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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

Managing Editors

News Editor

Features Editor

Articles Editor

Online Editor

Copy Editors

Yale Scientific

M A G A Z I N E

Established in 1894

MARCH 2018 VOL. 91 NO. 1

Production Manager

Layout Editor

Art Editor

Photography Editor

Outreach Designer

Webmaster

Publisher

Operations Manager

Advertising Manager

Synapse President

Synapse Vice President

Outreach Coordinators

Social Media Coordinator

Staff

Victoria Dombrowik

Alice Li

Tiger Zhang

Erica Lin

Sunnie Liu

Miriam Ross

Grace Niewijk

Sonia Wang

Mindy Le

Anna Sun

Liz Ruddy

Christine Xu

Alice Tao

Hannah Verma

Megha Chawla

Vikram Shaw

Lisa Wu

Jason Yang

Advisory Board

Priyamvada Natarajan

Sandy Chang

Kurt Zilm, Chair

Fred Volkmar

Stanley Eisenstat

James Duncan

Stephen Stearns

Jakub Szefer

Werner Wolf

John Wettlaufer

William Summers

Scott Strobel

Robert Bazell

Craig Crews

Ayaska Fernando

Robert Cordova

Annie Yang

Jau Tung Chan

Antonio Medina

Isaac Wendler

Leslie Sim

Marcus Sak

Urmila Chadayammuri

Emma Healy

Grace Chen

Diyu Pearce-Fisher

Matthew Kegley

Hannah Geller

Lauren Telesz

Allie Olson

Sandra Li

Yulan Zhang

Theo Kuhn

Joshua Perez-Cruet

Eileen Norris

Diane Rafizadeh

Stephanie Smelyansky

Will Burns

Charlie Musoff

Allie Forman

Conor Johnson

Marcus Sak

Joshua Matthew

Sunnie Liu

Kelly Zhou

Ivory Fu

Eric Wang

Laurie Wang

Alice Wu

Kevin Chang

Jiyoung Kang

Allie Olson

Jessica Trinh

Nasser Odetallah

Seth Anderson

Lisa Wu

Leslie Sim

Lukas Corey

Lauren J Kim

Sonia Wang

Fangchen Zhu

Vikram Shaw

Jason Yang

Emma Healy

Emma Wilson

Anusha Bishop

Lauren Gatta

Sunnie Liu

Elissa Johnson

Astronomy

Biological and Biomedical Sciences

Chemistry

Child Study Center

Computer Science

Diagnostic Radiology

Ecology & Evolutionary Biology

Electrical Engineering

Emeritus

Geology & Geophysics

History of Science, Medicine, & Public Health

Molecular Biophysics & Biochemistry

Molecular, Cellular, & Developmental Biology

Molecular, Cellular, & Developmental Biology

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

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

CT 06520. Non-profit postage permit number 01106 paid for May 19,

1927 under the act of August 1912. ISN:0091-287. We reserve the right

to edit any submissions, solicited or unsolicited, for publication. This

magazine is published by Yale College students, and Yale University

is not responsible for its contents. Perspectives expressed by authors

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We reserve the right to edit letters before publication. Please send

questions and comments to ysm@yale.edu. Special thanks to Yale STC.


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

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