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DECEMBER 2019 VOL. 92 NO. 4 | $6.99

12

RUNNING UP AND

DOWN YOUR SPINE

UNRAVELING A

15

MEDICAL MYSTERY

HARNESSING

18

LIGHT

LEAPING INTO

20

PICOSCIENCE

THE ORIGIN OF

22

THE NUCLEUS


w w w . y a l e s c i e n t i f i c . o r g


CONTENTS

VOL. 92 ISSUE NO. 4

More articles online at www.yalescientific.org.

12

15

18

20

22

Running Up and Down Your Spine

COVER ARTICLE: Using 3D imaging of spine segments, researchers at Yale and collaborators

in France have elucidated the organization of the lymphatic system, which plays a key

role in the transportation and collection of substances throughout the body.

Unravling a Medical Mystery

A nine-year-old patient came to doctors with a never-before-seen illness. A team of Yale

researchers discovered the cause, and in doing so, uncovered new information about an

important protein in the immune system.

Harnessing Light

Researchers in Yale’s Department of Electrical Engineering recently discovered a breakthrough

method of measuring the wavelength of a single photon, and implemented it on

a single chip.

Leaping into Picoscience

Researchers in the lab of Charles Ahn successfully manipulated the electronic properties of

cobalt at the atomic level, within a cobaltate-titanate oxide heterostructure. This discovery

adds to the search for more efficient high temperature superconductors.

The Origin of the Nucleus

Researchers at Yale have recently identified proteins in Archaea with nuclear localization

sequence (NLS)-type motifs, even though they have no nuclei. The presence of NLS-type

motifs in such cells without nuclei could provide valuable insight into the origin of the nucleus

in evolutionary biology.

www.yalescientific.org

December 2019

Yale Scientific Magazine

3


WHY DO OCTOPI

HAVE WARTS?

By Laiba Akhtar

&

Cybernetic

When Janet Voight received deep-sea

Graneledone pacifica specimens, she noticed

that they looked different from their shallow water

counterparts. “I received these really precious deepsea

octopi, and I was supposed to say whether or not

they were the same as the species off of the coast of Oregon.

They clearly belonged to the same genus, but they

looked different,” Voight said.

Voight’s research showed the differences were consistent

with a pattern of clinal variation, where a trait varies with

location within a single species, rather than species differentiation.

That is, as the depth increased, the specimens

had more warts, fewer gill lamellae, and fewer suckers,

alongside being smaller in size. Although Voight’s research

highlighted these details, a big question remains: why do

these differences occur?

“Honestly I don’t know,” Voight responded. She plans to

look more closely at the tissue samples under a microscope

to answer this. “Right now, I’m having a colleague do some

histological sectioning of some of these warts to figure

out what they’re made of and why they’re there. I’m hoping

we’ll stumble on something, but so far nothing.”

Despite this, Voight’s work promotes further research

into understanding the creatures of the deep

sea. She hopes to use what she has learned here to

analyze other species in this globally-distributed

genus and see just how different they are.

“With this, we can change the focus of the

characteristics we use to identity species

and species boundaries,” she said.

ARE SMART-

SHIRTS NEXT?

By Tai MichaelsA

bodysuits

sound like something

from a sci-fi movie, but could

they soon be making the jump to

nonfiction? Professor Yury Gogotsi’s

lab at Drexel University has demonstrated

the potential of a new conductive yarn

formed by coating fibers with MXenes—2D

transition metal carbides discovered by Gogotsi

and collaborators in 2011.

They not only demonstrated the effectiveness

of their innovative conductive yarns in the lab, but

they also created textiles using industrial knitting machines,

put them through forty-five washing cycles at

elevated temperatures, and ran a barrage of twisting and

stretching tests. “Knitting these yarns was very challenging,”

said researcher Simge Uzun. But they pressed on and

made incredible progress—the tests only reduced their

electrical conductivity of the yarns by a few percent.

A critical advantage of the new MXene-coated yarns is

that sensing and energy storage can be integrated into the

fibers instead of requiring bulky batteries and sensors as

in current methods. This could be key to making wearable

technology a reality rather than just a novelty. Wearable

MXene-based fabrics could open doors to real time

health monitoring, improved virtual reality, and uses

we haven’t even begun to consider.

In addition to continuing their research on multifunctional

MXene-based textiles, the A.J. Drexel

Nanomaterials Institute is also exploring the possibility

of working with companies to make the

fabrics commercially available in the future.

So keep an eye out—Mxene fabrics may be

coming soon to stores near you.

4 Yale Scientific Magazine December 2019 www.yalescientific.org


The

Editor-in-Chief

Speaks

A NEW DECADE

With Issue 93.1, the Yale Scientific Magazine steps into a new decade. Over the twelve decades that

we have been in print, the Yale Scientific has transformed from a student monthly for the Sheffield Scientific

School to a quarterly publication with national readership. Through the first and second World

Wars, economic crises, disease outbreaks, and many other epoch-making events, the Yale Scientific

has remained steadfast in its mission to feature scientific advancements, especially those made at Yale,

in an accessible way. We occupy the unique intersection between research, education, and communication

on campus, which is an important one given Yale’s world-class status as both a research and

liberal arts institution. To fulfill this role, we must constantly look forward. We are uniquely positioned

to do so because we are fully undergraduate-run—every year, a new masthead brings fresh ideas and

perspectives to ensure that the Yale Scientific maintains its relevance in scientific communication.

In this issue, we continue spotlighting the most exciting research done at Yale and beyond. Our

cover article by Christina Hijiya reports on the key role of our enteric (intestinal) nervous system in

maintaining our immune defenses. This newly discovered connection is the result of a collaboration

between neurologists and immunologists. It testifies both to nature’s complexity as to the value

of cross-specialization research. Recently, science at Yale is increasingly defined by integration across

fields of study, from the Yale Science Building, designed to harbor a breadth of disciplines under one

roof, to the many research institutes on West Campus, not to mention our international collaborative

network with other institutions worldwide.

At times, the overarching objective of science can be lost in the minutiae of equations, graphs, and

code. Many articles in this issue showcase science that is relevant to our lives: how UV damage causes

cancer on a molecular level (p. ?), how exercise is related to lower risk for atherosclerosis (p. ?), a new

way to understand the evolution of sex (p. ?), and, for you coffee lovers, how adding sugar into your

coffee affects the way caffeine works (p. ?). A scientific understanding of the world around us is always

useful.

Science is also about more than the end results. We have as much to learn from the process of scientific

discovery—obstacles, detours, and eureka moments. To this end, our new quarterly Meet the

Profs! webinar series, in collaboration with the Yale Science and Engineering Association and the Yale

Alumni Association, features researchers each issue with opportunities for live audience questions. We

also maintain a strong online presence, with exclusive content on our website and the Scope, the YSM’s

blog that addresses the implications of current events from interdisciplinary scientific perspectives,

whether it be the recent Australian wildfires or the COVID-19 outbreak.

As we begin this volume of YSM, we would like to acknowledge the mentorship of the previous

masthead and everyone who has worked tirelessly to bring the Yale Scientific to where we stand today.

We are also grateful for our strong partnership with the Yale Science and Engineering Association. The

YSEA has been a stalwart supporter of our work to communicate science beyond campus, particularly

with alumni. Finally, thank you to all our readers for your continued interest and support. We look

forward to sharing with you scientific advancements that will define the next decade.

ABOUT THE ART

William Burns, Editor-in-Chief

In this issue’s cover, I represent the clarity

of new 3D imaging technologies in

visualizing lymphatic networks. This illuminating

work is currently being used to

improve spinal tissue repair technologies;

on top of this, the more we see, the more

we understand about how lymphatic vasculature,

in particular spinal vessels, play

integral roles in immune system maintenance

and response.

Ivory Fu, Arts Editor

MASTHEAD

December 2019 VOL. 92 NO. 4

EDITORIAL BOARD

Editor-in-Chief

Managing Editors

News Editor

Features Editor

Articles Editor

Online Editors

Copy Editors

Scope Editors

PRODUCTION & DESIGN

Production Manager

Layout Editor

Art Editor

Photography Editor

Webmaster

BUSINESS

Publisher

Operations Manager

Subscriptions Manager

Advertising Managers

OUTREACH

Synapse Presidents

Synapse Vice President

Social Media Coordinator

Outreach Coordinators

STAFF

Alexandra Haslund-Gourley

Alice Tao

Alice Tirard

Alice Zhang

Antalique Tran

Anusha Bishop

Arianna Lord

Betty Xiong

Blake Bridge

Brett Jennings

Britt Bistis

Catherine Zheng

Dhruv Patel

Eddy Zhong

Ellie Gabriel

Ethan Garvin

Frances Cheung

Franchette Brosoto

Hannah Ro

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

Immanuel Bissell

Isabella Li

James Han

Jennifer Yoon

Jenny Tan

Julia Zheng

Katherine Dai

Katrina Starbird

Kelly Farley

Laiba Akhtar

Lawrence Wang

Lorenzo Arvanitis

Makayla Conley

Maria Fernanda Pacheco

Maria Lee

Matt Spero

Medha Majety

Michelle Barsukov

Miria Kopyto

Mirilla Zhu

William Burns

Conor Johnson

Sunnie Liu

Anna Sun

Lukas Corey

Marcus Sak

James Han

Lauren Kim

Isabella Li

Xiaoying Zheng

Kelly Farley

Georgia Woscoboinik

Mafalda Von Alvensleben

Maria Lee

Ivory Fu

Kate Kelly

Matt Tu

Richard Li

Alexandra Brocato

Sebastian Tsai

Tony Leche

Annie Yang

Leslie Sim

Lisa Wu

Hannah Ro

Chelsea Wang

Oscar Garcia

Katherine Dai

Molly McLaughlin

Nadean Alnajjar

Neal Ma

Neeha Kothapalli

Nicholas Archambault

Nithyashri Baskaran

Serena Thaw-Poon

Siena Cizdziel

Siraj Patwa

Sophia Zhao

Stephanie Hu

Sydney Hirsch

Tai Michaels

Tiffany Liao

Tony Leche

Tony Potchernikov

Viola Lee

Xiaoying Zheng

Yu Jun Shen

Zi Lin

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

Undergraduate Admissions

Yale Science & Engineering Association

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

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to edit letters before publication. Please send questions and comments to

yalescientific@yale.edu. Special thanks to Yale STC.


HYDRATED

SQUIRRELS

TARGETING

THE MITO-

CHONDRIA

Staying Hydrated During Hiberation

BY MIRIAM KOPYTO

IMAGE COURTESY OF FLICKR

Humans are thirsty animals—it’s built into our DNA. But have

you ever thought about what happens in your body when you feel

an overpowering urge to quench your thirst? Thirst is triggered by a

surge in compounds, like ions, that affect the properties of fluids. The

measure of these so-called osmolytes in the blood is called serum osmolality.

