
matching process between donors and recipients.
Factors such as a patient’s medical
urgency, the compatibility between donor
and recipient, and the time on the waiting
list guide how organs are distributed.
Despite this, there are around 116,000
people waiting for a vital organ transplant,
while in 2017 there were only about 35,000
organ transplants. The average wait time for
a liver transplant is around 11 months; for a
kidney transplant that number increases to
5 years.
Even after a patient receives a transplant,
there’s still no guarantee that their new organ
will prove an effective treatment. In the case
of a bad match between the recipient and
donor, the recipient’s immune system will
recognize the new organ as a foreign object
and will attack it, sometimes damaging it irreversibly.
Though transplant rejection can
be minimized using drugs that suppress the
immune system, these immunosuppressant
drugs can make the patient more susceptible
to other diseases.
Patients need a more targeted approach to
prevent the immune system from destroying
the transplant, but also allow normal immune
function to occur—perhaps through
a delivery system of some sorts. Enter Professor
of Biomedical Engineering Mark
Saltzman, who has long worked on using
nanoparticles to create better drug delivery
systems.
Small but mighty
What is the smallest object visible to the
human eye? Those with imperfect vision
might squint to see the words on a page in
front of them. Others might say a human
hair, just 0.1 millimeters wide, or 10 percent
of the width of your typical credit card. The
typical human cell is far smaller than what
the eye can see—around ten cells can fit in
the thickness of a single average hair. But
on the nano-scale, thousands to hundreds
of thousands of tiny nanoparticles can fit
across a hair.
Science has turned its focus to nanoparticles
as a potential drug delivery mechanism
because of their size. Because they are so tiny,
they not only have a comparatively large surface
area available for reactions, but also are
able to cross cell and tissue barriers that current
delivery systems cannot, making them a
more efficient system for drug delivery.
The key is finding ways to engineer
nanoparticles to target specific cells, such as
delivering growth-suppressing drugs to tumors
in cancer patients. Nanoparticles can
IMAGE COURTESY OF FLICKR
Nanoparticles can be used to target drug
delivery to specific types of cells.
be designed with specific properties to increase
their effectiveness—for instance, by
giving them a positive charge to interact better
with the drug they are carrying. Antibodies
that recognize and bind to characteristic
targets on the cell types of interest can also
be attached to the surface of the nanoparticles
to make the delivery more specific.
In a typical transplant organ, the circulating
blood from the host primarily interacts with
cells that line the blood vessels of the transplant
organ called endothelial cells. White
blood cells, the fighters of the immune system,
are found in the blood and interact with
major histocompatibility complex (MHC)
proteins found on the surface of the endothelial
cells. If an MHC protein not typically
produced by the body is found, then the white
blood cells hone in on those cells and initiate
inflammatory responses, which can then kill
the cells of the transplant organ.
IMAGE COURTESY OF WIKIMEDIA COMMONS
A kidney facing end stage renal disease. After
kidney failure, patients can only be put on
dialysis or undergo transplant surgery.
www.yalescientific.org
March 2018
Yale Scientific Magazine
13

FOCUS
biomedical engineering
perfused for one to two hours, we could treat
them in other ways to make them less prone
to rejection,” Saltzman said.
The researchers decided to target CD31,
a protein found on all endothelial cells.
Nanoparticles coated with antibodies able to
recognize CD31 were injected into the perfusion
device while blood passed through
a donor kidney, along with a non-targeted
set of nanoparticles without the antibodies.
The results, a colorful set of images showing
where each set of nanoparticles accumulated,
indicated that targeted particles could
accumulate to levels two to five times higher
than in the control group, whereas some
areas showed profound targeting with levels
up to ten times higher than the control.
“That was one surprise. No one ever
looked at where particles go in a human organ
before at this level,” Saltzman said. “It
allowed us to make some hypotheses about
what would give you the best distribution
through the kidney.”
But by effectively showing that nanoparticles
can be targeted to the endothelial cells of
an organ through machine perfusion, the researchers
are one step closer to engineering
a drug delivery system that can use machine
perfusion to improve transplant outcomes.
Combining past and present
Yale professor Mark Saltzman’s lab works on nanoparticle drug delivery systems.
Some approaches now aim to mask the
transplant organ from the immune system
by decreasing the amount of MHC protein
recognizable as foreign. Jordan Pober, Professor
of Immunobiology at Yale, has long
been interested in the role of endothelial
cells in the immune response. Together with
Saltzman, he worked on a project in which
MHC protein was deleted in a mouse with
a transplanted human artery by delivering
molecules called small interfering RNAs
(siRNAs) through a nanoparticle delivery
system. This effectively prevented the immune
system from attacking the transplant
and allowed the new organ to heal.
But another problem with current drug
delivery systems is that injecting drugs into
the bloodstream may not get to the target at
sufficient levels to be effective. Thus, Pober
and Saltzman began collaborating with researchers
from the University of Cambridge
to create a system able to treat organs to improve
long-term outcomes, before they are
even transplanted into the body.
IMAGE COURTESY OF WIKIMEDIA COMMONS
There is still far more to go, and the researchers
have received another grant to
work on the project. “It’s a new area. We’re
treating human organs outside the body, and
[there are] studies we need to do to show this
is safe before we can use them in humans,”
Saltzman said. “But I love the mystery.”
Right now, the research on machine perfusion
has shown that scientists can target
endothelial cells, but getting to the right targets—the
cells on the transplant organ—is
another question. “Now the question is can
we improve the delivery, but also can we
choose the right targets,” Pober said. Saltzman
and Pober hope to combine their research
on knocking down MHC proteins in
the transplant organ with their research on
machine perfusion, in hopes of creating a
new transplant treatment system to improve
outcomes.
“There just aren’t enough organs. Now
there are two things you can do about that:
one, to have people who have [transplants]
to keep from losing them, and second, using
tissue engineering to keep [transplants]
from the invading immune system,” Pober
said. They hope to decrease the frequency of
the first.
In the future, hopefully cases like Patient X
will be far less common through the help of
treatments being developed by Saltzman and
Pober’s labs. And with an increase in viability
of organs, perhaps the organ transplant
waiting list will decrease and more people
will receive life-saving treatments.
Targeting from the start
Ex vivo normothermic machine perfusion
(NMP) is a mouthful to pronounce, but it may
be the key to improving transplant outcomes
and increasing the number of transplant organs
available. The process involves pumping
warm blood at body temperature through a
transplant organ outside of the body, keeping
the organ alive for longer and helping to
repair damage to the organ. This allows even
organs that previously did not seem viable to
become suitable for transplantation.
“We thought, if these organs were being
ABOUT THE AUTHOR
SONIA WANG
SONIA WANG is a current senior in Jonathan Edwards College majoring in Biochemistry and
Economics. She used to be managing editor and news editor for the Yale Scientific, and looks
forward to writing more for them this semester. She currently works in the Joan Steitz lab on
microRNA degradation.
THE AUTHOR WOULD LIKE TO THANK Mark Saltzman and Jordan Pober for giving their time to
this article.
FURTHER READING
Tietjen, Gregory T., et al. “Nanoparticle targeting to the endothelium during normothermic machine
perfusion of human kidneys.” Science translational medicine 9.418 (2017): eaam6764.
14 Yale Scientific Magazine March 2018 www.yalescientific.org

DELIVERING
THE INHIBITOR
Delivering therapeutic treatments
to cancer, diabetes, and
neurodegenerative targets
by Mindy Le
art by Elissa Martin
www.yalescientific.org
December 2017
Yale Scientific Magazine
15

FOCUS
organic chemistry
Within our bodies’ cells,
a myriad of chemical
reactions orchestrate life.
These reactions ensure our health and are
essential to all of our bodily functions, including
metabolism and homeostasis within
the bodily environment. But when these reactions
are unable to function properly, disease
can result.
One of the important chemical reactions
that occur in our bodies is protein tyrosine
phosphorylation, which is a modification
of newly synthesized proteins. When regulation
of this reaction is disturbed, diseases
such as diabetes, cancer, and neurodegeneration
arise. Jonathan Ellman, Professor of
Chemistry and Pharmacology at Yale, and
his team of researchers have developed a
method for delivering therapeutic drugs to
target certain proteins involved in the dysregulation
of the protein tyrosine phosphorylation
pathway.
Striking a balance
During protein tyrosine phosphorylation,
a phosphate molecule is added to an amino
acid called tyrosine, which is a common
building block of proteins. To help the reaction
happen more efficiently, this addition
is catalyzed by an enzyme called protein tyrosine
kinase. Kinases are a class of proteins
that add phosphates to other molecules.
Proteins tyrosine kinases act concurrently
with protein tyrosine phosphatases (PTPs),
which remove phosphate groups from tyrosine.
The body requires a proper balance of
these kinases and phosphatases to ensure a
proper balance of tyrosine phosphorylation
levels on proteins within our cells.
The wide and seemingly unrelated range of
diseases related to dysregulation of protein
tyrosine phosphorylation pathways suggest
a universal importance for these molecules
within our bodies. Specifically, it highlights
the significance of the enzymes that catalyze
such reactions. Of particular interest are the
aforementioned PTPs, a family of enzymes
with the general function of removing phosphate
groups from tyrosine. For example,
bacterial PTPs have interestingly been found
to exacerbate infections such as tuberculosis.
Medical interest in PTPs arose due to their
implications in human disease. However,
challenges involving PTP-based drugs have
made such research and drug development
difficult. “PTPs continue to be challenging
targets for progressing inhibitors to the clinic
because their active sites are highly conserved
and charged,” Ellman said. Active
sites are areas within enzymes such as PTP
that specifically bind to protein targets. For
PTPs, the target is the phosphate group on a
tyrosine found within different kinds of proteins.
Because PTP active sites are charged
and conserved, meaning that they possess an
electrical charge and are universal to many
PTP types, designing drugs to specifically
target and successfully react at the active site
is tricky. “Thus, it is difficult to develop inhibitors
that are potent and selective against
a specific PTP while also having appropriate
physicochemical properties to be effective
drugs, such as level of polarity to efficiently
cross cell membranes,” Ellman added.
Motivated to study PTPs, Ellman tackled
the problem of PTP drug development
by designing a platform to inhibit PTPs for
disease treatment. The platform consists of
glutathione-responsive selenosulfide prodrugs
that have a specific function of inhibiting
PTPs. Prodrugs are inactive precursors
to drugs that, once processed by the body,
can exert their biological function in a controlled
manner. This selectivity in the prodrug’s
mechanism is crucial for designing and
understanding how the prodrug acts within
the human body.
The mechanism
IMAGE COURTESY OF WIKIMEDIA COMMONS
As part of their drug delivery system, Ellman
made use of the natural concentration
differences of this molecule, glutathione, in
order to deliver their PTP inhibitor. Glutathione
is an antioxidant important for preventing
damage to our cells.
Glutathione (GSH) is an antioxidant important
for preventing free radical damage
to our cells, which is spontaneous damage
that occurs all over our body due to things
like ultraviolet (UV) radiation from sunlight
and even from the body’s own metabolism.
GSH is synthesized in our body from food
sources obtained from our diet. Because
there is a large difference between GSH levels
inside and outside of our cells, the research
group used this natural difference in
concentration to activate a specific PTP inhibitor,
which comes from a novel group of
chemicals called selenosulfide phosphatase
inhibitors. This class is named after the key
part of the inhibitor structure responsible
for labeling the enzyme: the inhibitor targets
a sulfur-containing group found within
the phosphatase enzyme, hence the “sulfide”
in the name. The researchers chose the
GSH-responsive motif as a method for prodrug
delivery due to these cellular properties.
The drug’s mechanism of action relies on
its selenosulfide pharmacophore, the part of
the drug that is responsible for its pharmacological
interaction, which reacts with cysteine,
an amino acid in the active site of PTP,
to form a product that inhibits PTP. The inhibitor
is useful because its structure contains
sites available for certain molecules to
be added in order to change the potency and
selectivity of the inhibitor for a specific PTP.
The researchers then took their platform
further by developing specific PTP inhibitors
that could act against two PTP targets:
the virulence factor mPTPA secreted by Mycobacterium
tuberculosis and the striatal-enriched
protein tyrosine phosphatase (STEP),
a tyrosine phosphatase that is specific to the
central nervous system. They chose to do
this as a proof-of-concept experiment to
demonstrate the efficacy of their prodrug
platform. Both molecules were found to inhibit
their respective targets potently and selectively.
Drug efficacy in the test tube
Tuberculosis, the lung disease that infects
one-third of the world’s population
and causes over one million annual deaths,
is caused by the Mycobacterium tuberculosis
bacterium. On top of that, over 50 million
people develop multidrug resistant tuberculosis,
and current treatments for this disease
are limited. As such, when two PTPs secreted
by the bacterium, mPTPA and mPTPB,
were identified as potential drug targets, this
discovery spurned new interest in developing
tuberculosis treatments. “Tuberculosis
drug resistance is a serious, ongoing prob-
16 Yale Scientific Magazine March 2018 www.yalescientific.org