Subsequently, hormones like vasopressin act on the kidneys

and blood vessels to prevent additional fluid loss by reducing urine

output and increasing the reabsorption of water into the body. You

might think the same mechanism is present in all mammals. Yet, Elena

Gravecha and her team at the Yale School of Medicine were surprised

to find that ground squirrels, which hibernate for up to nine

months without food or water, have lowered serum osmolality.

Hibernating squirrels go into a state of torpor, where they reduce their

breathing rate, heart and metabolic rates, temperature, and excretion.

Every few weeks, hibernating squirrels reach a state called interbout

arousal (IBA), an active-like state in which they return to their regular

body temperature. Researchers Ni Feng and Madeleine Junkins found

that unlike squirrels during torpor, those in IBA reverse their serum

osmolality back to normal, suggesting there is an internal mechanism

to reverse osmolality without the influence of water. Moreover, when

squirrels in IBA are presented with water, they exhibit suppressed thirst,

despite being physiologically similar to active squirrels.

One possible application of Gravecha’s research lies in NASA space

travel. “If we can put astronauts in [a hibernation-like state], they will

need fewer resources, and we can shorten space travel due to lightened

weight,” Gravecha said. Additionally, Ni explained that “therapies that

make one stay hydrated, despite not having water” are an exciting possibility

for people affected with fluid imbalance. This research also holds

promise for the organ shortage; modifying organs so they are more robust

in cold conditions could possibly increase the organ supply.

Safety to Combat Liver Disease

BY SOPHIA ZHAO

IMAGE COURTESY OF FLICKR

Nonalcoholic fatty liver disease (NAFLD), which afflicts up to onethird

of the general adult population, is swiftly becoming the most

common cause of chronic liver disease. NAFLD is also associated

with type two diabetes and cardiovascular disease. In a Yale-spearheaded

study recently published in Science Translational Medicine,

a novel therapy has been shown to safely and efficiently reduce liver

fat and improve metabolic symptoms related to NAFLD that lead to

type two diabetes.

Characterized by insulin resistance and major fat buildup in the

liver tissue, NAFLD must be treated directly. “Specific metabolites of

fat in the liver are the culprits—they block insulin action, which then

leads to hyperglycemia (high blood sugar),” explained senior author

and Yale professor Gerald Shulman.

Shulman and his team sought to reduce excess liver fat by enhancing

activity in the mitochondria, the primary regulator of energy metabolism

in cells. Following this course of action, liver cells exhibit an

increase in mitochondrial oxidation and are able to burn more fat.

Specifically, the group manipulated a drug that was widely pegged

as a weight-loss cure-all in the early 1900s but was later banned for

inducing abnormally high body temperatures. The researchers’ efforts

culminated in a new drug design that precisely targets mitochondria

in the liver. This specificity avoids the toxic repercussions of

the previous version of the drug. After testing the improved drug in

two species of nonhuman primates, the scientists found that it lowered

liver fat and hepatic insulin resistance without adverse effects,

demonstrating its significant capability to reverse NAFLD.

“We are marching along to show that this is a safe approach to treat

the two related pandemics of type two diabetes and NAFLD, and I

am looking forward to taking this liver-targeted mitochondrial therapeutic

approach to the clinic,” Shulman said.

6 Yale Scientific Magazine December 2019


SAUCIE

NETWORKS

PAIRED

GROWTH

IN SPACE

IMAGE COURTESY OF FLICKR

IMAGE COURTESY OF

WIKIMEDIA COMMONS

Innovation for Single-Cell Analysis

BY BETTY XIONG

In the digital era, large amounts of data are collected

without efficient means to analyze the information, especially

in medicine. To solve this problem, a group of scientists,

led by professor Smita Krishnaswamy of Yale University,

created SAUCIE (Sparse Autoencoder for Clustering,

Imputation, and Embedding), an artificial neural network

that evaluates single-cell datasets to organize useful information

and identify immune response patterns to different

pathogens and diseases. In the initial research phase, the

researchers used SAUCIE to analyze patients with dengue

fever along with a healthy control group from the same region

of India; now, SAUCIE is also being used to analyze

diseases ranging from diabetes to the flu.

Neural network machine learning provides an innovative

method to create narrow classifications and focus on

important data at the cellular level. In addition, SAUCIE

is advantageous because it can function unsupervised—it

automatically evaluates data without requiring scientists’

supervision. The artificial neural network detects the difference

between random and meaningful information, presenting

only relevant data to scientists. “This is only the

beginning of single-cell analysis,” said first author Matthew

Amodio. For a long time, scientists were only able to analyze

patients’ blood by taking a physical sample and measuring

the average outcome of all the datasets within cells.

Now, single cells can be analyzed efficiently, and SAUCIE

can be used on whatever single-cell datasets researchers

have to improve their analysis. In the future, SAUCIE will

be extremely useful in conducting research and shortening

the time needed for researchers to evaluate gathered data.

What Stars Reveal About Black Holes

BY DHRUV PATEL

Black holes, which possess such intense gravity that almost

nothing—not even light—can escape its hold, have long intrigued

astronomers, physicists, and people everywhere. These

black holes often lie at the center of galaxies, gradually pulling

in surrounding stellar material. Previous research found

a positive correlation between black hole mass and surrounding

stellar mass, but the reasoning behind this correlation remained

a mystery, until now. A recent Ph.D. from Yale Angelo

Ricarte sought to elucidate the causes of the correlation between

black hole mass and stellar mass along with a team of

researchers—including Yale professor Priyamvada Natarajan,

Yale postdoctoral fellow Michael Tremmel, and University of

Washington professor Thomas Quinn. To study the connections

between black hole and stellar formation rate, the scientists

used Romulus simulations, cosmological simulations that

compute the formation of galaxies and dark matter from the

Big Bang to the present day.

The results were striking: the team found that the black holes

and their host galaxies seemed to co-evolve, regardless of their

masses, ages, or environments. “About seventy percent of the

variations in black hole accretion rate can be explained by just

three galaxy properties,” Ricarte said. These properties are: star

formation rate, black hole-to-stellar mass ratio, and cold gas

fraction. Overall, this means that the growth rate of a black

hole roughly matches the growth rate of the stellar mass of its

host galaxy. However, it is also known that if a black hole becomes

too large for its host galaxy, its growth rate will decrease

relative to the galaxy, and vice versa. There is no doubt that

such a discovery will play a pivotal role in future research that

explores the formation, growth, and function of black holes.

December 2019

Yale Scientific Magazine

7


NEWS

Chemistry

IRON

WITH THREE

ARMS

Discovering the

hidden powers

of iron

BY SYDNEY HIRSCH

IMAGE COURTESY OF WIKIMEDIA COMMONS

In biological systems, iron-sulfur (Fe-S) clusters act as components

of electron transfer proteins. These clusters occur in

various different forms, including cubanes (4Fe-4S) and diamond

(2Fe-2S) structures. All known iron-sulfur clusters

yield high-spin electron configurations, meaning that one

electron is placed in each of the five d-orbitals of the iron before

any pairing occurs. Around two years ago, a team of scientists,

including Yale University professor Patrick Holland,

began conducting research on a new type of Fe-S cluster. Their

primary objective was to create a cluster with higher reactivity.

Holland and his team were surprised to find that they had

produced a cluster of low-spin electron configuration. Unlike

high-spin configurations, a compound of low-spin electron

configuration has its lower energy d-orbitals filled before any

are placed on those of higher energy, resulting in a minimal

number of unpaired electrons.

The newly discovered clusters are low-spin due to the reduction

of their Racah B parameter, which describes the level of

electron-electron repulsion in the atoms. The high covalency

of the iron-sulfur bonds reduces the Racah B, thus resulting

in a lower spin. Clusters yielding low-spin electron configurations

are “more reactive and form stronger bonds” than

those with high spin, according to Holland. The structures

that his team discovered—three [4Fe-3S] clusters that differ

in oxidation state of the iron atoms—all have trigonal planar

bond geometry about the central atom. This geometry is due

to the presence of diketiminate molecules that bind to a metal.

“These molecules crowd the top and bottom of the iron-sulfur

clusters, which prevents them from forming more than three

bonds to sulfurs,” Holland said. This factor contributes to the

increased reactivity, as the new Fe-S clusters can react only

with smaller atoms like nitrogen in compounds such as hydrazine

(N2H4). In previous studies, Holland explained, scientists

could have overlooked low-spin iron-sulfur clusters because it

was not thought that they could even exist.

The presence of an unsaturated three-coordinate iron site in

all three clusters inspired Holland and his team to explore how

they react with nitrogenase-relevant molecules. An unsaturated

iron site is simply one that makes less than the maximum

number of bonds it can. One of the clusters reacted quickly

with hydrazine, showing that the Fe 2+ -based cluster is able

to cleave nitrogen-nitrogen bonds. Furthermore, this was the

first time the researchers saw a hydrazine-derived NH2 group

on an iron-sulfur compound.

Similar reactivity is seen in FeMoco, which is the primary

cofactor (a compound necessary for enzyme catalysis)

of nitrogenase—an enzyme responsible for the reduction of

nitrogen gas (N2) into ammonia (NH3). FeMoco facilitates

this conversion. The scientists observed other similarities

between their iron-sulfur clusters and FeMoco as well. For

example, the clusters had short Fe-S bond distances to the

central iron that resembled the belt iron sites in FeMoco. In

addition, a planar arrangement like this has been previously

proposed as an intermediate state of FeMoco. Therefore,

these new compounds may be able to teach us about natural

nitrogen reactions in the future.

Holland’s team began conducting research with the objective

of crafting more reactive iron-sulfur clusters, anticipating

that their results would have a high-spin electron configuration

analogous to those of already known Fe-S compounds. Thus,

the discovery of low-spin electron configuration in the more

reactive structures came as a surprise to them and prompted

consideration as to whether or not relevant Fe-S clusters had

been overlooked in the past. The low-spin configuration occurred

as a result of highly covalent bonds, and diketiminate

ligands contributed to the increase in reactivity. The scientists

also noted the parallels between their synthetic compounds

and FeMoco, the natural cofactor of nitrogenase. Overall, their

work promises potential future identification and utilization of

biologically relevant three-coordinate iron-sulfur compounds.

8 Yale Scientific Magazine December 2019 www.yalescientific.org


Cell Biology

NEWS

RIG-ING

THE IMMUNE

SYSTEM

Mechanisms of

immune receptor

activation

BY MAKAYLA CONLEY

IMAGE COURTESY OF FLICKR

The human immune system is widely studied due to its integral role

in health, from preventing infection to the development of autoimmune

diseases. At Yale University, professor Anna Pyle’s lab is specifically interested

in the function of innate immune receptor retinoic acid-inducible

gene I, or RIG-I, which serves as a first line of defense against infection.

RIG-I, among other similar receptors, is responsible for detecting viral

RNA or damage and alerting the rest of the immune system. However,

mutations in RIG-I can lead to over-activation and excessive signaling,

causing individuals to be more susceptible to autoimmune disorders.

Because of this, researchers in the Pyle lab are interested in studying the

activation of the domain in RIG-I responsible for signaling.

When designing an experiment to study the conformational changes

of the protein in the signaling pathway, the Pyle team ran into several issues

with methods currently used to study similar pathways. According to

Thayne Dickey, a former postdoc in the Pyle lab, a big problem was that

“cells are messy.” In vivo studies in molecular biology face a myriad of challenges

due to the dynamic nature of cells and interdependence of many

molecules and their functions. Because of the complications of in vivo

studies, researchers in Pyle’s lab spearheaded the effort to create an in vitro

method to study RIG-I in order to streamline analysis of its activation.

The team of researchers was particularly interested in how RIG-I becomes

activated to eject its signaling domain and how incorrect activation

leads to autoimmune disorders. The researchers turned to a technique

called Florescence Resonance Energy Transfer, or FRET. This

assay involves labeling a protein in two places with different fluorophores,

in which the florescence of one fluorophore excites the other

fluorophore. “FRET tells us the distance between two positions in the

protein, so if it changes structure we can see that by a change in fluorescence,”

Dickey explained. FRET has previously been used in the field of

drug discovery because it enables scientists to test millions of potential

drugs, offering a rapid fluorescent output that shows which compounds

have the desired effect. Despite the prevalence of FRET in drug discovery,

it is rarely used in vitro when studying purified proteins and conformational

changes. “The possibility of extending fluorescent analysis…

to RIG-I analysis was attractive,” Dickey recalled. When comparing this

assay to other similar options, Dickey said that FRET stands out because

of its high throughput and reliability.

One of the largest challenges the researchers encountered next was

getting an efficient label for the protein of interest. Dickey revealed

that trial and error was necessary to figure out how to stick the fluorophores

onto the protein. “The conjugation site had a dozen constructs,”

Dickey said. In some constructs, the protein would not be labeled

correctly, so the whole assay would fail. It was critical for protein

labeling to accurately measure the ejection of the RIG-I signaling domain

because it is the first step in receptor activation.

Finally, with a working assay that revealed conformational changes

of RIG-I before and after activation, the team analyzed the role of ATP

and RNA binding in the signaling pathway. Previously, ATP was assumed

to play an integral role in the ejection of the signaling domain

of RIG-I and was required for full activation of RIG-I. However, after

running the FRET assay, the researchers found that ATP only has a

small effect on the conformation and ejection of the signaling domain.

It changed the way Dickey thought about RIG-I since “[this experiment]

shows that RNA is sufficient to [activate RIG-I] on its own and

ATP is not actually required for the activation of RIG-I.” While there is

still some uncertainty around the role of ATP, the lab found that RNA

binding alone caused a reduction in FRET consistent with the signaling

domain being ejected from the protein. Taking it a step further,

this result implies that RNA binding is the key biophysical step in the

activation of RIG-I that could be targeted by drugs.

Another key result of this study was the reversible property of RIG-I

signaling domain ejection. When the binding RNA was digested with nuclease,

the FRET measurement increased back to the levels of the initial

inactive state of the protein. This finding demonstrated that RIG-I can be

deactivated and returned to its inactive state after the signaling domain

has been ejected. The use of the FRET assay was essential to discovering

these conformational changes in the protein. The discoveries of the Pyle

lab present the opportunity for RIG-I to be a potential therapeutic target

for blocking autoimmune disorders. Already, the lab is diving into applications

of RIG-I activation and all it can offer the field of immunotherapy.

www.yalescientific.org

December 2019

Yale Scientific Magazine

9


NEWS

Molecular Biology

LONG

LIVE THE

ORGANOIDS

Vascularization

in brain

organoids

BY MARIA LEE

Through cutting-edge advancements in the field of genetics, researchers

are now able to grow three-dimensional models of organs,

called organoids, using in vitro methods. Generating organoids for

the human brain has become a pioneering research effort, especially

in regards to the use of human embryonic stem cells (hESCs) to create

human cortical organoids (hCOs). However, due to the fragility of

these delicate models and the specific conditions required for growth,

organoids can be quite difficult to generate and maintain for long periods

of time. Hence, scientists continue to search for ways to optimize

the generation of these three-dimensional in vitro models. One important

aspect of organoid growth is the ability of blood to circulate

both nutrients and oxygen efficiently. Recently published in Nature

Methods, In-Hyun Park and his team at the Yale School of Medicine

have discovered a way to induce vascular-like structures in hCOs that

increase their functional maturation.

The key to inducing these vascular-like networks was the expression

of the human E26 transformation specific variant two gene (ETV2).

ETV2 over-expression enables the conversion of hESCs into endothelial

cells, which line blood vessels. hCOs with twenty percent ETV2-infected

cells were controlled to express ETV2 at a specific time point.

“The remaining eighty percent were parental cell lines,” explained Bilal

Cakir, first author of the paper. The different cells formed a three-dimensional

embryoid body after they were plated. “During the early

stage of brain organoid development, the ETV2 expressing cells generated

vascular-like structures within hCOs, called vhCOs,” Cakir said.

The researchers of this study performed several tests to analyze the

process and effects of vascularization in vhCOs. “The most striking

findings were that there is significantly less cell death after long-term

culture in the vhCOs, and also that neurons become much more mature

compared to control hCOs,” Cakir said. To study the effects of vascularization

in vhCOs on organoid growth and cell death, he analyzed

differences in size and growth rate of these organoids. He discovered

that at day eighteen, before vhCO cells underwent ETV2 induction, the

sizes of the organoids were similar. At day thirty and post-ETV2 induction,

however, control hCOs were larger than vhCOs. But the growth

rate of vhCOs increased over time, and at days seventy and 120, the two

PHOTOGRAPHY BY KATE KELLY

types of organoids had similar sizes again. Cakir believes that vascularization

in vhCOs occurred around the time of their early growth lag

and subsequent growth rate increase. In addition, vhCOs had significantly

smaller amounts of cell death than control COs as the organoids

continued to grow, suggesting that vhCO vascularization decreases cell

death and enables organoid growth by carrying out oxygen diffusion.

To study how neuronal maturation and activity are influenced by

ETV2 induction in vhCOs, Cakir performed whole-cell patch clamp

recordings to elucidate the action potentials produced by vhCOs and

control hCOs. Results revealed that only one out of twenty control hCO

cells produced any action potentials, while multiple action potentials

were recorded for eight out of twenty vhCO cells. This data suggests

vhCO vascularization enhances neuronal activity and maturation. Researchers

also conducted gene set enrichment analyses that measured

the resemblance between vhCO-derived neurons and in vivo developing

human brain neurons. Results showed that vhCO-derived neurons

were similar to gestational week sixteen to nineteen human neurons,

whereas the corresponding control hCO-derived neurons were more

similar to gestational week ten to twelve human neurons. These results

show that ETV2-induced vascularization increased the speed at which

neurons were able to functionally mature in brain organoids.

Cakir’s team concluded that a functional vascular-like structure

can be created in vhCOs through induced ETV2 expression that subsequently

reprograms EC cells. Some key characteristics of this vasculature

are its ability to decrease cell death and expedite functional

neuron maturation. Despite these findings, Cakir believes that further

optimization of brain organoid development is needed. “The vascularized

organoids still need to be optimized to be used for even later

stages,” Cakir said. In addition, he acknowledges the importance of

brain organoids and their potential for studying various neural disorders:

“Brain organoids hold the platform for investigating early stages

of neuron wiring [and] are very critical for studying neuropsychiatric

and neurodevelopmental disorders,” he said. ETV2-induced vascularization

of brain organoids provides a platform for researchers to study

these diseases at early stages, opening up a wide range of possibilities

for future neurodevelopmental research.

10 Yale Scientific Magazine December 2019 www.yalescientific.org


Microbiology

NEWS

TARGETING

TUMORS

WITH RNA

Collaboration between

RNA structure

and immunology

BY TONY LECHE

PHOTOGRAPHY BY MARIA FERNANDA PACHECO

Cancer is the second-largest killer in America and one

of the most difficult diseases to treat. How do we possibly

target cancer cells when they appear almost exactly

the same as our own healthy cells? Recently, two Yale research

groups have developed a new therapy that specifically

shrinks or kills cancers in mice and can potentially

be applied to future treatment in humans.

Pursued by the Pyle lab and the Iwasaki lab, the research

team designed and synthesized a unique RNA called Stem-

Loop RNA 14 (SLR14). SLR14 specifically binds to RIG-I,

an important pattern recognition receptor (PRR) located

inside the cell that recognizes viral double-stranded RNA.

In this model, SLR14 can mimic viral infection in the cell to

activate the RIG-I pathway, leading to tumor cell apoptosis

or immune system activation to kill tumors.

“Targeting PRRs to treat cancer has been studied for

many years,” said Xiaodong Jiang, one of the head researchers

of the project from the Iwasaki lab. “Compared

with other PRR agonists, there are relatively few studies on

RIG-I agonists in cancer treatment. One important question

is how to design RNA or agonists that can specifically

bind and activate RIG-I, and how to precisely deliver them

into the tumor.” As of now, the research group has used

an in vivo delivery system, where SLR14 (RNA) is directly

delivered to the tumor, and has observed favorable tumor

responses and regressions in mice.

“Our aim is to activate the innate sensor pathway within

the tumor microenvironment to induce a potent antitumor

response,” Jiang explained. “By mimicking virus infection

in tumors, SLR14 binds to RIG-I and activates the

downstream signals to induce type I interferons (IFNα and

IFNβ). Through this strategy, we can directly induce tumor

cell death, or indirectly kill tumors by inducing immunogenic

cell death.” But how does SLR14 avoid killing

healthy cells along with the tumors? Previous research

demonstrated that normal cells express higher level of anti-apoptotic

signals than tumor cells, which allow them to

stay healthy and survive.

SLR14 also appeared able to enhance the effectiveness of

existing cancer therapies. Tumors can block off the cytotoxic

function of surrounding T cells through PD-L1 (on

tumor cells) binding to PD-1 (on T cells). Blocking PD-1

or PD-L1 with antibodies, or immune checkpoint blockade

therapy, has shown remarkable success in some types of

cancer patients. In this study, SLR14 has been observed to

improve the antitumor efficacy of anti-PD1; in some cases,

it also showed good efficacy in anti-PD1 resistant tumors.

In addition, SLR14 activates the T cell response to kill tumor

cells by recognizing antigens specifically expressed in

tumor cells but not healthy cells.

The research team found success in several types of mouse

tumor models, including mouse melanoma and colon cancer.

More research is still needed, however, before the treatment

is ready to be applied to human patients. Jiang and

the rest of the researchers are excited for the future goals of

the project: “First, we aim to optimize the delivery system,

looking at aspects such as dosage and how to apply RNA intravenously.