organic chemistry
FOCUS
lem and often occurs through mechanisms
that limit a drug’s accessibility to its biomolecular
target. Tuberculosis PTPs are intriguing
because the bacteria secrete these
enzymes, rendering them much more accessible
than the targets of most tuberculosis
drugs, which reside within bacterial cells.
However, additional research is needed to
validate mPTPA and mPTPB as drug targets,”
Ellman remarked.
This work also addressed a key problem
in PTP inhibitor development. Namely,
there is a high amount of structural similarity
among PTPs that makes it difficult
to achieve high selectivity of their developed
inhibitors. The researchers evaluated
the selectivity of their mPTPA inhibitor
against a collection of known human PTPs,
and also a generic cysteine protease, which
is an enzyme that breaks down proteins using
a key cysteine amino acid found within
the protein of interest. Here they found that
their mPTPA inhibitor had great selectivity
against each enzyme in this panel, indicating
that their inhibitor could act in a controlled
and predictable manner.
Drug efficacy in a biological setting
After testing their PTP inhibitors in a testtube
setting, the next step was to evaluate their
prodrug in a cellular context. However, in animal
models, it was found that both mPTPA
and mPTPB inhibitors were needed for significant
antibacterial activity. Because they
chose only to develop an inhibitor against
mPTPA at this stage of their research, they instead
decided to develop selenosulfide prodrug
inhibitors to another PTP target in order
to do a more simple and straightforward analysis
of the prodrug activity in the cell.
The second target, STEP, is a central nervous
system (CNS)-specific tyrosine phosphatase
that may be a therapeutic target for
neurological disorders like Alzheimer’s disease.
After testing a variety of potential prodrugs,
they identified one that could inhibit
STEP in rat cortical neurons.
After demonstrating the activity and specificity
of their PTP inhibitors, they reported
their success in developing a prodrug strategy
to facilitate the delivery of a novel class of
PTP inhibitors into cells in an efficient manner.
Their development of inhibitors for two
PTPs that can selectively inhibit mPTPA and
STEP very potently also acted as a robust
ABOUT THE AUTHOR
IMAGE COURTESY OF WIKIPEDIA
Protein tyrosine phosphatase (PTP), shown here, is a target for treatment for several diseases
including diabetes, cancer, and neurodegenerative disorders. Researchers at Yale have designed a
method for delivering PTP inhibitors in order to restore balance of tyrosine phosphorylation levels
within our cells.
proof-of-concept demonstration, showing
that their strategy for targeting PTPs is feasible
and has great potential.
Future promises of PTP-inhibitor drugs
In the future, Ellman hopes to expand
upon this research. “We intend to investigate
a number of questions to advance the
approach. For example, we will evaluate proteome-wide
specificity of identified inhibitors,”
he said. Of the inhibitors developed
in his lab so far, their group will need to see
how these inhibitors act across the entire
proteome, which is the collection of all proteins
present in our cells. In doing so, they
can determine if the inhibitor acts on a different
protein or group of proteins that was
not anticipated, which could have severe
consequences if the inhibitor targeted a protein
essential for our survival.
Furthermore, Ellman hopes to expand
upon the collection of PTP inhibitors already
developed in his lab. “We additionally
intend to test the generality of the approach
by developing potent and selective inhibitors
of other PTPs as well as other enzymes,”
Ellman said. If successful, this could result
in a greater number of potential drugs for
disease treatment involving PTP inhibition.
For example, some PTPs have been implicated
in cancer, and inhibitors of these enzymes
have been suggested as potential
drug candidates to be used in combination
with immunotherapy treatments. Although
such treatments would require more study
and clinical tests, the future of cancer treatment
using PTP inhibitors remains promising.
The use of PTP inhibitors extends
beyond cancer treatment, having vast implications
in both neurodegenerative disorders
and diabetes, two diseases with wide prevalence
in society that warrant crucial further
research and drug development.
MINDY LE
MINDY LE is a junior in Ezra Stiles College studying Molecular, Cellular, and Developmental
Biology. She is an avid squirrel enthusiast who works in Professor Patrick Sung’s lab, researching
DNA repair in the context of breast and ovarian cancer.
THE AUTHOR WOULD LIKE TO THANK both Professor Jonathan Ellman and Caroline Chandra Tjin
for their time and dedication to their research.
FURTHER READING
Tonks, N. K. 2013. “Protein tyrosine phosphatases--from housekeeping enzymes to master regulators of
signal transduction.” FEBS J. 280: 346-378.
www.yalescientific.org
March 2018
Yale Scientific Magazine
17

Surprises
in the
CLOUDS
Understanding cloud
behavior through
computational modeling
by CHRISTINE XU | art by LAUREN GATTA
On some days during the coldest months
of winter, we are greeted by fluffy snow
falling from the sky when we venture outside.
On other days, it’s rain or an unpleasant
combination of freezing sleet and snow.
What comes from the clouds on a given day
might seem random, but scientists are coming
up with new ways to predict these seemingly
mysterious weather patterns.
Amir Haji-Akbari, assistant professor of
Chemical and Environmental Engineering
at Yale, uses computational simulations to
study how ice and snow form from microdroplets
of water in clouds. Clouds are large,
visible masses of condensed water vapor
floating high up in the atmosphere; studying
the behavior of the water molecules
that make up these clouds can therefore
help scientists understand different weather
patterns. Haji-Akbari employs computer
models to predict how the water droplets in
clouds form into frozen particles in a process
called nucleation, providing some insight
into weather patterns.
“Ice formation is a very important component
of what happens in clouds. It’s a very
important part of cloud microphysics, and
the amount of ice you have in a cloud determines
how likely it is to produce rain and
snow,” Haji-Akbari said.
Clouds contain water droplets that are light
enough to float in the air without falling.
These water droplets come from evaporating
water from the Earth’s surface that condenses
or freezes as it gets higher up in the atmosphere,
often times around a nucleus such as
a dust particle or an aerosol. Eventually, that
water comes back to the Earth’s surface in the
form of rain or snow. However, it is unclear
18 Yale Scientific Magazine March 2018 www.yalescientific.org

environmental science
FOCUS
IMAGE COURTESY OF PIXABAY
Computational techniques can be used to examine the processes that occur within clouds containing microdroplets of water that can condense to
form ice and snow.
how and when water droplets and ice crystals
form, and scientists like Haji-Akbari are trying
to develop new ways of understanding the
physics behind these processes.
In a recent study published in PNAS, Haji-Akbari
investigated how the vapor-liquid
interface affects the freezing of water molecules.
He simulated the formation of two
different types of ice crystal structures called
the hexagonal cage structure and the double
diamond cage structure. The hexagonal
cage structures tend to be found in the kind
of ice we see in everyday life, because their
chemical structures make them more stable.
Double-diamond cage structures, on the other
hand, are typically found in cubic ice and
only form at extremely low temperatures. By
studying the behavior of these ice structures,
Haji-Akbari analyzed how likely they were to
form under various conditions. Specifically,
he observed that the vapor-liquid interface
in thin films of water promotes the formation
of double-diamond cages. Haji-Akbari’s findings
answer longstanding questions about ice
formation near surfaces.
In order to carry out his study, Haji-Akbari
used computational techniques to simulate
molecular behavior, which involves
generating models to predict events on a microscopic
scale in a way that wouldn’t be possible
through traditional physical experimentation.
One technique used was forward flux
sampling, which maps out the pathway that a
system takes during the occurrence of a rare
event, such as ice and snow formation.
“These are phenomena that occur very
quickly, but you have to wait a very long time
for them to occur,” Haji-Akbari said. “You can
think of, for example, a power outage. You have
to wait a long time for it to happen, but when
it happens it happens in a matter of seconds.”
Haji-Akbari studies how a system transitions
from the pre-rare event to the post-rare event
state, such as when ice forms in clouds.
Haji-Akbari is now pursuing several other
research questions that build on his past findings.
He is interested in a phenomenon called
contact freezing, in which a collision between
a liquid droplet and a dry nucleating particle
causes freezing. The question is whether
the mechanical impact of the collision causes
freezing, or whether this is due to an interaction
between the solid-liquid and liquid-vapor
interface. Additionally, Haji-Akbari is studying
how new computational methods could better
predict the waiting time required for rare
events such as ice formation to occur.
This research has many applications not
only in understanding and predicting climate
patterns but also in potentially developing
strategies to address climate-related
issues. For instance, cloud seeding is a
technique already used in many parts of the
ABOUT THE AUTHOR
world to induce rain. In cloud seeding, crystals
such as salts are dispersed into clouds in
order to provide additional nuclei for droplet
condensation. Haji-Akbari’s research focuses
on a related process, liquid droplets
nucleating to form ice crystals. He hopes
that research such as his will improve on the
efficiency and safety of techniques to modify
the weather, for instance to induce or prevent
snow and ice formation.
Haji-Akbari pointed out climate patterns
around the world that have recently been
disrupted by climate change, noting examples
of drought in several countries. To him,
asking and trying to address scientific questions
about atmospheric dynamics can lead
to a better understanding of our environment
and even the ability to change the climate.
“These are problems that are not only
theoretically interesting, but also useful for
the challenges that our society and our species
face in the world,” Haji-Akbari said.
CHRISTINE XU
CHRISTINE XU is a senior in Saybrook College. She has been writing for Yale Scientific Magazine
since her freshman year and was the previous News Editor. She enjoys both nonfiction and
creative writing, and also does neurobiology research at the Yale School of Medicine. In the future,
she hopes to pursue a career in medicine, research, and writing, and importantly would like to
own a cat.
THE AUTHOR WOULD LIKE TO THANK Dr. Haji Akbari for both his time and his enthusiasm in
sharing his work.
FURTHER READING
Haji-Akbari, Amir, and Pablo G. Debenedetti. “Direct calculation of ice homogeneous nucleation rate
for a molecular model of water.” Proceedings of the National Academy of Sciences 112, no. 34 (2015):
10582-0588. doi:10.1073/pnas.1509267112.
Haji-Akbari, Amir, and Pablo G. Debenedetti. “Computational investigation of surface freezing in a
molecular model of water.” Proceedings of the National Academy of Sciences 114, no. 13 (2017): 3316-
321. doi:10.1073/pnas.1620999114.
www.yalescientific.org
March 2018
Yale Scientific Magazine
19