Second, we want to test in other models such as

breast and lung cancer,” Jiang said. Once these pre-clinical

models are finished, the ultimate goal is to perform clinical

trials and move forward with the studies in human tumors.

This project spreads over several interdisciplinary subject

areas, specifically RNA biology and immunology.

“Anna Pyle is an expert in RNA. [Her lab] focuses on the

structure of RNA. Akiko Iwasaki is a well-known immunologist,

specializing in antiviral immunology. I want to

emphasize that this has been a very good team work, and

we are having a very successful collaboration,” Jiang emphasized.

By bringing together experts in RNA biology

and immunology, a previously known anti-tumor mechanism

has been improved and identified as a promising

therapy for treating cancer.

www.yalescientific.org

December 2019

Yale Scientific Magazine

11


RUNNING

UP & DOWN

YOUR

SPINE

Imaging the elusive

vertebral lymphatic network

BY MARIA FERNANDA PACHECO

ART BY ALICE TIRARD

Modified historical drawing of lymphatic vessels and

the thoracic duct from 1805. Image courtesy of Special

Collections & Archives, the University of Liverpool.


FOCUS

cell biology

Between our cells lies a concealed,

interwoven tapestry of vessels that plays

a central role in transporting material all

over our bodies. The primary function

of these lymphatic vessels is to drain

our tissues of fluid that leaks out from

the systemic circulatory system, helping

us to get rid of excess substances, toxic

metabolic waste, and potentially harmful

pathogens. Lymphatic vessels can be found

almost everywhere—from our skulls to

the vertebral column. But visualizing

vertebral lymphatic vessels is not always

as easy as visualizing blood vessels,

for example. The fact that lymph—the

material that lymphatic vessels carry

around—is transparent, combined with the

microscopic space through which it travels,

confers this network an almost invisible

quality. The task becomes even more

complicated in the spaces that surround the

spinal cord, where the minuscule vertebral

lymphatic vessels (vLVs) are so expertly

hidden within the bone chambers of the

vertebral column that, despite the fact that

the scientific community has been aware of

their existence for a few years, no one had

known exactly how they were organized in

three dimensions.

However, earlier this year, this barrier

in scientific imaging was finally broken by

a collaborative effort between researchers

at Yale and institutions in France and

Finland. Led by Jean-Léon Thomas, an

associate professor of neurology at the

Yale School of Medicine, and Laurent

Jacob, a postdoctoral researcher at the

Brain and Spine Institute (ICM) the

Université Pierre et Marie Curie in Paris,

the team innovatively combined

a series of advanced imaging

methods, including iDISCO+

(immunolabeling-enabled threedimensional

imaging of solventcleared

organs) tissue clearing and

light-sheet fluorescence microscopy

to reconstruct—in three dimensions—

the anatomy of the lymphatic vasculature

within the spinal cavity of mice for the

first time. Their reconstruction reveals the

projections of lymphatic vessels as they

extend from spinal nerve roots to lymph

nodes in the rest of the body and to the

thoracic duct, the body's largest lymphatic

duct. "We wanted to better localize all of

the connections between the vertebral

lymphatic vessels and the lymph nodes,

as well as their connections with the

periphery,” Jacob said. “We were able to

precisely describe this network all along

the spinal cord.”

Intricate details call for intricate methods

The intricate microscopic architecture

of the vLV network meant that advanced

immunohistology, complex imaging

methods, and other state-of-the-art

techniques had to be combined. After

sectioning the vertebral column into

segments, the tissues were subjected to

iDISCO+, a protocol in which tissues

were decalcified and treated with organic

solvents. This process removes fat

molecules from the tissues to make them

more transparent and easier to

microscopically examine in greater detail.

Next, whole mount immunolabeling

was performed, whereby the lymphatic

endothelial cells were stained using two

antibodies that bound to two lymphatic

endothelium-specific markers, LYVE-1

and PROX1. These antibodies worked as

labels, enabling the researchers to the track

and monitor these lymphatic endothelial

cells around the spinal cord and inside

the vertebral canal. They then turned to

light-sheet fluorescent microscopy, which

uses a sheet of light to visualize sections of

tissue deep within the sample. Light-sheet

microscopy can scan large surfaces of

tissues very quickly at high resolution. The

group then pieced all of this information

together using a 3D software called

Imaris to produce a comprehensive final

set of images and videos. Importantly,

their imaging approach preserves the

surrounding anatomical structures of

the spinal cord, framing this vertebral

lymphatic system within the context of

surrounding muscle and bone tissue,

lymph nodes, and nerve cells.

Being able to visualize the threedimensional

vLV network is crucial to

understand its function more than other

systems in the body. "You need to see

the connections between the vessels and

the lymph nodes because, essentially,

the [lymphatic] vessels are like pipes,"

Thomas said. "If you don't know where

the pipes are connected––that is, where

they are draining and where they are

collecting fluids––you don't have all of

the information.” Truly comprehending

the macroscopic arrangement of this

network, therefore, also involves

thinking about how it relates to lymph

nodes, which serve as collection

points for lymph throughout the

body. With these connections in

hand, the images provide essential

information for the vertebral lymphatic

system to be studied mechanistically,

structurally, and even functionally.

A step beyond imaging: the function of vLVs

While the initial objective of this paper

was to report images that revealed the

three-dimensional arrangement of the

vertebral lymphatic vasculature, the

researchers now found themselves with

many opportunities to study its function.

www.yalescientific.org December 2019 Yale Scientific Magazine

13


For example, some scientists hypothesized

that vLVs could be implicated in immune

responses that help the body repair areas

where spinal cord lesions have been locally

sustained. To look into that question, the

researchers injected a chemical known to

damage spinal cord cells into adult mice

and measured the extent of vLV networking

after one week. According to the data they

acquired, increased inflammation in the

spinal cord in response to the injury led to

an increase in the size of vLVs, confirming

a previous report that indicated that

lymphatic vessels regulate the immune

surveillance of tissues in the central

nervous system.

Moreover, the group also explored the

functionality of this vertebral lymphatic

network as a drainage system. To do so,

they injected molecular tracers into specific

locations on the vertebral column, and

then analyzed their distribution in the

surroundings of the injection site after

fifteen to forty-five minutes. Using their

immunolabeling approach, they were

able to observe that those tracers were,

in fact, present in the fluid collected by

the lymph nodes locally connected to the

vertebral lymphatic vessels. This finding

substantiates the theory that the vLV

network is involved in the absorption

of molecules and the draining of tissues

(pooling the fluid into lymph nodes),

thereby validating the possibility that this

vertebral lymphatic network could play an

essential role in circulating immune cells

between the central nervous system and

the lymph nodes around the spinal cord.

In addition, the researchers also found that

the vLV system is organized into segmented

regions that connect to local lymph nodes,

suggesting that lymph is drained at the level

of each vertebra, rather than as a continuous

stream down the spine.

Looking into the unknown:

other roles of vLVs

PHOTOGRAPH COURTSEY OF KATHERINE DAI

A photograph of the members of the Thomas Lab at the Yale University School of Medicine.

Knowing that the vLV network could

help in immune surveillance of the

central nervous system, others can now

study the transport mechanisms leading

to the development and progression of

inflammation, infections, and pathologies

in the central nervous system. "We can

ABOUT THE AUTHOR

cell biology

think differently now that we know that

there are lymphatic vessels around the

spinal cord and how they are arranged,"

Jacob said. "We can ask new questions, such

as what their role in a neuropathological

context could be, or in the context of

spinal cord lesions, or in the context of

neurodegenerative diseases, for example."

Another potential function of vLVs is

in cancer metastasis, that is, the process

in which cancer cells are disseminated

away from the site of the primary tumor.

"It is possible that this network could be

important for transporting and propagating

all kinds of pathogens or metastatic cells

from the periphery of the body towards

tissues in the CNS, as well as tissues that

surround it, which are the meninges, the

vertebral bones, and the skull," Thomas

said. As many as seventy percent of cancer

patients develop spinal metastases. In that

context, the vLV architecture could provide

a roadmap to understand how metastatic

cells move along the spinal cord, possibly

abetted by the vLV network.

By shedding light onto a biological

arrangement that had not been previously

studied, Thomas, Jacob, and their

collaborators have given the scientific

community a valuable resource. With

this three-dimensional structure in hand,

scientists can now work towards a deeper,

more structurally driven understanding

of the vertebral lymphatic system,

and through it, explore new theories

surrounding the spread of infections,

central nervous system immune functions,

and the development of metastatic tumors.

MARIA FERNANDA PACHECO

MARIA FERNANDA PACHECO is a first-year student at Grace Hopper college and prospective

Neuroscience and Literature & Comparative Cultures double-major. In addition to writing for

the Yale Scientific, Maria Fernanda is also a Community Health Educator, teaching mental health

workshops in public schools around New Haven, a volunteer for the Yale Alzheimer’s Buddies,

and a member of Yale’s chapter of Timmy Global Health—a non-profit dedicated towards the

expansion of accessibility to healthcare in countries all over the world.

THE AUTHOR WOULD LIKE TO THANK Dr. Jean-Léon Thomas and Dr. Laurent Jacob very much for

their insight, time, enthusiasm and kindness in sharing their research and the findings obtained

by their group.

FURTHER READING

Jacob, L. et al. (2019). Anatomy and function of the vertebral column lymphatic network in mice. Nature

Communications, 10(1). doi: 10.1038/s41467-019-12568-w

Antila, S., et al. (2017). “Development And Plasticity Of Meningeal Lymphatic Vessels”. The Journal Of

Experimental Medicine 214 (12): 3645-3667. doi:10.1084/jem.20170391.

FOCUS

14 Yale Scientific Magazine December 2019 www.yalescientific.org


Medicine

FOCUS

The doctors were stumped. The nine-year-old girl in front

of them, who would later be code-named patient A.1, was

anemic and fatigued. She had a chronic cough and difficulty

breathing, and her ears, skin, and urinary tract were constantly

infected. In the coming years, her situation would worsen

as she developed colitis, the inflammation in her digestive

tract. Clinical blood tests found abnormal white blood cell

counts, a hint that her disease was related to immune system

dysfunction. To reconcile this clue with her diverse range of

symptoms, her team of physicians at the National Institutes of

Health (NIH) turned to Carrie Lucas, now assistant professor

of immunobiology at the Yale School of Medicine, for help.

Ten years after the onset of patient A.1’s symptoms, researchers

in the Lucas lab and their collaborators have finally

uncovered the cause of her illness: a defective immune system

protein called PI3Kγ. This previously unseen disease

has now been named Inactivated PI3K-gamma Syndrome

(IPGS). By elucidating the molecular mechanisms behind

IPGS, the researchers both enabled improved treatment for

patient A.1 and clarified the role of PI3Kγ in immune system

regulation, overthrowing previous assumptions from mouse

model studies. This information is particularly valuable because

PI3Kγ is a promising new target for immunotherapy,

which uses patients’ own immune systems to fight disease.