FOCUS
neuroscience
BRAVING
THE COLD
A genetic adaptation makes certain
squirrels and hamsters immune to the cold
by Elizabeth Ruddy
art by Emma Wilson
You step outside of your building,
bundled up in four different layers and
a marshmallow coat. Buried beneath
scarves, hats, and gloves, it’s still not
enough to keep the cold out. Your face
stings from the biting wind, and you
can feel icicles forming on your nose.
There’s snow melting in your boots and
you’ve long since lost the ability to feel
your hands. You feel like you’ll never be
warm again. While we may cower in the
face of cold weather, for some animals,
the cold is no big deal. In fact, they don’t
even feel it.
A team of researchers at Yale led by Elena
Gracheva and Sviatoslav Bagriantsev
are currently investigating a molecular adaptation
in the Syrian hamster and a species
of squirrel native to North America,
called the thirteen-lined ground squirrel,
that enables them to endure harsh winters.
The body temperatures of these rodents
adjust to match the air around them,
enabling them to hibernate for months in
temperatures just above freezing without
noticing the gruelling winter.
Bring on the cold
The root cause of this ability comes down
to genetics. “Being sensitive to the cold
would prevent the rodents from hibernating,
much like how being cold would
prevent us from sleeping,” Gracheva said.
Therefore, there must be some quirk in
their DNA that allows them to withstand
the extreme cold for such extended periods
of time.
In behavioral studies performed on the
rodents, the researchers found that when
While we may cower in
the face of cold weather,
for some animals, the
cold is no big deal. In
fact, they don’t even feel
it.
given the choice between two plates of
different temperatures, the squirrels and
the hamsters did not avoid the cold as
strongly as mice did. This suggests that
there are genetic differences among rodents
that allow some species to endure
the cold but not others. This diminished
sensitivity to the cold could be
caused by a number of different factors
such as a reduced ability to perceive cold
in the nerves responsible for registering
temperature, known as somatosensory
nerves, or a suppression of the instinct to
avoid cold in the central nervous system
of certain rodents.
A cold-sensing protein
In a study published in Cell Reports,
Gracheva and her colleagues found that by
imaging the somatosensory neurons of the
rodents, they were able to isolate the adaptation
to a specific protein called TRPM8.
TRPM8 is an ion channel, which is a type
of protein found in a cell’s membrane that
allows specific charged atoms or molecules
to pass through. Many ion channels open
and close in response to certain stimuli in
order change the electric potential of the
cellular membrane, and thus are particularly
important in allowing nerve cells to
relay electrical signals to the brain. Specifically,
TRPM8 is a cold-activated ion channel—when
the temperature decreases, this
channel opens and excites neurons, leading
to generation of electrical signals that
are transmitted throughout the rodents’
nervous system. “The neuron then sends
electric impulses to signal to the brain that
20 Yale Scientific Magazine March 2018 www.yalescientific.org

neuroscience
FOCUS
cold temperature has been encountered,”
Bagriantsev said.
Something different in the TRPM8 of
the thirteen-lined ground squirrels and
Syrian hamsters makes the protein insensitive
to the cold. Upon isolating the protein,
the researchers were able to identify
the adaptation in a specific group of six
amino acids, the building blocks of proteins,
that are the difference between cold
sensitive and cold insensitive organisms.
Although the scientists do not know exactly
when the hibernators developed this
adaptation evolutionarily, they do know
that the squirrels and the hamsters developed
it independently. “They use different
structural elements at the molecular
level but arrive at the same end product,
which is cold-insensitive ion channels,”
Gracheva said.
Because the adaptations were developed
independently, there are slight differences
in temperature reactions between the
two species. Specifically, hamsters are
slightly more sensitive to the cold than
the squirrels. However, when compared
to species without the adaptation, such as
the mice, these differences are negligible.
In a previous report published by the lab,
researchers found that the thirteen-lined
ground squirrel is also extremely resistant
to heat, enabling it to survive in harsh climates
such as deserts, though this ability
stems from an adaptation in a protein
other than TRPM8.
Next steps
IMAGE COURTESY OF WIKIPEDIA
The Syrian hamster has also demonstrated a
marked tolerance for the cold.
Now that the exact adaptation has been
located, the researchers are working
to reintroduce cold sensitivity into the
TRPM8 of the squirrels and hamsters by
substituting their key amino acids for the
ones found in the mice. The researchers
are also attempting the opposite—inserting
genetic substitutions into the mice to
see if they can become cold-insensitive.
Through this research, the team has taken
significant steps towards a better understanding
of the hibernation puzzle. Scientists
still do not fully understand what
induces hibernation among certain species
and how it is possible biologically. For
example, little is understood about what
causes heart rates to slow down, how these
species go months without consuming nutrients
or water, or how the animals do not
lose bone mass during this time of inactivity.
TRPM8 is one piece to the puzzle. The
genetic adaptation explains how certain
hibernating species can sleep through
extremely cold temperatures. However,
it is not that TRPM8 becomes cold-insensitive
specifically for the hibernation
period. Rather, the adaptation is encoded
in their DNA such that they have this
cold-insensitivity from birth. “We still
don’t know everything about what causes
hibernation,” Gracheva said. “It’s possible
that certain genes do turn on when
the rodents enter this state but TRPM8 is
not specifically related to hibernation. It
is cold-insensitive all the time.”
In addition to studying hibernation,
the group also plans to investigate whether
cold-insensitive rodents can adapt to
temperatures below ten degrees Celsius.
The group’s goal is to the test the limit of
the animals’ tolerance, as well as to try to
understand how these animals ward off
hypothermia.
Potential human applications
Don’t put away your jackets yet though,
because even though the researchers are
ABOUT THE AUTHOR
IMAGE COURTESY OF ELENA GRACHEVA
Graphical abstract of the difference between
the cold-insensitive rodents and the control
group of mice.
working on replicating the cold-insensitivity
in mice, there’s a long way to go before
we could even think about substituting
the adaptation into humans.
But there are other ways this research
applies to humans—specifically in the
field of medicine. For example, one major
detriment to chemotherapy is that patients
often develop an extreme aversion
to even mild cold. It is possible that this
research could be used to minimize these
effects and help patients be able to better
tolerate the cold.
“This study furthers our understanding
of how vertebrates, including humans,
feel cold. It will help develop
approaches toward better organ preservation
and contribute to the development
of novel techniques for lowering
human body temperature, which is required
during some medical procedures
and may be useful for long-term space
travel,” Bagriantsev said.
So good luck tomorrow on your walk
through the bitter February cold. Just
remember to channel your inner thirteen-lined
ground squirrel.
ELIZABETH RUDDY
ELIZABETH RUDDY is a Sophomore Physics major in Berkeley. She enjoys dancing, writing for the
Yale Scientific, and hibernating.
THE AUTHOR WOULD LIKE TO THANK Professor Gracheva and Professor Bagriantsev for sharing
their time for this article.
FURTHER READING
Kimzey, S. L. “Temperature Adaptation of Active Sodium-Potassium Transport and of Passive Permeability
in Erythrocytes of Ground Squirrels.” The Journal of General Physiology, vol. 58, no. 6, 1971, pp. 634–
649., doi:10.1085/jgp.58.6.634.
www.yalescientific.org
March 2018
Yale Scientific Magazine
21

FOCUS
evolutionary biology
DIVERGENCE
The Molecular and Cellular Basis of the Human Brain Evolution
by Anna Sun || art by Emma Healy
Millions of years have passed since humans parted ways with our closest nonhuman
primates on the evolutionary pathway. During this time, humans have developed
languages and writing skills, harnessed fire and begun cooking, created
innovative technologies that now govern our daily lives, and even studied how life itself
works. So why have no other nonhuman primates ever rivaled our level of cognitive ability?
In hopes of answering that very question,
much debate among scientists today
centers around the differences between
the brain structures of humans and nonhuman
primates. While some argue that
the larger size of the human brain alone
is responsible for higher-order thinking,
others insist that there is more to the story.
Perhaps in addition to increased size,
the connections between cells and the
different cells themselves provide a better
explanation. André Sousa and Ying
Zhu, researchers at the Yale School of
Medicine, analyzed tissue samples from
sixteen regions of the brain to further investigate
the cellular and molecular differences
between human and nonhuman
primate brains. Examining individual
gene expression differences in the brains
of chimpanzees, macaques, and humans,
these researchers discovered human-specific
differences in the expression of the
TH gene responsible for dopamine production
and the MET gene that is related
to Autism Spectrum Disorder, gaining
insight into the basis of certain neurological
and psychiatric disorders.
Our closest relatives
In order to determine human-specific
differences in the brain structures, the
researchers chose to study chimpanzees,
our closest living relative, as well
as the rhesus macaque, one of the most
commonly studied nonhuman primates.
“Ideally, the easiest way to study human
brain evolution would be to analyze
the brains of all extinct human species,”
Sousa remarked. However, since
the brain does not fossilize, he and his
colleagues instead had to compare the
human brain with the brains of our closest
living relatives to determine which
features are most likely human-specific.
For ethical reasons, they could only use
postmortem tissue for direct molecular
experimentation.
The researchers particularly analyzed
the upregulation or downregulation of
22 Yale Scientific Magazine March 2018 www.yalescientific.org

evolutionary biology
FOCUS
genes, to correspondingly compare increased
or decreased gene expressions
in different parts of the brain in the
different species studied. “What drives
these differences in gene expression are
often changes in regulatory non-coding
regions,” explains Sousa. “Additionally,
mutations in non-coding regions of
DNA don’t change the protein product,
but rather change when, where, and how
much is produced.”
Because humans and chimpanzees diverged
from a common ancestor more
recently than they did from macaques,
the researchers were able to use these
three branches of a much more extensive
evolutionary tree in order to narrow
down the origins of a modified
gene. For example, if a specific gene
appeared to be upregulated in humans
but downregulated in both chimpanzees
and macaques, then this would indicate
a human-specific change. Similarly, if
a gene was upregulated in humans and
macaques, but downregulated in chimpanzees,
then this would demonstrate a
chimpanzee-specific change. This gene
regulation would then correspond to an
increase or decrease in the production of
proteins in cells and thus a change in the
trait, or phenotype, displayed by each
species.
A glance at brain structure
The human brain is about three times
larger than the chimpanzee brain. The
primary assumption is that a bigger
brain should be able to hold more information
and form more complex circuits
between nerve cells. “We believe
that instead of one big change in brain
structure that accounts for a lot of differences,
there are actually many small but
distinct differences in human brains that
“
This image shows the molecular characterization of TH+ cells.
Instead of one big change in brain
structure that accounts for a lot
of differences, there are actually
many small but distinct differences
in human brains that add
together to make big differences.
www.yalescientific.org
”
- André Sousa
add together to make big differences, for
example, in cognition,” Sousa said.
Uncertain of where they would find
the most differences in the brains of the
three species, the researchers approached
this study without a main brain region of
interest. Because the neocortex is known
predominantly for its role in higher cognitive
function, they hypothesized that
the greatest number of differences across
the species would be located in this region.
Their data demonstrated that, as
expected, most genes were similar and
therefore conserved among humans,
chimpanzees, and macaques. However,
the most interspecies differences in
changes in gene expression were actually
discovered not in the neocortex but in
the striatum, a region of the brain primarily
involved in voluntary movement,
planning, and reward. “This is likely because
it is a transition station between
the neocortex and other regions of the
brain, so changes in this region may also
lead to changes in the neocortex,” Zhu
reasoned.
The key is in dopamine
IMAGE COURTESY OF ANDRE MIGUEL SOUSA
All primates have dopamine, a crucial
neurotransmitter responsible for motor
control and emotional responses. The
researchers discovered that the TH gene,
responsible for the production of dopamine,
was more expressed in the human
striatum than in the striata of chimpanzees
and macaques, which indicates that
humans most likely have more dopamine
in the striatum than in the other
species studied. “There are two possible
explanations for this observation,” Sousa
said. “First—there are exactly the same
number of TH cells among the three species,
but each human cell is producing
considerably more dopamine; or second—humans
have more TH cells than
chimpanzees and macaques.” Because
these comparisons were made at the
tissue level, the researchers performed
cellular-level analysis and were able to
conclude that the latter case was true:
humans have more TH cells in the striatum
than the other two species. In fact,
chimpanzees and the other non-human
African great apes (bonobos and gorilas)
March 2018
Yale Scientific Magazine
23