A needle in a haystack of genes

The Lucas lab at Yale studies rare genetic diseases of the immune

system: “not the standard allergies or colds like kids normally

get, but those patients who get really severe infections

really easily, or who have fevers and feel really sick, but show

no signs of an infection,” Lucas said. The researchers’ subjects

are generally children because early onset of disease is an indicator

of a possible mutation in a single gene. Diseases that appear

in adulthood, conversely, are more likely to be caused

by complex genetic and environmental triggers. Understanding

a single mutation that causes a disease reveals

specific insight into the affected gene.

Patient A.1’s symptoms and young age

led the researchers to hypothesize that

she had a single-gene mutation. To

find it, the researchers needed

to sequence her entire

exome, the portion of

the genome that encodes

for func-

pro-

tional

tein, with

con-

key insights into an

immunotherapy target

UNRAVELING A

MEDICAL MYSTERY

by Isabella Li | art by Anusha Bishop | photography by Nithyashri Baskaran

www.yalescientific.org

December 2018

Yale Scientific Magazine

15


FOCUS

Medicine

sent from the patient and her family. They examined

the unique variants in her genetic code.

However, there are thousands of variants between

any two individual’s exomes, most of which do

not cause disease. The task now was to comb

through all these variants in search of the single

mutation underlying patient A.1’s symptoms.

To help whittle down their initial list, the researchers

analyzed the genes of patient A.1’s mother

and father, who were healthy. As with everyone

else, patient A.1 inherited half of her genome—

that is, one of two alleles of each gene—from each

of her parents. Thus, any combination of variants

she shared with her parents could be excluded.

“We can filter the list and say, if only the kid is sick,

then we can rule out all these variants,” Lucas said.

After further refining their list, the researchers

identified a prime suspect: a mutated PIK-

3CG gene, encoding the PI3Kγ protein. Patient

A.1’s healthy parents both possessed one mutated

PIK3CG allele and one normal PIK3CG allele.

A single copy of the defective gene was not

enough to cause disease, but by chance, both parents

passed their mutated allele on to patient A.1,

leaving her with two defective alleles. This double

mutation provided strong evidence that defective

PI3Kγ could be to blame.

Figuring out the pathway

Previous research had implicated PI3Kγ as an

actor in the immune system. As part of the phosphatidylinositol

3-kinase (PI3K) family, PI3Kγ

initiates immune signaling pathways by appending

phosphate groups to lipids in the cell membrane.

Because of its central role in signaling,

PI3Kγ has become a potential target for immunotherapy.

Expecting abnormalities in her immune

system, the researchers analyzed

patient A.1’s blood to determine

the types and amounts of

white blood cells

present.

“THEIR

EXPERIMENT

ALSO HIGHLIGHTED

They used flow cytometry, a method of counting

cells in a mixture using a laser that detects fluorescently

stained markers specific to a given type.

Our immune system comprises two arms. The

adaptive immune system, which includes T- and

B-cells, develops to respond in a highly specific

manner to pathogens—foreign disease-causing

agents—as we encounter them. Meanwhile, the

innate immune system comprises non-specific

“first responders,” which recognize common molecular

patterns on pathogens to kick off the adaptive

response by, for example, promoting inflammation.

In her adaptive immune system, patient

A.1 had a low count of regulatory T-cells, which

stop the immune system from attacking our own

cells, and memory B-cells, which remember past

pathogens to prevent future re-infection. This

finding explained her recurrent ear, skin, and

urinary tract illness. Conversely, she had a high

count of T cells expressing CXCR3, a marker that

allows them to infiltrate nose, gut, and lung tissue,

in line with her difficulty breathing and colitis.

In her innate immune system, patient A.1 exhibited

abnormally high levels of small signaling

proteins called cytokines, which induce inflammation.

Accordingly, when the researchers

treated healthy cells with a chemical that inhibits

PI3Kγ, they found increased expression of

the IL12B gene, which encodes the IL-12 and

IL-23 cytokines. This further aligned with patient

A.1’s breathing and digestive tract issues.

“Her [innate immune white blood cells] make a

lot of pro-inflammatory cytokines—more than

they should. One of [PI3Kγ’s] functions is to

tamp down that inflammation,” Lucas said.

In essence, the researchers found that normal-functioning

PI3Kγ has both adaptive and

innate immunity functions, supporting regular

T-cell activity while preventing inflammatory

cytokine activity.

“Dirty” mice, better results

While the researchers’ findings held promise,

they were also confusing: laboratory mice

previously engineered to lack PI3Kγ did

not display the same symptoms as

patient A.1. To rationalize

the discrepancy, the

researchers

POTENTIAL DRAWBACKS

OF MODELING HUMAN IMMUNE

PROCESSES IN STERILE LAB ORGANISMS.”


looked to past work by the Masopust and

Jameson labs at the University of Minnesota,

where blood samples from pet-store

mice and laboratory mice were shown to

express vastly different immune cell profiles.

“Laboratory mice are kept in super clean environments…

they don’t even get exposure

to the normal air, and so they have very few

infections or challenges throughout their

full developmental spectrum,” Lucas said.

In contrast, pet-store mice, having been exposed

to various environmental pathogens,

have more mature immune systems. The researchers

predicted that the immune systems

of conventional laboratory mice could

not accurately reflect PI3Kγ activity.

To circumvent this issue, they decided to cohouse

laboratory mice that were deficient in

PI3Kγ with “dirty” mice they bought from pet

stores. Andrew Takeda and Timothy Maher,

co-first authors on the paper, noted that this

method presented unique challenges as the

“dirty” pet store mice were accompanied by a

host of microbes that threatened the sterile lab

environment. “We can screen for some specific

pathogens normally kept out of the lab, but

the pet store mice could be carrying additional

viruses, bacteria, and parasites that we haven’t

identified,” Takeda said. For this reason, the

researchers had to conduct their research in a

special facility, typically reserved for research

with more dangerous pathogens.

This unconventional setup introduced complications,

as pet store mice may bring lethal

pathogens that can lead to experiments being

cut short. The researchers’ pathogen screens

once had missed Mycoplasma pulmonis, a

deadly bacterial infection towards which pet

store mice have developed resistance, which

resulted in their experiment ending just three

weeks in. “The twenty-one days, that’s just

starting the experiment. There’s four to six

weeks of preparing the lab mice before,” Maher

said. “So that’s three months, just gone.”

Ultimately, the researchers found that when

incubated with the “dirty” mice and their associated

pathogens, the immune systems of

PI3Kγ-deficient laboratory mice became activated

to behave in a similar manner to that of

patient A.1. This behavior included decreased

regulatory T-cell counts, poor B-cell responses,

and increased production of IL-12 and IL-

23, supporting their hypothesis that PI3Kγ

regulates T- and B-cells and cytokine activity.

Their experiment also highlighted potential

drawbacks of modeling human immune processes

in sterile lab organisms.

Insights into the immune system

Having identified a double PI3Kγ-mutation

underlying patient A.1’s illness, the researchers,

in collaboration with her physicians, improved

patient A.1’s treatment. For instance,

to combat her inflammation, she was prescribed

an IL-12 and IL-23 inhibitor called

ustekinumab, an FDA-approved drug for

psoriasis and Crohn’s disease. Beyond patient

A.1’s specific Inactivated PI3K-gamma Syndrome,

the researchers’ work has uncovered

fundamental knowledge about the PI3Kγ

protein’s role in immune response, with broad

medical implications. For example, PI3Kγ inhibitors

have shown promise as immunotherapy

treatments for cancers. By understanding

the effects of PI3Kγ deficiency, doctors can

now anticipate and manage potential side effects

when targeting the protein.

While the Lucas lab remains interested in

refining their understanding of PI3Kγ, they

have also expanded their scope, using the

same methodology to study additional rare

genetic diseases. By working backwards from

symptoms to their genetic causes, the researchers

are able to investigate lesser-known

genes. “In a lab, you don’t just think up these

different rare mutations. [In a rare genetic

disease] these mutations just happen, and it

helps you get a better understanding of basic

immunology and how cells really work in humans,”

Maher said. Takeda believes in the dual

impacts of this line of research: “the project

starts out because there’s a patient who’s sick

and they don’t know why. It’s really rewarding

to be able to help figure out why someone

has this mystery disease while understanding

something new about the immune system.”

ABOUT THE AUTHOR

Medicine

ISABELLA LI

ISABELLA LI is a sophomore in Jonathan Edwards College hoping to major in molecular, cellular,

and developmental biology. Outside of writing for YSM, she conducts research on non-coding

RNAs and is a member of the Asian American Students Alliance and Negative Space.

THE AUTHOR WOULD LIKE TO THANK Andrew Takeda, Timothy Maher, and Professor Carrie Lucas

for their willingness and enthusiasm in discussing their project.

FURTHER READING

Beura, L. K., Hamilton, S. E., Bi, K., Schenkel, J. M., Odumade, O. A., Casey, K. A., … Masopust, D. (2016).

Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature, 532,

512-516. Differentiation.” Cell Stem 23, no. 5 (November 1, 2018).

FOCUS

www.yalescientific.org

December 2018

Yale Scientific Magazine

17


FOCUS Technology

HARNESSING

LIGHT

BY MATT SPERO

ART BY MIRIAM KOPYTO

Measuring the

color of a

single photon

Galaxies

Photons, little packets of light, are everywhere.

By some estimates, the Earth is bombarded

with 10 35 photons from the sun per

second. Considering that there are 10 20 grains

of sand on earth, the number of photons is

estimated to be about a quadrillion earths’

worth of sand. Despite being bathed in an

essentially steady stream of light, we have the

technology to isolate and measure the presence

of individual photons. Such technology

is aptly referred to as “single photon counters.”

While trying to measure single photons

may seem contrived and unimportant, photon

counting is in fact central to astronomy,

bioluminescence, medicine, genomics, quantum

communication, and materials science,

among other fields.

While we have been counting photons for

decades—on the Hubble Space Telescope,

for instance—engineering limitations have

made it near impossible to measure the

wavelength of a single photon. The wavelength

of a photon, or the distance between

successive peaks or troughs in the wave,

translates into the color of light, which is

the photon’s most important physical property.

Recently, a research team led by Hong

Tang—the Llewellyn West Jones, Jr. professor

of electrical engineering at Yale—and

Risheng Cheng—a graduate student in the

Tang lab—engineered a single-photon spectrometer

that can detect both the presence

and wavelength of an individual photon.

Frequency Asked Questions

The goal of spectroscopy is to study the

interactions between matter and light. There

is a plethora of spectroscopic devices, which

are commonly used to measure absorption

and emission of chemical compounds. Modern

spectrometers are highly sensitive and

can measure light from stars millions of light

years away, allowing researchers to gain insight

on the spectrum of electromagnetic

rays that radiate from celestial bodies. The

next logical step would be to marry spectroscopic

capabilities with single photon counting

technology, yet this step has proven more

challenging than expected. Attempts to simultaneously

detect a single photon without

ignoring its spectral information have resulted

in resolutions too low for accurate measurement

and machinery too bulky for practical

use. Single photon spectrometers would

benefit fields such as astronomy, which rely

on very weak sources of light and a limited

source of photons. “The single photon is a

very weak energy packet. Not all conventional

detectors can detect a single photon,”

Cheng said. But as with all engineering, the

goal is to extract as much information as

possible out of a single measurement.

Devices known as superconducting nanowire

single photon detectors (SNSPDs) are

state-of-the-art in single proton detection.

Current technology depends on the use of

either large wavelength scanners and signal

amplifiers or semiconductor-based single

photon counters with a small number of

detection channels. These methods present

18 Yale Scientific Magazine December 2019 www.yalescientific.org


a tradeoff between photon sensitivity and

spectral sensitivity. “Semiconductors all

amplify single photon energy thousands or

millions of times [to an electrically detectable

level], but you lose all information on

different photon energies and wavelengths,”

Cheng said. This equipment can also succumb

to a phenomenon known as “dark

count,” in which detectors report a photon

despite an absence of light. Dark counts are

caused by electrodes releasing electrons at

high temperatures.

An Electrifying Solution

Tang and his collaborators recently reported

a novel solution that could be implemented

at the millimeter scale. “There was a lot of

design simulation, application, and testing,”

Tang said. “There are many stringent requirements

and critical design parameters.” Their

broadband on-chip single-photon spectrometer

does not suffer from any of the issues

mentioned prior—a large amount of effort

was put into finely tuning its spectroscopic

sensitivity. The device is capable of measuring

wavelengths ranging from six hundred to two

thousand nanometers, encapsulating both infrared

and visible light regions. This feat was

achieved through the coupling of two distinct

circuits: one to disperse and diffract the light,

and the other to detect the light. Incredibly, all

of this circuitry was contained in a single chip.

The first circuit contains perhaps the most

important mechanical part of the device,

known as an echelle grating. A type of diffraction

grating, echelle grating is comprised of a

periodic series of grooves that split photons

based on their wavelength, a common feature

of spectrometers. Echelle grating was used for

its particularly high dispersive power. Following

diffraction, photons are scattered outwards—like

a garden hose spray with low to

high wavelength photons from one end to the

other—towards a curved superconducting

nanowire. Depending on its wavelength, the

diffracted photon can strike various points

on the nanowire. Together, the grating and

nanowire form a structure known as Rowland

mounting. When a diffracted photon hits the

nanowire, it generates a signal that is propagated

in both directions towards detectors on

either end. By measuring the time difference

between these two signals and knowing the

speed of these signals, the point on the wire

where the photon struck, and in turn, the

angle of diffraction, can be calculated. With

the angle of diffraction, the wavelength of the

photon can be determined.

Small Innovations Make All the Difference

To increase the resolution of the spectrometer,

the researchers also equipped the superconducting

nanowire with a microwave

delay line, which is capable of reducing propagation

speed along the wire to 0.73 percent

of that in a vacuum, the slowest speed reported

among superconducting nanowire delay

lines. This attenuation in velocity is possible

due to the capping of the wire with insulating

aluminum oxides. By reducing the velocity of

the signal, the time delay is naturally amplified,

translating into higher resolution.

To construct the nanowire, the researchers

employed a method called atomic layer

deposition. A material base is exposed to

multiple chemical precursors sequentially.

Each of these precursors then reacts

and attaches to the material surface in a

self-contained manner. This process is highly

efficient and can be used to develop pure

superconductive nanowire. “If there are any

defects in the device, it will not work as we

would like. So far, this is the best [nanowire]

that can be grown,” Cheng said. Testing

various frequencies of light ranging from

600 nanometers to 1970 nanometers within

the broadband device, the researchers found

that the spectrometer can differentiate between

two wavelengths at least seven nanometers

apart, which is a remarkable level of

sensitivity for an instrument on a chip.

Implications

The researchers considered various applications

as they completed this device. One

potential use is the detection of biological

stains, multicolored dyes that typically mark

particular aspects of tissues and cells. “In

most cases, biological luminescence occurs

at the single photon level,” Cheng said. Being

able to accurately and reliably measure

the strength of a small number of photons

could allow for a more detailed investigation

into human tissue. Additionally, while there

ABOUT THE AUTHOR

Technology

FOCUS

PHOTOGRAPHY BY SIENA CIZDZIEL

Hong Tang—the Llewellyn West Jones, Jr.

professor of electrical engineering at Yale—

and Risheng Cheng—a graduate student in

the Tang lab—engineered a single-photon

spectrometer that can detect both the presence

and wavelength of an individual photon.

are a variety of medical imaging modalities,

many—including X-ray—rely on the detection

of high energy particles. Implementation

of more efficient photon counting chips

can be used to reduce radiation doses while

maintaining image quality and improving

the signal-to-noise ratio.

Another field that could benefit from this

research is quantum communication, a new

way of transmitting information. In quantum

communication, detectors take advantage of

the superposition of quantum bits, which is

the ability of to represent a combination of 0

and 1 simultaneously. The spectrum could be

divided into several different channels, enabling

parallel transmission of the signal in

different wavelengths. With this technology,

the communication capacity within a single

photon detector could be increased one hundred-fold.

“If you use conventional transmission

with one fiber, you’ll need ten detectors

to receive ten wavelengths,” Cheng said. “In

our detector, we only need one recipient to

differentiate these wavelengths, reducing the

cost.” With the advent of this on-chip single-photon

spectrometer, it is now possible

to extract even more information from individual

photons, and its small scale will no

doubt facilitate its application to bringing

various dark corners of nature to light.

MATT SPERO is a junior Biomedical Engineering major in Morse College. In addition to writing for

the YSM, he is the president of both Yale Biomedical Engineering Society & Taps at Yale and is a

researcher in the Human Nature Lab.

THE AUTHOR WOULD LIKE TO THANK Hong Tang and Risheng Cheng for their time and enthusiasm.

FURTHER READING

Cheng, C., Chang-Ling, Z., Guo, X., Wang, S., Han, X., Tang, H. 2019. Broadband on-chip

single-photon spectrometer. Nature Communications, 10.

MATT SPERO

www.yalescientific.org

December 2019

Yale Scientific Magazine

19


FOCUS

Chemical Engineering

L E A P I N G

Manipulating

elemental properties

by atomic scale

engineering

BY HANNAH RO

PHOTOGRAPHY BY MICHELLE BARSUKOV

I N T O

If science aims to explain the structures

of the natural world, picoscience refines the

very structures themselves—at the atomic

level. Engineering at the scale of picometers

operates on a trillionth-of-a-meter scale,

dealing with materials that can be roughly

ten million times smaller than a human cell.

The research groups of Charles Ahn and

Sohrab Ismail-Beigi at Yale have ventured into

picoscience by manipulating bond configurations

between individual atoms, thereby altering

and engineering the element’s behavior

in solid state. A recently published study—in

collaboration with researchers from Flatiron

Institute, Brookhaven National Laboratory,

and Argonne National Laboratory—reported

the successful incorporation of cobalt and titanium

within an artificial crystal and the resulting

perturbations in electronic behavior.

This discovery heralds a future in which picoscience

may be used to develop, among other

things, more efficient superconductors.

The Potential of Superconductors

If you have ever undergone a magnetic resonance

imaging (MRI) test, or used a wireless

charger, you have seen a superconductor

at work. A superconductor is any material

that has zero electrical resistance when it is

cooled below a critical temperature, allowing

electric current to pass through with no energy

loss. In contrast, conventional conductors

such as copper wire impose resistance on

electrons travelling through them, leading to

energy loss in the form of heat. Superconductors,

with their perfect energy transfer efficiency,

would allow for cheaper and more efficient

methods of electricity transport; the only

catch is that large amounts of energy have to

be invested into cooling them down in the first

place. Early superconducting materials could

only operate at temperatures near –269 °C, the

boiling point of helium. Since liquid helium as

a coolant is expensive to generate and store,

the potential of superconductors was limited.

In 1986, materials derived from copper—

known as cuprates—were discovered to possess

superconductivity above -183 °C, a temperature

that could be maintained by liquid

nitrogen, a cheap and readily available coolant.

The development of these high-temperature

superconductors (HTS), which

would go on to win a Nobel Prize, ignited

a rush to understand the exact mechanism

behind superconductivity in the hopes of

developing superconducting materials that

operate at even higher temperatures. Ahn’s

research group aims to tackle both goals by

designing materials that possess electronic

properties similar to cuprate-based HTS.

“We try to understand, from a fundamental

viewpoint, why cuprates superconduct. To

do that, we try to design from basic principles

a new high temperature superconductor,”

said Frederick Walker, a senior research

scientist and co-author of the study.

Rather than focusing on the tried-and-true

formula of cuprate materials, the researchers

turned to cobaltate-based materials, which

were anticipated to exhibit cuprate-like properties.

“A lot of work was done by others and

our group to realize something like cuprates—

something very similar to copper but different

enough to realize similar or better properties.

Our group used to work with nickelates, but

as a continuous effort, we moved onto cobalt

as well,” said Sangjae Lee, first author of the

study and graduate student in the Ahn group.

The goal, therefore, was to artificially manipulate

cobaltate-based materials to behave like

those of cuprate. If this behavior was possible,

then the researchers would be one step closer

to realizing the properties responsible for cuprates’

exceptional superconductivity.

Harnessing Heterostructures

Altering the electronic structure of cobalt

to mimic that of copper was no easy feat.

An atom's electronic structure is its defining

feature, a sort of “atomic DNA.” Considering

that atoms do not spontaneously convert

between elements, it stands to reason

20 Yale Scientific Magazine December 2019 www.yalescientific.org


Chemical Engineering

FOCUS

IMAGE COURTESY OF SANGJAE LEE

A molecular beam epitaxy instrument, which

fabricates one-atom-thick layers of metal

oxides, allowing for artificial synthesis of

heterostructures.

that a large amount of energy—or ingenuity—would

be required to alter the electronic

properties of cobalt. “The orbital polarization

seen in cuprate is thought to be a significant

ingredient for superconductivity. We alter

[cobalt’s] electronic structure, which determines

how it behaves and superconducts. In

some sense, it’s alchemy,” Walker said.

The researchers tackled this predicament

by arranging atoms of one type alongside another

species in a crystal lattice. When two

different elements of different sizes are layered

in a lattice structure, they compress and

stretch, distorting the shape of the atomic orbitals,

and by extension, the distribution of

electrons within them. The researchers aimed

to manipulate the electronic properties of cobalt

in this fashion—by engineering a heterostructure

containing cobalt and a functionally

different element, titanium. To grow the heterostructure,

the researchers used a materials

fabrication process called molecular beam

epitaxy (MBE), which enabled them to precisely

layer alternating one-atom-thick sheets

of titanium oxide and cobalt oxide. The MBE

process enables precise synthesis of the heterostructure

by preventing intermixing of the

layers with a high vacuum environment, temperature

control, and computerized shutters

that control the thickness of each layer.