FOCUS
evolutionary biology
have no TH cells at all in the neocortex.
All primate species have dopamine production
centralized in specialized structures
of the midbrain. However, it is a
novel discovery that humans likely have
another localized production of dopamine
in the neocortex. “This is important
because it is the first time we showed
that cells in the neocortex are also able to
produce dopamine,” Sousa said.
Additionally, since TH was expressed
less in the neocortex of both chimpanzees
and gorillas, this suggests that the
expression of the gene was absent in the
most recent common ancestor of the African
great apes and reappeared in humans
somewhere recent along the evolutionary
timeline.
Dopamine’s involvement in motor
control, learning and memory, and the
reward system therefore holds great relevance
to human evolution and even
modern neurological diseases. For example,
Parkinson’s disease, a neurodegenerative
disorder that particularly affects
movement, is caused by a lack of dopamine
from the death of dopamine producing
cells. “This loss of cells may also
be related to some form of intellectual
impairment, but this is purely hypothesized
right now,” Zhu commented.
Still unraveling the mystery
In addition to the TH gene, this study
found small but distinct differences in
other genes, including MET and ZP2.
Specifically, the MET gene, which is associated
with autism spectrum disorder,
was enriched only in the human prefrontal
cortex, an area of the brain related to
very high cognitive functions. A potential
area of research would involve studying
whether this increase in MET levels
in the prefrontal cortex makes humans
more susceptible to autism.
As for the ZP2, this gene was found only
in the human brain and not in chimpanzees
or macaques. “What’s most surprising
about this gene is its location,” Sousa said.
This gene, which has been studied extensively
in the context of the reproductive
system, is crucial for the recognition and
mediation of the sperm in the egg. Future
research could also be directed at studying
this particular gene in order to figure out
what it is also doing in the brain and how
Human TH+ interneurons synthesize and transport dopamine.
it got there. With the discoveries of this
study in mind, researchers could examine
these specific genes to gain clearer insight
into the genetic and molecular changes in
evolution of the human brain.
Future direction
“We believe that there is a cumulative
effect of all of these small changes we
found that helps explain the evolution
of the human brain and differentiate it
between the brains of nonhuman primates,”
Sousa said. Human-specific differences
have huge implications for the
onset of neurological diseases, such as
Parkinson’s disease, in which a depletion
of TH + cells in the neocortex could be
detrimental to cognitive function. Additionally,
this study focused solely on
adult brains among the three species, but
ABOUT THE AUTHOR
IMAGE COURTESY OF ANDRE MIGUEL SOUSA
the researchers are interested in expanding
their research to cover other human
developmental stages in hopes of learning
about the differences in how brains
change over time.
A possible addition to future research
would be to include a more extensive
comparison including many more species.
The interspecies comparisons between
humans, chimpanzees, and macaques
in this study already demonstrate
substantial differences between humans
and our closest nonhuman primates,
which could then possibly affect the way
we employ animal models to study human
disorders or develop pharmaceutical
drugs. “Although we have made a
big step towards understanding cellular
and molecular distinctions in the human
brain, there is still much work to do,”
both researchers conclude.
ANNA SUN
ANNA SUN is a prospective Molecular, Cellular and Developmental Biology major in Pierson
College ‘21. She is very interested in bioinformatics and plans to spend this summer in a
laboratory conducting genetics research. In addition to writing for the Yale Scientific Magazine,
she is involved in the MCDB Student Advisory Committee at Yale and loves to spend time with her
friends discovering the food scene in New Haven.
THE AUTHOR WOULD LIKE TO THANK Dr. Sousa and Dr. Zhu for sharing their time and enthusiasm
about their research.
FURTHER READING
Enard, Wolfgang. “The Molecular Basis of Human Brain Evolution.” Current Biology, 24 Oct. 2016,
doi:10.1016/j.cub.2016.09.030.
24 Yale Scientific Magazine March 2018 www.yalescientific.org

FEATURE biomedical engineering
BY ANTONIO MEDINA
PRINTING OUT THE MIND
Bioprinting 3-D organs with soft, tissue-like materials
IMAGE COURTESY OF ZHENGCHU TAN
The second harmonic microscope onstructed by the researchers
used here to image a glass capillary.
Cars, toys, knick-knacks and prototypes—the array of objects
that can be brought to life with a 3D printer is vast and
growing. 3D printers are getting more impressive, capable of
making anything from usable engine parts to full-scale houses.
Now, an even greater goal is within reach: printing the brain.
3D printing technology has recently made significant breakthroughs
in diverse fields, including medicine, engineering,
and design. We live in a world where a technician can print a
prototype of an invention in just a few hours. The ability to create
a 3-D object, one that models the intricacies of a physical
system that was once only imaginable on a computer screen,
has opened the doors to hundreds of applications, particularly
in the field of biomedical engineering. These ambitions are
coming to fruition thanks to the work done by researchers at
Imperial College London, whose novel 3D printing process
creates material that can closely model the human brain.
Models of the human body made by 3D printing have been
around for the past 20 years. For example, Yale researchers at
the Center for Engineering Innovation and Design successfully
printed a large-scale model of a neuron in 2015. Academically,
this provides a new “dimension” to the way students and neuroscientists
can observe and study the human neural system. Bioprinting
takes this technology one step further. 3D bioprinting
uses the same techniques as a standard printer, which ejects material
to construct precisely mapped layers, but uses a combination
of cells and hydrogels as its material instead.
Bioprinting technology has already made waves in drug
testing, regenerative medicine, and even surgical tissue transplants.
The challenge of using these printers with real people,
however, is that whatever is produced often cannot accurately
represent an actual human organ; the product might be too
stiff or too dense, or it might misbehave when placed in the
same conditions as the organ it is modeled after.
Fortunately, cryogenic freezing is a promising solution: a
team of researchers at Imperial College London has developed
an innovative modification to standard bioprinting in which
a solution of a composite hydrogel (CH) is frozen rapidly to
produce material that is as soft as the tissue in the brain or
lung. The procedure uses precision technology to accomplish
a process known as rapid cooling. When a liquid material is
cooled below its freezing point, it transitions into a solid. The
final product is much harder than the liquid, in the way water
is much “softer” than ice. Controlled cooling slows down
the moving molecules of a liquid until they can’t move around.
These molecules try to arrange themselves in the most tightly
packed way possible so that when the material freezes, it is
stiff. This rearrangement of molecules takes some time, so if
one can rapidly freeze a material, the final product will be a
much softer, more flexible solid because the molecules didn’t
have time to pack optimally.
Using this principle, the new cryogenic bioprinting procedure
uses dry ice to rapidly freeze the CH ink solution as it
extrudes layer by layer. The result, according to Zhengchu Tan,
the postgraduate researcher spearheading the procedure, is
something that now enables the creation of arrangements that
match complicated biological structures, such as the tissue in
the brain. The innovative procedure provides an alternative to
cast molding organ replicas, where the hydrogel is poured into
a mold. “That’s how they’re normally made, but you can’t get
complex geometries like that—hollow geometries,” Tan said.
By using a 3D printer, one can now create the complex interiors
of distinct shapes and textures, not just the exteriors.
Another significant consequence of the cryogenic freezing
method is that the printed tissue behaves similarly to the brain
in the appropriate environment. “The resulting material structure
is as soft as the brain, so while it does hold its shape, the
brain is also deformed under gravity, and that’s a massive issue
during neurosurgeries,” Tan said. Their bioprinted tissue successfully
models this behavior. When hydrated and kept in the
same conditions as the brain, the material is also able to keep
its shape or deform as necessary.
Tan’s research paves the way for enormous opportunities in
medical research. It may soon be possible that 3D printed organs
can replace live subjects for drug testing or risky surgical
practices. Day by day, layer by layer, bioprinting technology
overcomes challenges in innovative ways. With each advancement,
more medical dreams become reality as we print our
way to a better future.
25 Yale Scientific Magazine March 2018 www.yalescientific.org

FEATURE environmental science
IT’S GETTING HOT IN HERE
Global warming takes its toll on sea turtles
BY ISAAC WENDLER
Sea turtles are the latest species affected by the rising
temperatures characteristic of global warming. Researchers
at the National Oceanic and Atmospheric
Administration (NOAA) fisheries have shown that the
rising ocean temperatures caused by global warming are
resulting in a greater number of newborn female sea turtles
than males.
Sea turtles, like many reptiles and fish, undergo temperature-dependent
sex determination (TSD). In organisms
affected by TSD, the sex of a member of the species
is determined by the temperature of the embryo
during development. Sea turtles nest on the beach, so
in this case, the increasing heat of the sand is directly
responsible for an individual’s sex. In general, a higher
temperature is correlated with a higher percentage of female
individuals in a sea turtle population. This finding
is well-established in the field of ecology, but this study
marks the first time that the trend has been found in major
populations of wild sea turtles.
As both ocean temperatures and terrestrial sand temperatures
continue to rise on beaches across the Great
Barrier Reef, a greater number of sea turtle populations
are giving birth to generations of mostly-female offspring.
In fact, the percentage of female adult offspring
in some populations has been observed to be as high as
86.8 percent.
This imbalance can be bad news for the species, as
such high frequencies of females can lead to an overall
decrease in male fertility. In general, a population must
have a stable ratio of sexes in order to achieve an ecological
balance and, if this ratio is not achieved, the species
may eventually be driven toward extinction.
Although this news is troubling, especially for the ecosystems
in and around the Great Barrier Reef, this study
also marks the development of a novel method for studying
sea turtles, one that can be generalized to the study
of other species.
The conventional method of reviewing the sex frequency
of sea turtle populations was by anatomical examination
of a nest, which is far more impractical and
less revealing than the genetics-based method used in
this study.
The research team, led by Dr. Michael Jenson, makes
use of a combination of both endocrinology and genetic
markers on sea turtles they find in the water. These
markers can then be traced back to the specific nesting
location of the turtle, which can then show the conditions
of the nest, including temperature. With this approach,
the researchers are not forced to travel across
many different nest locations in order to examine the
turtles inside.
Although the status of the sea turtle population of the
Great Barrier Reef is likely not on most people’s minds, it
serves as an omen as to what may come if global warming
is not curbed. After all, these turtles are only one of
many species affected by the consistent warming of the
planet. This relentless force influences other groups as
well: polar bears, whose habitat is melting by the day;
coral, whose shells are weakening from the acidification
of the oceans; maybe even humans, whose sources of
food are dwindling as ecosystems around the world begin
to decay.
Dr. Mary Beth Decker, professor in the Yale Department
of Ecology and Evolutionary Biology, has some
sage advice for those who want to help the fight against
global warming. “Communicate with your state, federal,
and local representatives and encourage them to make
good policy decisions with respect to energy and climate.
You can also always talk with your friends and family
and encourage them to do the same,” Decker said.
IMAGE COURTESY OF WIKIMEDIA
The heat of the sand that sea turtles nest on is directly responsible
for their sex.
26 Yale Scientific Magazine March 2018 www.yalescientific.org

genetics
FEATURE
IMMUNE TO OUR FOOD
Fast food, slow recovery
BY LESLIE SIM
IMAGE COURTESY OF THE LATZ LAB
Dr. Latz and Dr. Christ of the Latz Lab at University of Bonn.
Our world is plastered with weight-loss advertisements.
For every McDonald’s commercial, there is another one
for Lean Cuisine or Weight Watchers. In America, obesity
and health have become national concerns, as over a
third of the adult population is obese—a record high. It
seems that unhealthy eating habits don’t just contribute
to obesity; they also have long-term consequences that
originate from our immune systems and DNA.
Our immune systems have a memory similar to that of
our muscles and brains. For example, our immune systems
are able to recognize pathogens such as the influenza
virus so that in the case of a second infection, we
know how to fight the infection. This evolutionary advantage
in humans allows us to ward off infections and
illnesses on the daily. Without our innate immune system’s
memory, we would die from the common cold.
The Latz lab at University of Bonn, in which postdoctoral
fellow Anette Christ has researched the immune
system, has delved into these health concerns with a scientific
mindset. By pairing a problem we see in society
with curiosities about the innate immune system and its
response to certain types of diets, the researchers discovered
that the immune system responds similarly to the
typical Western fast food diet—high in fat, high in sugar,
and low in fiber—as it does to pathogens and infections.
The experiment was performed on three groups of
mice: one was fed a standard healthy chow diet, a second
was fed a Western diet, and a third group was given
a Western fast food diet and then switched over to the
chow diet after a period of time. After performing genetic
analyses on the different groups’ bone marrow cells, the
Latz lab discovered the presence of signatures linked to
inflammation and immune cell differentiation called inflammasomes
that release inflammatory messengers in
the group of mice on a Western diet. Inflammasomes are
usually only triggered by bacterial infections in order to
keep the immune system ready for a subsequent infection.
These signatures were originally observed in the group
that had switched diets, but they later disappeared after
the mice were put onto chow diet. Although still curious
about how exactly these signatures recognize characteristics
of the Western fast food diet, the lab was surprised
to discover that the immune system may treat high-sugar,
high-fat foods the way it treats bacterial infections.
Furthermore, they found that the Western fast food
diet affects histone-packaging in the DNA, which means
certain portions of the DNA unwind to cause a change in
the expression of genetic material of the cell. These epigenetic
changes coupled with inflammation have been
shown to play a major role in the development of atherosclerosis,
diabetes, and heart disease in the mice. This
finding suggests that nutrition and diet choices can have
major consequences on our health.
The next step in this research is determining whether
it applies to humans. In the near future, Christ hopes to
conduct a clinical study in which healthy volunteers will
be exposed to different diets for several different time
periods. While this study will have more variables, she
believes that it will produce results similar to those of the
study she has already performed with the Latz lab.
As health gurus and health movements are on the rise,
we often find ourselves wondering which diets are the
best for us: vegan? vegetarian? A raw diet? The answer
is probably none of the above. “There is no ‘correct’ diet
out there for us,” Christ said. Everyone is different—due
to different food resources and traditional cuisines, people
from different races or geographical locations may
have varied intestinal environments and genetic makeups
that complicate the answer. It’s nonetheless important
for people to be informed about what types of foods
they should choose for themselves in an attempt to live
a healthy life. We are what we eat, and our immune systems
agree.
www.yalescientific.org
March 2018
Yale Scientific Magazine
27

DISEASE DOUBLE WHAMMY
Crohn’s disease and Parkinson’s disease are now linked by the LRRK2 gene
BY MARCUS SAK
ART BY ELISSA MARTIN
At the 2016 Summer
Olympics in Rio, seven years after
being diagnosed with Crohn’s disease (CD), Kathleen
Baker set a swimming world record and bagged two medals. It
was after she had just set two national swimming records for her
age group back in 2010. Diagnosed, but with no effective treatment,
she would suffer from stomach cramps, nausea, and whooping cough,
dividing her time between doctors’ offices and pool practice. Baker’s
story is even more remarkable considering that she will never be cured
of CD. She gives herself biweekly injections. Like Baker, the other
million or so CD patients worldwide, usually diagnosed in their
teenage years, fight similar battles—they try to keep alive their
dreams of going to college, getting married, and pursuing careers.
Judy Cho, MD, Professor of Medicine and Gastroenterology
at Mount Sinai, heads a research group that works to identify
the genetic bases of CD and related inflammatory diseases. The
researchers hope that understanding the complex network of
interdependent molecular processes in cells will lead to a cure.
CD is extremely challenging to treat and manage, but Cho finds
treating CD to be personally rewarding. “CD is my favorite disease
to treat, because I wound up treating a lot of young adults
with whom I could make a big difference,” Cho said.
One big step towards a better understanding of CD was
recently taken in a study led by Cho and Inga Peter, Professor
of Genetics and Genomic Sciences at Mount Sinai.
This four-year-long study, involving 51 collaborators from
26 institutions, identified mutations in the LRRK2 gene
(pronounced “lurk-two”) strongly associated with CD. Since
LRRK2 has long been known to be the major genetic cause for

the neurodegenerative disorder Parkinson’s disease (PD), this study
provides a direct link between seemingly unrelated CD and PD and
hints at a common molecular basis for both diseases.
From its inception, this genetic study was unusual—the researchers
did not start with a hypothesis. Like any other disease, they knew
that certain variants in the genetic code were responsible for CD.
As such, they began by screening hundreds of thousands of possible
gene variants in order to compare the genes of CD patients with those
of healthy subjects. This initial comparison was done on 5,699 Ashkenazi
Jewish patients, since CD is more common in this population.
The researchers succeeded in identifying two categories of mutations:
risk mutations, which were more likely to be found in CD
patients, and protective mutations, which were more common in
healthy subjects. The mutations were determined to lie within the
LRRK2 gene, which was implicated in cellular processes central to
CD. The strong association between LRRK2 and PD raised many
questions, and it gave the project a direction.
To establish a proper link between CD and PD, the researchers
focused on individual mutations and expanded their screening to
include 24,570 CD and PD cases plus healthy controls. Ultimately, the
individual variants associated with CD were also strongly linked to
PD; furthermore, they correlated in the same direction—risk variants
for CD were also risk variants for PD, and vice versa. This suggested a
similar genetic architecture underlying the two diseases.
At this point, a problem arose. Mutations in LRRK2 are inherited
together with those in its gene neighbors, so association signals were
also being detected from its neighboring regions. To prove that it was
LRRK2 responsible for CD and not a neighboring gene, the researchers
turned to computational biology. They constructed a model of all
gene-gene interactions in the intestine, and then stripped it down to
the essential CD genes, intentionally excluding the genes known to
be involved in PD, including LRRK2. They then ran a simulation of
CD, knowing that only the genes required for CD would be pulled
back into their system. LRRK2 was the only gene in its neighborhood
that came up.
Up to this point, the researchers had been working based on statistical
evidence alone. Now came the most challenging part: to determine
whether the identified LRRK2 variants indeed led to biological
effects. Peter and her coworkers recalled CD carriers registered with
Mount Sinai Medical Center, from whom they obtained blood for
biological testing. “For a genetic epidemiologist, functional studies
are the most frustrating because you have no control over the data,”
Peter said. The risk variant worked—in functional studies, cells that
carried this variant exhibited traits characteristic of experimental
models of CD and PD. Unexpectedly, there was no indication that
the most strongly correlated protective variant had any functional
significance. The researchers had seemingly wasted a whole year of
collecting and testing blood samples.
Peter and her coworkers quickly moved on to the second most
promising neighboring protective variant; testing revealed that it
was the variant actually responsible for CD. Interestingly, all people
who were recalled for additional blood draws had both protective
variants, which explained why the statistical evidence alone was misleading.
This costly detour lays out an important lesson in genetic
studies. “In this type of analysis, statistical significance is not everything,”
Peter said. Often, statistics cannot account for the complexity
of biological processes.
Having confirmed the effects of the mutations on human cells,
medicine
FEATURE
the researchers moved on to the clinical scale, where they examined
the effects of LRRK2 mutations on the disease course. They
found that the risk mutation led to CD onset at a younger age, so
Peter wants to include LRRK2 mutations as markers during genetic
screening, which would allow clinicians to determine whether a
patient is susceptible to CD early on.
For Peter, incorporating LRRK2 in genetic screening is just a first
step. The discovery that the risk mutation leads to an overactive
LRRK2 protein implies that drugs could be developed to inhibit
LRRK2 and, thus, treat CD. Many PD studies have shown encouraging
results. In one study, LRRK2 inhibitors were found to rescue brain
cell degeneration in mice. In trying to reverse PD, however, the inhibitors
also had unforeseen effects on other cells that use LRRK2. More
research is needed on this cell type-specific targeting. The protective
variant is a promising candidate, as it reflects the natural biochemical
pathways that cells evolved to protect themselves against CD.
IMAGE COURTESY OF WIKIMEDIA COMMONS
Crohn’s disease intestinal cells, which are responsible for the inflammation,
observed under microscope.
Regardless of whether a drug can be developed, this study has
far-reaching implications for PD treatment. PD is notoriously hard
to treat because it does not show symptoms until years after its onset,
at which point treatment is no longer effective. As CD has an earlier
age of onset, clinicians can use the identified LRRK2 mutations to
determine which CD patients are at high risk of PD and administer
preventative measures.
Ultimately, the discoveries made use of a multipronged treatment
of mountains of data, including computational biology, statistical
analysis, as well as clinical and functional studies. “No one sophisticated
bioinformatics approach will allow you to get to the bottom of
the problem,” Peter said. She believes that this study demonstrates an
important research strategy: attack the problem from as many angles
as possible, and then confirm, confirm, and reconfirm the findings.
CD is still far from curable. Based on the findings in this study,
Peter and her coworkers are examining the effect of LRRK2 inhibitors
on reversing colon inflammation in mice. This push is driven by
the promise of genetics in answering many biological problems. “I
think we’re going to enter a golden age of medicine, where instead
of being a descriptive science, medicine is going to be a molecular
science,” Cho said.
www.yalescientific.org
March 2018
Yale Scientific Magazine
29