After growing the cobaltate-titanate oxide

heterostructure, the researchers characterized

its structure at the atomic scale using

a high-resolution synchrotron, which

uses bright X-rays to visualize the atomic-scale

structure and electronic properties

of a material. Using spectroscopic and electron

microscopy techniques, the researchers

confirmed that they had assembled distinct

layers of cobaltate and titanate with little intermixing.

The collected data indicated unprecedented

strong distortion of orbitals in

the cobaltate layer, confirming the electronic

structure of cobaltate within a heterostructure.

In other words, they successfully made

cobalt behave like copper.

This success was in large part supported and

enabled by the work of theoretical physicists,

who, throughout the process, had been using

quantum computations to predict and corroborate

experimental electronic properties.

“The structure of these materials, like where

the atoms are, how long the bonds are, and

the distortions at the picometer scale, is something

our theory, in principle, could calculate

correctly. Most of what [the experimentalists

did] agreed with the theory, but some of the

theoretical predictions are hard to measure,

and some of the experimental results we don’t

understand,” said Sohrab Ismail-Beigi, the

lead theorist of the study. Despite a few discrepancies

between theory and experimental

results, preliminary theoretical calculations

provided a roadmap for designing the heterostructure.

According to Ismail-Beigi, the theorists

and experimentalists work together in a

“closed loop” to generate ideas, build on previous

data, and minimize deviations. “It doesn’t

matter who suggests an idea first—sometimes

an experimentalist creates a system and measures

it, and sometimes, we’ll notice something

in the theory and suggest it to the experimentalists,”

Ismail-Beigi said.

ABOUT THE AUTHOR

Picoscience: The Final Frontier

Considered a forerunner of picoscience,

nanoscience has led to tremendous progress

and enabled technologies such as unmanned

drones, three-dimensional printers,

and biomolecular imaging. Picoscience,

which operates at a much smaller scale, is

for now the final frontier for condensed

matter physics. “All the properties of atoms

stem from how electrons behave. Electronic

behavior is sensitive to even very small

[picoscale] distortions in the material, and

how these kinds of distortions create or spur

interesting physics needs to be understood

in the regime of picoscience,” Lee said.

The successful design of the cobaltatetitanate

oxide heterostructure serves as

a case study for the potential of picotechnology

in discovering techniques to alter

properties of known elements. In particular,

transition metal oxide (TMO) systems

remain a primary area of interest for the

researchers for their dynamic electronic

properties. “TMOs have really interesting

electronic motion between atoms, which

makes them unusual superconductors.

These very difficult properties to model

also make them interesting,” Ismail-Beigi

said. With the goal of realizing higher temperature

superconductors in mind, the researchers

hope to continue manipulating

TMO systems at the picoscale level. “We

have an idea as to how we can make the cobaltates

superconduct and how we might

build on this work. We’re [tackling] one of

the premier problems in condensed matter

physics: how do you make a superconductor

at higher temperatures?”

A R T B Y S O P H I A Z H A O

HANNAH RO

HANNAH RO is a sophomore in Trumbull from sunny Southern California. In addition to writing

for the Yale Scientific, she volunteers with Synapse, researches neurodegenerative diseases in the

Lim Lab, and plans events for Korean American Students at Yale.

THE AUTHOR WOULD LIKE TO THANK Sangjae Lee, Dr. Frederick J. Walker, and Dr. Sohrab Ismail-

Beigi for their time and enthusiasm to share their research.

FURTHER READING

Sangjae Lee, Alex Taekyung Lee, Alexandru B. Georgescu, Gilberto Fabbris, Myung-Geun Han, Yimei

Zhu, John W. Freeland, Ankit S. Disa, Yichen Jia, Mark P. M. Dean, Frederick J. Walker, Sohrab Ismail-Beigi,

Charles H. Ahn. Strong Orbital Polarization in a Cobaltate-Titanate Oxide Heterostructure.

Physical Review Letters, 2019; 123 (11) DOI: 10.1103/PhysRevLett.123.117201

www.yalescientific.org

December 2019

Yale Scientific Magazine

21


FOCUS

cell biology

THE

Discovery of a

Cellular Fossil

ORIGIN

O F

BY

JAMES

HAN

THE

ART BY

ELLIE

GABRIEL

NUCLEUS

22 Yale Scientific Magazine December 2019 www.yalescientific.org


Our archaeological record of evolution

is dotted with a few key events,

such as life’s emergence from water

to land and the emergence of functional

wings on birds. However, one

of the most fundamental evolutionary

changes—the emergence of the nucleus—remained

a mystery until recently.

The study of more recent evolutionary

events, such as the emergence of wings

on birds, benefits from rich sources

of information, like fossils.

In contrast, as much as

we understand the

nucleus’s central

role in

eukaryo

t i c

cells,

its development

is still difficult

to study due

to the sparse data in

the archaeological record.

Thanks to a new study led by Dieter

Söll, a Sterling Professor of Molecular

Biochemistry and Biophysics at

Yale, molecular clues to nuclear development,

known as nuclear localization

signals (NLSs), have brought us a step

closer to understanding how, when, and

why the nucleus evolved.

What are NLSs?

Life on Earth is divided into three

domains: prokaryotes, eukaryotes, and

archaea. Within these domains, only eukaryotes

have a nucleus—a specialized,

membrane-bound compartment within

the cell that stores genetic information.

The nuclear membrane acts as a barrier

to compartmentalize the genetic information

and enable the cell to regulate

the amount of proteins that can enter

and interact with the genetic material. In

this way, the cell can regulate how much

each gene is expressed. Large and bulky

protein molecules are unable to pass

through the nuclear membrane themselves.

Instead, transport proteins interspersed

throughout the nuclear membrane—called

karyopherins—facilitate

the transport of eligible proteins in and

out of the nucleus via nuclear pores.

For proper cellular function, only

certain proteins can enter or leave the

nucleus. To allow karyopherins to

detect which proteins can enter the

nucleus, eukaryotic proteins contain

NLSs, short amino acid sequences

that karyopherins can recognize.

These NLSs are always contained

in nucleic acid binding regions—

regions of the protein that can interact

with nucleic acids. Proteins

with NLSs that can be recognized by

karyopherins can enter the nucleus,

while those without cannot. “In eukaryotic

cells, [NLSs] serve as a ticket

to get into the nucleus, recognized by

karyopherins that bind the signals. The

very same sequences can bind to ribosomal

RNA and facilitate three-dimensional

folding of RNA,” said Sergey Melnikov,

a postdoctoral fellow in Söll’s lab

and the first author of the recent study.

What did they do?

The project began with a peculiar set

of results. To study how the nucleus and

nuclear transport pathways may have

evolved in eukaryotes, the researchers focused

on ribosomes—cellular machinery

responsible for synthesizing proteins—

and studied differences in ribosomal

protein sequence and structure in eukaryotes,

prokaryotes, and archaea. The

team studied different aspects of protein

structure in these domains, including

Cell biology

FOCUS

both their sequence and three-dimensional

structure. Knowing that NLSs

were the unique features that allowed

eukaryotic proteins to enter the nucleus,

the group first looked for proteins in

prokaryotes and archaea with sequences

resembling NLSs. To their surprise,

they found four ribosomal proteins with

NLS-like sequences in archaea. This was

surprising, since archaea have no nucleus.

Ribosomes are also comprised of

nucleic acids, and these NLS motifs were

found to exist in nucleic acid binding

regions, where they glue the ribosomal

proteins and RNA together. To investigate

the function of these NLS-type motifs

in archaea, the team then compared

the secondary and tertiary (three-dimensional)

structures of the motifs in

archaea proteins and eukaryote proteins.

They found that in addition to having

similar sequences, the NLS-type motifs

in archaea and NLSs in eukaryotes have

similar three-dimensional structures.

This discovery was even more surprising.

“At that moment, I knew that I could

learn something from this,” Melnikov

said. The existence of motifs thought to

be involved in nuclear transport in cells

without nuclei seemed wasteful, even

paradoxical. In search of a conventional

biological explanation for these NLStype

motifs in archaea, Melnikov sought

out to find chaperones—proteins that

assist other proteins in performing a

specific function—in archaea that could

have used NLS-type motifs for recognition

or transport. His search ultimately

turned up nothing. This failure, however,

hinted that the very existence of

these NLS-type motifs with no apparent

function in the cell was a window to

even bigger questions. “Sometimes even

the most trivial fact can become a great

discovery when you look at it from an

interesting angle,” Melnikov said.

Having identified these motifs, the researchers

then studied whether the motifs

were universally present throughout the

archaea domain or only in certain subsets.

The researchers expected that among the

four main lineages of archaea, only the

most recently diverged—and therefore

most closely related to eukaryotes—would

feature these NLS-type motifs. However,

researchers instead found that the motifs

were conserved in all lineages, even the

most ancient and least eukaryote-like.

www.yalescientific.org

December 2019

Yale Scientific Magazine

23


FOCUS

Cell biology

Why would cells without a nucleus

have proteins with NLS-like sequences

and structures? One possible explanation

was that these sequences could have coevolved

with changes in ribosomal RNA.

The researchers theorized that changes in

the nucleic acid elements of the ribosome

over time may have selected for changes

in the protein elements resembling NLSs.

To test this theory, the team compared the

structures of ribosomal RNA known to be

binding partners with NLS-type motifs in

prokaryotes and archaea. To their surprise,

they found no differences between the two

ribosomal structures, suggesting a different

factor was at play.

Finally, the research team tested whether

archaea NLS-type motifs could function

in living cells. Using eGFP-fusion proteins,

proteins whose fluorescence allows researchers

to track their locations within the

cell, the team replaced NLSs within eukaryotic

proteins with their archaea NLS-type

motif counterparts. They found that these

modified proteins could equally well bind

to karyopherins and enter the nucleus. That

is to say, the archaea NLS motifs were not

only similar in sequence and structure to

eukaryotic NLS, they could also fulfill the

same biological function.

Lessons from nuclear evolution

All things considered, these NLS-type

motifs in archaea represent yet another example

of a common phenomenon in evolution.

The presence of NLS-type motifs in

cells that do not contain a nucleus provides

valuable information about the sequence of

possible events that led to the emergence

of the nucleus. Archaea without nuclei but

with NLS-type motifs represent intermediate

species between “start” and “end” points

in nuclear evolution, analogous to the fossil

of an intermediate between a bird with

wings and its ancestor without wings. “It

took millions of years to evolve, but for most

of this time wings were not strong enough

to support flight. For a species to have kept

evolving them, these premature half-wings

had to have been useful for other reasons,”

Melnikov said. “[As to] how this major organ

of flight emerged, we believe that these

premature wings helped animals either

glide or climb in an accelerated motion.” In

other words, before the wing could support

flight, it had to be doing something useful to

“justify” its evolutionary persistence beyond

a few generations.