BIG BANG GIVE
ME A TWIRL
by Urmila Chadayammuri
art by Jason Yang
Radio telescopes reveal surprisingly neat rotation
in extremely young galaxies
“We are made of star stuff.” These timeless words from astrophysicist
and space evangelist Carl Sagan are more than poetic rhetoric. The carbon,
nitrogen, oxygen and silicon—so central to life on earth—and the
iron in our blood are all produced when hydrogen fuses into heavier
elements in the cores of massive stars. The nuclear fusion process is
what powers these stars to light up our sky. As the stars age and die, they
release these elements into the gas around them, which will eventually
form planets, sometimes populated by sentient organisms that build
telescopes to peer back out into where they came from.
A team led by Renske Smit, a postdoctoral fellow at Cambridge University,
recently measured the star-forming gas in two galaxies that sent
us light when the Universe was just one seventh of its current size. This
means that any photon—a packet of light—that left a source at that time
would, therefore, have its wavelength stretched out, or made redder on
the electromagnetic spectrum, by this same factor. Astronomers say the
galaxies are at “redshifts” of 6.8. In effect, we are seeing these galaxies as
they were when the Universe was just 800 million years old.
Using the Atacama Large Millimeter Array (ALMA), a collection of
radio telescopes in the high, dry Chilean desert, Smit looked for the light
emitted by carbon atoms. When a carbon atom collides with another
particle, the energy of that collision can kick one of the outer electrons of
the carbon to a higher energy level, which is called collisional excitation.
But electrons like to stay in the lowest energy states available, so it will
soon jump back down. In the process, it releases a photon of wavelength
157.7 micrometers, which matches the energy difference between those
two electron levels.
Quantum mechanics dictates that an atom will always emit a photon
of exactly the same wavelength for a given electron transition. However,
30 Yale Scientific Magazine March 2018 www.yalescientific.org

astronomy
FEATURE
IMAGE COURTESY OF WIKIMEDIA COMMONS
The James Webb Space Telescope is a space telescope developed in
coordination with NASA.
if the atom is moving away from us, this wavelength will get longer and
redder; if it is moving towards us, the light gets shorter and bluer. This
is known as the Doppler effect; most of us experience the aural version
of it every time an ambulance drives past, its siren getting shriller as it
approaches and then dropping as it drives away.
Since the Universe is expanding away from us, light coming from
its most distant sources is red-shifted. Smit explains that the brightest
emission in the most distant galaxies, which has optical wavelengths in
a lab, becomes redshifted into the mid-infrared. In her PhD thesis at
the Leiden observatory in the Netherlands, Smit used the infrared space
telescope, Spitzer, to measure redshifts precisely for a very large sample
of galaxies. The CII line, with a wavelength of 157.7 micrometers, is
already in the infrared, but it gets further redshifted into longer radio
waves. This is exactly what ALMA can detect.
“Getting time on ALMA is hard,” said Pascal Oesch, former postdoctoral
fellow at Yale and now assistant professor at the University of
Geneva, a co-author on the paper. The entire array of telescopes must be
reconfigured every time a researcher wants to look at a different range
of wavelengths. “You really have to know the redshifts and locations of
the targets, and Renske constrained those tightly with her Spitzer observations,”
Oesch said.
Now picture a disk of swirling gas, moving clockwise. Rotate the disk
so you’re viewing it from the side. Gas to the right half of the disk will
appear to be moving towards you, and on the left it’ll be moving away
from you. If there were carbon atoms emitting photons at exactly 158
micrometers everywhere in the disk, you’d think the light from the right
side of the disk actually had a wavelength shorter and bluer than that,
and that from the left larger and redder. Now think of two coins sitting
on this disk, at different distances from the center. As the disk rotates, the
coin farther from the center moves a longer total distance than the one
closer in. In other words, the velocity of the disk is greater at larger radii.
So the 157.7 micrometer line is redshifted increasingly more the further
left you look from the center, and blueshifted more the further you look
right. The line gets broadened into a bell shaped curve, the width of
which tells you how fast the gas in the disk is rotating.
Current simulations of galaxy formation in the early Universe show
these galaxies colliding with their neighbors often in what are called mergers.
These mergers disrupt the formation of any disks, and tend to leave
IMAGE COURTESY OF WIKIMEDIA COMMONS
The Atacama Large Millimeter Array (ALMA) is a collection of radio
telescopes in the Chile, five kilometers (sixteen thousand feet) above sea
level. Since light from a single source in the sky lands at slightly different
points on each telescope, the images can be combined using a technique
called interferometry to get extremely high resolution. Together, the
telescopes can see fainter objects than any one of them could on its own.
Source: The European Space Organization.
behind gas clumps with lots of star formation in the center. “We expected
the carbon emission to be pretty concentrated,” Smit said. Therefore, she
only expected to see lines from the center of the rotating disk. Instead, the
line-emission was extended enough that she could measure the velocity
variations across the galaxy. “The fact that we could actually see the rotation
meant that CII emission was more spread out,” Smit said.
That was not the only surprise. The CII line emission is only generated
if the carbon undergoes a lot of collisions, usually with electrons coming
from dust. “We see the carbon line but we don’t see any dust, and that is
a puzzle we haven’t solved yet,” Smit said.
Oesch doesn’t think it’s that surprising to find so little dust in these galaxies:
dust is released during a relatively late stage in a galaxies’ evolution,
and since they are still so young, the stars simply may not have reached
this phase of their lives. Further, he says, they may not have found
dust because they were looking for a very specific kind. “You have to
make assumptions of the temperature of the dust to predict how much
emission you would see,” said Oesch. It is just another example of how
carefully astronomers have to design their experiments to encompass all
of the components of a galaxy that they’re interested in.
Astronomers are also very careful about making inferences from
small samples. Smit is excited about the upcoming James Webb Space
Telescope, which will detect hundreds or even thousands of galaxies
at these high redshifts. James Webb will have an IFU, or Integral Field
Unit, a device that takes a spectrum on every pixel of the camera.
“We’ll at least be able to get low resolution but large samples,” she said.
Smit already has time on ALMA to look at six more galaxies, which
will help us build a picture of how common galaxy disks really are in the
early Universe. She is also preparing to observe one of these galaxies at
a much higher resolution. “We’ll be able to see how organized the disk
is, or if its messier than we thought. It’ll tell us about the physics of at
least one disk in much more detail,” Oesch said. She emphasizes that
this really a new frontier of observation. “Maybe it’s not a single disk—
maybe it’s multiple clumps merging! We really haven’t been able to do
any of this before.”
www.yalescientific.org
March 2018
Yale Scientific Magazine
31

FEATURE biomedical engineering
Defeating
Diabetes
Advances in Cell Encapsulation
Technology
By EMMA HEALY
Art by ANUSHA BISHOP
A young boy is rushed into the Emergency Department after
being discovered unconscious. He’s with his mother, who reports
that earlier that evening, her son had been thirsty, nauseous, and
urinating frequently. He’s now gasping for air, and his breath smells
fruity and sweet, like a sugary pear candy. It’s the smell of ketone
bodies, molecules produced by the liver that cells use as fuel, and
their presence is indicative of ketoacidosis—a dangerous complication
of diabetes. Ketone bodies are acidic, so as they accumulate,
the blood’s pH drops, leading to hyperventilation, nausea, and, in
extreme cases, severe neurological and cardiac complications.
Given his symptoms, the boy likely suffers from type 1 diabetes,
an autoimmune disease in which the patient’s immune system
destroys islet cells in his pancreas. These cells are responsible for
producing insulin, a hormone that helps your body absorb glucose
from the bloodstream. Without sufficient insulin, blood sugar levels
increase and contribute to disease. Diabetic ketoacidosis is a
rapid-onset complication of type 1 diabetes that occurs because
glucose is trapped in the bloodstream, so cells need an alternative
source of energy—the ketone bodies—to keep functioning.
Diabetes treatments focus on maintaining normal insulin levels
with daily injections, which sound easier than they are. These insulin
injections can be uncomfortable, and remembering to keep
to a schedule can be stressful and tiring. Furthermore, figuring out
correct doses can be challenging, as these injections serve multiple
purposes: patients must inject to maintain background levels of insulin,
prepare for meals, and correct high blood sugar. Complicating
the issue, different insulin products act on different time scales,
and each person’s insulin sensitivity is unique. There is always the
risk of overdose, especially after a missed meal, which could lower
blood sugar beyond safe levels. For these reasons, researchers at
Cornell University are improving designs on an alternative treatment
for type 1 diabetes: cell transplantation. “Instead of delivering
insulin through injection, we are trying to develop a technology to
deliver cells, which can sense the glucose concentration and secrete
insulin autonomously,” said Duo An, the PhD candidate at Cornell
who led the research.
As with any transplant procedure, islet cell transplantation has
risks. Since the cells are foreign to the host, the body recognizes
them as invaders and launches an immune response. To prevent
transplant rejection, patients must take immunosuppressive medications
for the remainder of their lives, decreasing their ability to
fight infectious diseases. Despite its dangers, immunosuppression
is often a necessity unless the transplanted cells can be protected
against the host’s immune system, as Cornell’s team is trying to do
with cell encapsulation, a technique where they deliver cells within
special membranes.
Cell encapsulation is not a new procedure. Attempts to coat
transplanted materials with protective membranes occurred in as
early as the 1960s; however, the technology is far from perfect. Even
a current and promising cell encapsulation system, called hydrogel
microcapsules, has a critical flaw: the microcapsules are difficult
to retrieve completely after implantation. “To cure type 1 diabetes
patients, we estimate that 500,000 pancreatic cell aggregates are
required, which means you need to put tens of thousands of these
microcapsules into the patients,” said An. “Because they are individual
microcapsules, it’s almost impossible to retrieve all of the
materials.” Without a better way to remove the microcapsules from
a patient, clinical application of these devices has been restricted. If
the membrane failed or the cells died and the microcapsules could
not be safely removed, the situation could be dangerous to the recipient.
Recognizing this obstacle to cell encapsulation technology,
the Cornell research team sought to design an encapsulation
32 Yale Scientific Magazine March 2018 www.yalescientific.org

iomedical engineering
FEATURE
IMAGE COURTESY OF HEALTH.MIL
For patients with diabetes, blood tests to monitor glucose levels are
important for the management of the disease.
IMAGE COURTESY OF WIKIMEDIA COMMONS
Brown algae is an important component of alginate hydrogels, the
material that made the cell encapsulation device biocompatible.
device that is therapeutically successful, scalable, and retrievable.
Their original concept was simple. “At the beginning, we were
thinking, ‘What if we used a thread to connect all of these microcapsules,
like a necklace? Then they can be easily implanted and
retrieved through a simple procedure,’” An said. Interestingly,
this preliminary design was inspired by a spider’s web—the necklace-like
structure would look like a strand of spider silk collecting
droplets of dew, and the thread itself would mimic the properties of
adhesive spider silk. In the final design, however, the hydrogel was
layered uniformly around the string and islet cells, more closely
resembling a tube than a strand with beads.
While the concept was simple, the design proved to be more difficult.
The hydrogel, the islet cells, and the modified sutures used to
make the underlying thread all had to be compatible. Coordinating
these components required a diverse array of knowledge, which
challenged the researchers. “I needed to learn from basic chemistry,
materials science, cellular biology, and biomedical engineering.
I even needed to have some medical knowledge for the surgical
procedure,” An said. In the end, the team’s efforts paid off, and they
built a successful device.
The base layer for the device is a nylon suture, a biocompatible,
medical-grade material that is often used for stiches. The suture
was a good starting point, since it is commercially available and
has been proven safe, yet it lacked certain properties that the researchers
desired. Using a chemical treatment, they modified the
sutures to contain small pores and to release calcium chloride.
Both of these modifications improved the thread’s ability to bind
uniformly to the hydrogel: the porous surface allowed the hydrogel
to penetrate the thread and strengthen the adhesion, and calcium
promoted chemical bonds between the materials.
Once the modified thread had been made, the researchers crosslinked
it with a hydrogel made from alginate, a biomaterial obtained
from brown seaweed. The uniform layer of alginate hydrogel
made the device biocompatible and prevented fibrosis, the thickening
and scarring of tissue that sometimes occurs when foreign
materials are implanted into animals. Blocking fibrosis around the
device was critically important, since fibrosis would have blocked
substances from diffusing to and from the device. While the cell
encapsulation system is designed to protect transplanted cells from
the immune system, it must still be semi-permeable so oxygen and
nutrients can reach the cells.
After fabricating the device, the researchers tested the system’s biocompatibility
and its ability to correct diabetes in mice. They also
performed experiments in dogs to test whether they could increase
the scale of transplantation in a larger mammal. The thread-reinforced
hydrogel microcapsule system was successful in each trial,
causing little to no fibrosis around sites of implantation, demonstrating
therapeutic potential in diabetic mice, and remaining intact for
complete retrieval from dogs. These results are a major step forward
for cell encapsulation technology, as the new device will likely minimize
the risks associated with this type of transplantation, making it
a more viable option for treating type 1 diabetes.
At the moment, the Cornell team hopes to improve their cell encapsulation
system, modifying it to become even more biocompatible
and mechanically stable. They also want to scale up further, so
they can deliver enough cells to cure a human patient. Research is
ongoing in all of these areas, and the team eventually hopes to get
the device into clinical trials.
Type 1 diabetes currently affects over one million Americans and
is most often diagnosed in children and young adults. For these
children, the leading cause of diabetes-related death is diabetic ketoacidosis,
and it occurs most frequently when someone fails to
administer a proper dose of insulin. “The final goal of this research
is to find a cure to type 1 diabetes, so that patients no longer need
to get painful and tedious insulin injections every day,” An said.
While we are still far from curing type 1 diabetes, a cell encapsulation
device could simplify management of this disease, reducing its
burden on millions of lives.
www.yalescientific.org
March 2018
Yale Scientific Magazine
33

FEATURE environmental science
COUNTERPOINT
WHICH CAME FIRST, THE BUTTERFLY OR THE FLOWER?
by Annie Yang
A butterfly lands on top of a flower and imbibes nectar with
its coiled mouthpiece; the butterfly and the flower seem to
be an inseparable pair. For a long time, our understanding
of the symbiotic relationship between the two organisms led
scientists to believe that Lepidoptera, the order of insects
that includes butterflies and moths, evolved alongside the
first angiosperms or flowering plants. However, a group of
researchers recently discovered new evidence that suggests
that the evolutionary history of Lepidoptera and angiosperms
may not be as simple as scientists had previously delineated.
Paul K. Strother, a researcher and professor at Boston
College, visited microfossil paleontologist Bas van de
Schootbrugge in Germany in 2012 because they were
interested in looking for prehistoric remnants of freshwater
algae. When the research team drilled into the Schandelah-1
well, however, they inadvertently uncovered enigmatic scales
in sediments from the late Triassic and early Jurassic periods.
While they deduced that these were insect scales, they were
unable to immediately conclude what insects they belonged
to because many different insects have wings lined with
thousands of these kinds of scales. Thus, they had to develop
a method to extract the infinitesimal and delicate scales from
the sample in order to determine their origin.
Timo van Eldijk, an undergraduate at Utrecht University
at the time, took charge of the laboratorial work. To isolate
the scales, he exposed the sediments to harsh acids and then
used a needle tipped with a piece of human nostril hair to
transfer each one individually to a separate slide. He then
IMAGE COURTESY OF TIMO VAN ELDIJK
This image depicts a living descendant of a moth that did not
possess a proboscis. Solid scales extracted from this group of
primitive Lepidoptera support that the earliest butterflies and
moths had jawlike mouthparts.
examined the slides under a microscope and discovered that
there were two types of scales in the sample: solid, round
ones and hollow, jagged ones. By comparing the scales to
previously classified specimens, van Eldijk determined that
the solid scales belonged to the earliest Lepidoptera, who
relied on mandibles or jawlike mouthparts to chew their
food, corroborating the results of earlier insect evolutionary
studies.
The discovery of the newfound hollow scales, however,
revealed something truly remarkable. Because hollow scales
are characteristic of extant, or currently living, Lepidoptera,
specifically the Glossata, a suborder containing moths
and butterflies that have an elongated feeding and sucking
mouthpart called a proboscis, the discovery of these hollow
wings in the sample suggests that moths and butterflies had
already evolved proboscises during the late Triassic period,
nearly 70 million years before plants evolved flowers.
If this is true and there were no flowers during the late Triassic
period, what did moths and butterflies use their proboscises
for? The researchers have considered the possibility that
flowering plants existed earlier than fossil records show, but
Strother finds this explanation unconvincing. “There are
individual plant specimens [from the Triassic Period] that
might have been what was to become of a flower,” Strother
said. “But the thing is that there is always a glitch. There is no
robust record to support early flowers claims.” He explains
that the more plausible explanation is that they evolved
the proboscis in response to the dry and arid climate. The
appendage would allow them to feed on pollination droplets
and saps from gymnosperms, or seed-bearing plants like pine
trees, in order to replenish their lost moisture.
The results of this research alter our understanding of
Lepidoptera and angiosperm coevolution. The research
suggests that the Lepidoptera fed primarily on gymnosperms
but changed their feeding preferences when angiosperms
evolved, consequently coevolving with them and forming the
symbiotic relationship as we know it today.
Since the scales that van Eldijk studied are only a small
part of what was uncovered from the well, there are still
vestiges of other organisms that have yet to be explored.
Strother explains that the next step is to analyze the rest of
the sample. Furthermore, because prehistoric fossil records
are still largely elusive, the research team is also beginning
to look at sediments from other time periods. “Now that we
can recognize these things, what we want to do is to have
a stepwise, continuous record of understanding. There is a
punctuated record, so we are working to fill in for earlier
times,” Strother said.
34 Yale Scientific Magazine March 2018 www.yalescientific.org

FOCUS
technology
repurposed
by
Jau Tung
Chan
From Garden Destroyer to Lab Assistant
Taraxacum officinale, or more commonly
known as dandelions, are a well-known nuisance
in gardens throughout the world because they
infest crops. In a recent development, however,
dandelions may have turned over a new leaf,
having found a purpose in an unlikely setting: the
scientific laboratory.
Last year, a team of high school students, under
the guidance of professors from Xi’an Jiaotong
University in Xi’an, China, completed an in-depth
study about how dandelion seeds can be used as
pipettes to create and manipulate microlitersized
droplets, a fifth the size of droplets from
eyedroppers. In their research, they were not only
able to capture and release consistent droplet sizes
repeatedly, but were also able to model the droplet
sizes quantitatively based on characteristics of the
seeds, such as the length of their hairs.
To use the dandelion seed as a pipette, the
researchers first pushed the seed downward against
a liquid surface to form a dip, much like the dip
when someone stands in the middle of a trampoline.
When they pulled the seed upwards out of the
liquid, the seed remarkably did not completely
separate from it. Instead, the hairs on the seed—
which traditionally allowed wind to disperse
the seed—formed the shape of a paintbrush tip,
enclosing a droplet of the liquid within them.
The key to the consistent droplet sizes—according
to Feng Xu, one of the professors involved in
the research—lies in a fine balance between two
opposing factors: the surface tension of the liquid,
and the stiffness of hairs on the seed. Surface
tension is an elastic force on the surface of liquids,
arising from the attraction of liquid molecules to
each other, akin to how the elastic membrane of
an inflated balloon keeps the balloon in a spherical
shape instead of popping. Surface tension tends to
reduce the droplet size. On the other hand, the stiff
hairs on the seed tend to increase the droplet size
by tending to straighten themselves out, similar to
how a plastic ruler snaps back straight after being
bent. The combination of these two effects creates
a unique balancing point for droplet size, like the
stalemate arising when both sides of a tug-of-war
are equally strong.
By quantitatively modelling these forces and
experimentally verifying their predictions, the
researchers were able to optimize the system
to hold the largest droplet size. They varied the
number, distribution, and length of hairs on
the dandelion seed. Xu recounts an unexpected
result. “Nature optimized the dandelion seed
to give it the capability to capture the maximum
amount of liquid,” he said. In hindsight, this makes
evolutionary sense, since dandelion seeds need
maximal water for optimal growth.
There currently aren’t many tools for creating
and manipulating microliter-sized droplets. A
significant advantage dandelion seeds have over
regular micropipettes is that they are omniphilic,
which means that they can be used for both water
and oil. Most common materials can only do one
or the other, but not both.
That being said, there are certainly restrictions
to this new laboratory tool. In order to release a
droplet from the dandelion seed, the researchers
must place the seed into a liquid with lower surface
tension than that of the droplet liquid so that the
droplet will be released. This condition limits the
contexts in which the method may be used. Still,
Xu is optimistic about using the dandelion seed to
inspire new synthetic fiber structures—similarly to
how Velcro was inspired by the clinging of burrs
of the Burdock plant to clothes. For example,
some synthetic materials can change their stiffness
in response to environmental factors, such as
temperature or light. If the fiber structure is
manufactured from the dandelion seeds, then just
by adjusting those environmental factors—without
a need to even contact the structure—we can allow
stiffness to win that tug-of-war with surface tension,
thereby releasing the droplet anywhere we want. An
added advantage of the consistent manufacturing
of such fiber structures is that droplet sizes will be
more precise than regular micropipettes.
Looking ahead, future directions for this research
include the manufacturing of such micro-scale
synthetic fiber structures, and the adaptation of
this method for other scientific tools. Currently,
Xu is pursuing the latter, developing similar fiber
structures to manipulate cells instead of liquids,
which could potentially change the way human
tissues are created. Ultimately, the researchers have
uniquely repurposed a common garden weed into
a scientific tool.
35 Yale Scientific Magazine March 2018

COLIN HEMEZ (ES ‘18)
THINKING DEEPLY ABOUT ENGINEERING
BY JASON YANG
UNDERGRADUATE PROFILE
IMAGE COURTESY OF COLIN HEMEZ
Hemez, a Goldwater Scholar, has been working in Professor Isaacs’ Lab at
the Systems Biology Institute since sophomore year.
Yale College senior Colin Hemez (ES ’18) cherishes long runs,
rock-climbing, and sleep. These routines ground Hemez, allowing
him to reflect on himself and the world around him. For Hemez, life
is not about success or achievement; instead, it’s about thoughtfully
exploring problems that are interesting and important. “I really think
deeply about what kinds of problems I want to work on, maybe more
deeply than I should,” said Hemez. His deep reflection has led him to
genome-editing research, a double major in Biomedical Engineering
and Art History, and the combined Bachelor’s and Master’s program
through the Yale School of Public Health.
Born in France but raised in New Mexico near Los Alamos National
Labs, Hemez was exposed to the world of scientists from an early age.
Naturally, during his first year at Yale, he joined the iGEM (International
Genetically Engineered Machine) competition team at Yale. As
a team, they conducted synthetic biology research and presented their
findings at the annual iGEM International Jamboree. More importantly,
Hemez got to know one of the team’s sponsors: his future research
mentor, Dr. Farren Isaacs, Associate Professor of Molecular, Cellular,
and Development Biology.
Since sophomore year, Hemez has been working in Professor Isaacs’
lab at the Systems Biology Institute on Yale’s West Campus. Conventional
biology is very bottom-up: it asks how specific molecules, genes,
or pieces fit into the bigger picture. However, systems biology is more
top-down, using many of the hottest recent developments in biology,
including deep sequencing, DNA synthesis, and novel imaging tools
to a get a broader view of biology. Very interdisciplinary, systems biology
brings together molecular biologists, biomedical engineers, ecologists,
and evolutionary biologists.
“What really gets me excited about the work I do in the Isaacs lab
is that it’s really at the intersection of basic science and engineering,”
Hemez said. Hemez loves the study of science, but at the end of the
day, he is an engineer by training. One of his most recent projects is
understanding how bacteria whose genetic information isn’t stored
in DNA can still interact with normal bacteria that use DNA. He explains
that potential applications include engineering gut bacteria that
have specific genetic capabilities and do not interact unintentionally
with normal bacteria, as bacteria with alternative genetic codes cannot
exchange genetic information with other bacterial community members.
Not only is Hemez studying biological principles, but he also
hopes to use them to better the world.
So how does art history fit into all of this? Hemez’s interest in art
history budded when he took an online course in high school. Though
Hemez is not necessarily looking to find the intersection of biomedical
engineering and art history, the technical analysis he performs in art
history has, in turn, informed his scientific pursuits. “The visual stimuli
we see around us are hugely influential on the way we make sense
of the world. Science is communicated visually,” Hemez said. He hopes
that future scientists will strengthen the way science is presented. In
art history, he gets a chance to think deeply about specific works, and
he believes that, in science, there is something to be gained in slowing
down, closely analyzing, and “digesting,” as engineers must understand
the motivations and ethics behind the problems they’re facing.
Hemez feels very honored to be a Goldwater Scholar, one of only
three Yale students in his class to be given this distinction. He additionally
attributes his incredible experience in research to the Beckman
Scholars program, which provides research support for 18 months, an
exceptionally long time for a scholarship. “The Beckman Foundation
really encourages the scientists they’re funding to dig deep into the
problems they’re studying, to take their time with it, to see what comes
out of it,” Hemez said. He values the process of deeply exploring science
and letting his work evolve organically along various tangents,
but he worries that many scientists fear the pressure to publish.
Hemez hopes to apply his engineering to solving public health problems,
particularly engineering microbial communities that work together
to produce medicines, biofuels, and other important natural
products. He knows that graduate school is essential to his goals, and
could ultimately lead to a faculty position, which he believes would
provide unparalleled freedom to work on useful projects that interest
him. Hemez feels very grateful to Isaacs and his graduate student
mentors, and is often humbled by their brilliance. Whatever Hemez’s
future holds for him, he hopes to continue exploring his interests, all
while thinking deeply about engineering problems.
36 Yale Scientific Magazine March 2018 www.yalescientific.org

BY LISA WU
ALUMNI PROFILE
DR. HUGH TAYLOR (SM ‘83)
LEADING RESEARCH IN REPRODUCTIVE HEALTH
IMAGE COURTESY OF DR. HUGH TAYLOR
Dr. Taylor’s laboratory has identified transdermal estrogen treatments
(commonly referred to as the “patch”) as more effective at enhancing
sexual function when compared to placebo and oral estrogen treatments
Dr. Hugh Taylor (SM ’83) sort of wound up becoming Chief of Obstetrics
at a prominent hospital. Taylor remarks that he was always
interested in science, but he still didn’t necessarily expect to end up
going to medical school, spend an additional four years in a laboratory,
and rise through the ranks to become the Chief of Obstetrics and
Gynecology at Yale-New Haven Hospital, as well as the Anita O’Keeffe
Young Professor of Obstetrics, Gynecology, and Reproductive Sciences.
Even once he entered medical school, he certainly didn’t expect
to choose gynecology as his specialty. Taylor’s path was by no means
completely pre-determined, but he ended up exactly where he needed
to be—a reassuring reminder to millions of concerned pre-medical
candidates that arbitrary chance and fate, as volatile and uncertain as
they seem, can be a good thing.
Taylor, like many other doctors and surgeons, grew up interested in
science and in people. His path towards becoming a physician-scientist
began at Yale, where a campus culture strongly centered on community
involvement empowered him to commit to a life of public
service. “I think the responsibility that comes with a Yale education
is important,” Taylor said. For him, that responsibility compelled him
to join a laboratory during his residency to learn more about using
laboratory research to help patients. In addition to seeing patients,
performing some of his field’s most difficult surgeries, and leading
his department, Taylor now runs a laboratory that examines the underlying
mechanisms of endometriosis, a disease in which the mucous
membrane lining the uterus that thickens during the menstrual
cycle becomes displaced. The experience has been a long haul and a
long-term investment—overwhelming workload with little financial
incentive—but he maintains that it is well worth the outcome. “As a
doctor, I get immediate, personal feedback that my work is helping an
individual. And as a scientist, I get to impact a much wider audience,”
Taylor said.
Taylor’s desire to benefit his community through his work also influenced
his decision to specialize in gynecology. During medical
school, Taylor was interested in several different medical specialties,
but gynecology stood out as an area in which clear progress could be
made. “I considered internal medicine, but OB-GYN was extremely
exciting,” he said. “There were so many unsolved issues, and I saw
some clear opportunities for research.”
When it comes to reproductive health, the truth is that the United
States is lagging behind the rest of the world. “It’s amazing that despite
the United States’ status as one of the most developed nations,
our country still has one of the highest rates of complications associated
with pre-term delivery of babies in the world,” Taylor said. Taylor’s
laboratory has been prolific in its efforts to close the gap; his laboratory
has identified a group of stem cells in the uterus that have been
linked to endometrial growth. They can be extracted with a simple office
biopsy—a procedure that removes a small amount of tissue—and
induced to develop into insulin-producing cells, cartilage, and neuronal
cells. Taylor recently completed a four-year long study that found
that when compared to a placebo and oral estrogen treatments, the
transdermal estrogen replacement patch resulted in increased sexual
function. However, transdermal hormone replacement therapy can
still cause adverse side-effects. Consequently, Taylor emphasizes that
the treatment of sexual dysfunction, like the treatment of any condition,
should be modified specifically to each patient’s needs. “It’s all
a part of a general effort in medicine, whether it be cancer or gynecology,
to personalize therapy to deliver optimal results,” Taylor said.
Taylor may have not have entered Phelps Gate with a definitive
plan, but he was still able to embark on a medical career spanning the
lab bench, patient care centers, and hospital conference rooms. “You
should think big and dream,” he said. “It’s a big world, and there are
a lot of opportunities in medicine to make the world a better place.”
www.yalescientific.org
March 2018
Yale Scientific Magazine
37

Science in the Spotlight
The Evolution of Beauty
By Megha Chawla
PHOTOGRAPHY BY KELLY ZHOU
4.5/5
The Evolution of Beauty is a compelling
and insightful look at beauty in nature
through the eyes of Richard O. Prum, the
William Robertson Coe Professor of Ornithology
at Yale. The book is Prum’s response
to decades of research in the evolutionary sciences that have
embraced Darwinian thought and theory of natural selection, while
woefully ignoring Darwin’s theory of sexual selection. Through a
lifetime of observing birds in nature and researching the evolution
of ornamental beauty, Prum contends to revive the arbitrary sexual
selection hypothesis, or as he calls it, “Beauty Happens.”
According to Prum, animals have subjective tastes and preferences
and the agency to act upon them via mate choice. Prum
compares adaptationists, who believe that all traits have evolved
to provide a better chance of survival and communicate information
about mate quality, to economic theorists, who expect actors
in a free market to behave completely rationally and purposefully.
“Of course,” Prum says, “Evolution, like markets, is spurred by
the irrational and subjective choices of its actors.” He provides a
motley of colorful examples from the bird world to support this
hypothesis, like the evolution of the male peacock’s seemingly
useless tail which may even be harmful to survival, but has persisted
because the ladies like it.
In the animal kingdom, it is often the female who chooses a mate
among available males. Because of this, Prum’s argument also has
a feminist flair. He describes how male and female ducks’ genitalia
and the male bowerbird’s elaborate bower-building ritual might
have evolved for the same purpose—to protect females from forced
copulation. Prum even extends his hypothesis to the evolution of
the female orgasm in great apes and the size and shape of the human
penis, claiming that female sexual autonomy has led to their
evolution—or, in his words, “Pleasure Happens.”
The Evolution of Beauty is interdisciplinary at its core, and Prum
passionately comments on evolution from multiple perspectives.
While the book has been well-received—the New York Times named
it as one of the ten best books of 2017—Prum says the response
from the scientific community has been mostly mute. “I’m perfectly
happy to lose the battle and win the war,” he said, hoping his work
will inspire further research recognizing aesthetic preference as a
strong force in evolution.
On the whole, The Evolution of Beauty endures as a brilliant
anthology of beauty and desire in the natural world, written in
engaging prose that is vivid, graphic, and at times unexpectedly
funny. Prum humorously and appropriately quotes Sean Hannity’s
remarks on his research: “Don’t we really need to know about duck
sex?” If you thought you, like Sean Hannity, didn’t care about the
mating habits of ducks, or never gave them any thought at all, this
book will make you strongly reevaluate your indifference.
38 Yale Scientific Magazine March 2018 www.yalescientific.org

Science in the Spotlight
The Great Quake
By Vikram Shaw
IMAGE COURTESY OF USGS
5/5
At 5:36 p.m. on Good Friday, March 27, 1964,
a violent shaking disrupted a peaceful Friday
night in the village of Chenega, Alaska. The
villagers, primarily Alutiiq natives, noticed
the water level of their cove rapidly recede, curiously
exposing the bottom of the ocean floor. The villagers
knew what it meant, but many of them did not have enough
time to get out. Moments later, a thirty-five-foot-high wall of
water came barreling towards them.
In a compelling tale of disaster, resilience, and scientific discovery,
New York Times journalist and Yale graduate Henry
Fountain tells the story of the biggest recorded earthquake
in the history of North America in his new book, The Great
Quake. After Fountain wrote an article in the New York Times
about the quake’s 50th anniversary, an editor at a New York
book publisher told him that the story sounded like a good
book. Fountain quickly mobilized, and by the end of 2015, he
had visited Alaska for a couple of months and completed most
of his research. “I wanted to tell the narrative of the people affected
and tell the tale of science through the eyes of George,”
Fountain said.
George Plafker, a geologist who started with little knowledge
of earthquakes but a lot of knowledge of the Alaskan
backcountry, was one of the main players behind the scientific
breakthroughs that the quake catalyzed. At the turn of the
century, earthquake science was young and misguided. Eduard
Suess, for example, put forth the leading earthquake theory of
the time by comparing the earth to a drying apple that would
wrinkle as it shrank. A small minority of scientists instead favored
the emerging ideas—rejected by most—that would later
become known as plate tectonics. It was not until after the
Alaskan quake, however, that Plafker helped settle the debate.
The book tells the stories of the two communities that were
hit the hardest by the quake: Valdez, a small costal town that
arose from the Gold Rush, and Chenega, a village of around
eighty native Alaskans and an American schoolteacher. Following
these two villages through the disaster, the book is both
exciting to read and informative. Fountain makes sure that no
details are spared when it comes to the moments leading up
to and just after the quake. He also details the months on end
spent by many geologists, including Plafker, who dedicated
their lives to understanding what happened.
Fountain closes his book with a sobering reminder: by several
estimates, including Plafker’s, the Pacific Northwest is due
for a megathrust earthquake—the same kind that occurred in
Alaska. “The Northwest will probably have a quake like it in
the next 50 years,” Fountain said. “They’re all expecting it to
happen.”
www.yalescientific.org
March 2018
Yale Scientific Magazine
39

C A R T O O N S
TEARS
FELLOWSHIPS WISHING WELL: OUT OF ORDER
MIDTERM SEASONAL SPECIALS
THE ALL-NIGHTER
ZOMBIE
DROWN
SORROWS
IN SUGAR
ENERGY
DRINK
EMOTIONAL
SUPPORT
THE LAST-MINUTE
PANICKER
DESPERATION
QUADRUPLE
SHOT
ESPRESSO
TEA BECAUSE
YOU ARE ON
TOP OF IT
THE OBNOXIOUS
OVERACHEIVER