In the same way, the presence of NLStype

motifs in cells that have no use for

nuclear transport capabilities suggests that

these motifs may have initially played other

roles in cells. Currently, the researchers

ascribe three biological functions to NLSs:

recognizing nucleic acids, providing a recognition

site for karyopherins to mediate

transport across the nuclear membrane,

and increasing specificity of the protein’s

interactions with nucleic acids through

karyopherin binding. The results from this

study clues scientists to the order in which

these functions may have evolved. The researchers

suggest that NLSs may have originally

evolved as a method for proteins

to bind more specifically to nucleic acid

sequences. They further hypothesize that

chaperone proteins evolved to recognize

specific NLSs, increasing specificity similar

to how chaperone proteins recognize hydrophobic

sequences on proteins. Finally,

as the nucleus developed, these chaperones

became karyopherins, transporting proteins

with the specific NLSs into the nucleus.

What’s next?

ABOUT THE AUTHOR

IMAGE COURTESY OF WIKIMEDIA COMMONS

Just as the wing evolved through a non-functional intermediate,

the nucleus and associated nuclear machinery evolved

through intermediates as well.

To the authors, a key question remains

unanswered: why ribosomal protein regions

in prokaryotes and archaea that bind to the

same ribosomal RNA targets have different

structures. In the paper, the researchers provide

three possible explanations—differing

evolutionary histories between prokaryotic

and archaea ribosomal proteins, differences

in the mechanisms prokaryotes and archaea

use to create ribosomes, and that this differentiation

is a method for increasing specificity

in an increasingly complex cellular

landscape—but further research is needed

to fully understand these differences.

While the results concerning NLSs and

ribosomal components described in this

study are exciting, much remains to be explored.

“The riddles of life are written in

ribosomes,” Melnikov said. Of the roughly

sixty proteins universally encoded in all life,

ribosomes and their associated machinery

account for around half. Because of their

ubiquity, ribosomes offer researchers not

only clear footholds upon which to build

phylogenetic trees and compare the relatedness

of different life forms, but also a rare

glimpse into the types of environmental

conditions a cell evolved to adapt to. In the

future, Melnikov hopes to research methods

by which different conditions of an environment—such

as temperature, salinity, or

pH—can be deduced purely from a cell’s ribosomal

structure and sequence.

While understanding evolution at the cellular

and microscopic level may be a daunting

task, advances in computational power

and biochemical methods, more than ever,

support and further our understanding. For

now, from initially puzzling data concerning

ribosomal components, researchers have

managed to shed new light on the origin of

cellular machinery, the nucleus, and life.

JAMES HAN

JAMES HAN is a sophomore in Trumbull College interested in Biochemistry and Statistics.

He writes for the Yale Scientific Magazine and works in Professor Hongyu Zhao’s lab studying

statistical methods to detect genes responsible for various diseases.

THE AUTHOR WOULD LIKE TO THANK Dr. Sergey Melnikov for his enthusiasm and time to talk

about his research.

FURTHER READING

B1. Armache JP, Anger AM, Marquez V, Franckenberg S, Frohlich T, Villa E, Berninghausen O,

Thomm M, Arnold GJ, Beckmann R. 2013. Promiscuous behaviour of archaeal ribosomal proteins:

implications for eukaryotic ribosome evolution. Nucleic Acids Research 41(2):1284–1293.

24 Yale Scientific Magazine December 2019 www.yalescientific.org


FEATURE Medicine

T R I P L E T H R E A T

THREE-DRUG COMBINATION INCREASES FRUIT FLY LIFESPAN

BY KELLY FARLEY

IMAGE COURTESY OF FLICKR

The key to fighting aging, a complex disease, may be a complex

response involving three different types of drugs targeting

three different pathways.

In the last century, American life expectancy has nearly doubled

from forty-seven years in 1900 to seventy-eight in 2019. With antibiotics

and vaccines, child mortality rates have sharply dropped alongside

mortality rates at every age. But as lifespans have increased, so

have the average years lived with disability. Research has turned towards

age-related diseases, with heart disease, cancer, Alzheimer’s

disease, and diabetes replacing infectious diseases as the most common

causes of death. In the Partridge Lab at University College London,

scientists discovered a combination of three drugs that increases

the lifespan of fruit flies by almost fifty percent, indicating that

perhaps prescribing multiple drugs targeting different aspects of aging

is essential for improving late-stage quality of life.

Combination therapies are routinely used to attack complicated

diseases from as many angles as possible, thus increasing the chance

of a cure and decreasing the chance of eventual drug resistance.

These therapies have been applied to a spectrum of diseases, including

HIV, cancer, and, recently, cardiovascular disease. To delay aging,

the researchers combined three inhibitors all acting on different

pathways associated with aging: trametinib, lithium, and rapamycin.

Trametinib is normally used to treat melanoma, a form of cancer,

by inhibiting overactive enzymes driving uncontrolled cell growth.

Lithium is a chemical inhibitor of a molecule associated with cancer,

inflammation, Type II diabetes, and Alzheimer’s disease. Rapamycin

is used to prevent kidney transplant rejection by inhibiting the activation

of immune cells. Each drug had been previously associated

with extended fruit fly lifespan by the Partridge lab, but this is the

first time the three drugs were tested together.

To administer the drugs to the fruit flies, researchers fed a sugar-yeast-agar

medium to female flies two days after hatching. Researchers

then measured the number of dead and alive fruit flies

every day until all flies had died. Used individually, each drug in

the combination extended lifespan by an average of eleven percent.

Used in pairs, the drugs extended lifespan by an average of thirty

percent. Amazingly, the three-drug combination increased the

median fruit fly lifespan by forty-eight percent.

One possible explanation for the life-prolonging properties of

the combination is that the drugs reduce the damaging side effects

of each other. Jorge Castillo-Quan, one of the researchers, first realized

the possibility of the combination in 2014 when he found

that lithium could block fat accumulation in sugary diets and

thought that it could also block fat accumulation from rapamycin

use as well. Indeed, when combined with rapamycin, lithium reverses

any effects on metabolism; feeding frequency, food intake,

and drug intake were unaltered in the treatment group versus the

control group. Dampening the effects of rapamycin on metabolism

allows for the drug to be used more safely.

With metabolism unaltered, the question of how the therapy increases

lifespan remains. Life is a balancing act of growth, reproduction,

and maintenance. If an organism spends more of its limited

resources on growth or reproduction, it will have less left over

to dedicate towards maintenance of health into old age. Thus, researchers

proposed that perhaps a decrease in resources devoted to

reproduction could explain the increased lifespan. However, at the

concentrations used, only trametinib decreases reproductive efficiency

(as measured by the number of eggs laid daily), so this theory

fails to explain why the other two drugs also increase lifespan.

Although the targets of the individual drugs do not seem to overlap,

the drug combination could activate other unknown mechanisms.

“This will be difficult to test because it is likely the combined

effect of impacts on different tissues but is very important to address

in the near future,” Castillo-Quan said.

Promising results in fruit flies raise the question of how relevant

these data are to age-related disease in humans. While genetic and

dietary interventions have also been shown to slow aging in laboratory

animals in the past, this joint pharmaceutical therapy is particularly

promising because of its straightforward optimization and

ease of implementation. All of the aforementioned drugs are already

approved for and being used in humans for other conditions.

Nowadays, elderly patients regularly take multiple drugs to treat

different conditions–perhaps one pill for diabetes, another for high

blood pressure, and one to lower cholesterol for example. “A cocktail

or polypill for aging is hence only logical, even more so when we

know that cells and tissues adapt to drugs over time and drugs have

side effects other drugs can counteract,” Castillo-Quan explained.

Aging, like most bodily processes, is exceedingly complex. It is not

one disease but rather a collection of processes. It makes sense that

our most effective treatment would be complex too.

www.yalescientific.org

December 2019

Yale Scientific Magazine

25


FEATURE Molecular Biology

BAD

BY JENNY TAN

IMAGE COURTESY OF NATIONAL PARK SERVICE

The Bd pathogen infects amphibians through the skin.

Globalized trade has spread diseases to all corners of

the world, causing various disruptions to ecosystems.

One pathogen in particular, called Batrachochytrium

dendrobatidis (Bd), is thought to be one of the deadliest

wildlife fungi. Discovered in 1987, it infects amphibians

through the skin and often proves to be fatal. In Latin

America, forests that used to be teeming with amphibians

are now relatively quiet.

Prior research had only ever documented the presence

or absence of the Bd pathogen within given regions of the

globe. However, no studies had analyzed the genomes of

these fungi. Professor Erica Rosenblum and a team of researchers

at the University of California, Berkeley sought

to use genome sequencing to identify different lineages

of the fungus and locations where lineages cross over to

create new strains. The team also hoped to map out the

evolutionary history of the pathogen, allowing them to

assess how the disease may spread in the future.

Rosenblum and others used a unique method to characterize

each Bd DNA sample. “It doesn’t require any destructive

sampling,’’ Rosenblum said. The method only

BACTERIA

requires a small swab from the skin of an amphibian. After

sequencing the entire genomes of a few samples of

pathogen, they picked parts of the genome that were useful

for identification, deciding on around 200 positions

on a particular chromosome. From here, they developed

an assay to test the genetic composition of these various

loci quickly and cost-effectively.

For decades, scientists from all over the world have been

collecting Q-tips of DNA samples to determine the presence

of the Bd fungus. Many of these samples have been

sitting idly in freezers. Using the technique developed by

Rosenblum’s lab, these older samples can be used to piece

together the story of how the pathogen originally spread.

“We can go back in time and look at when, let’s say, this

lineage first arrived in Brazil,” Rosenblum said.

After their analysis, the research team categorized the

pathogen strains based on geographic location: Asia, Europe,

Africa, and the Americas. Significantly, they found a new

type of lineage of the fungus in Asia. This finding further

supports the hypothesis that the disease has Asian origins.

Further studies should focus on creating a more comprehensive

map of Bd lineages, using even more DNA samples

of the Bd pathogen. There are still many instances where

researchers know that the Bd pathogen is present, but the

exact lineage is unknown. With the new method that the

team used in this study, older Bd samples are available for

analysis. Thus, another avenue for future research is understanding

the timeline of each Bd fungi lineage. “I am

most excited about using museum samples to go back and

really reconstruct what happened, going back hundreds

and hundreds of years,’’ Rosenblum said. Understanding

when Bd appeared in relation to the decline in amphibians

will be important for future analysis and predictions.

Given the growing range of the Bd pathogen, Rosenblum

thinks it is important to monitor and limit its

spread. From the food industry or the pet industry, the

shipment of animals is a big part of global trade. This

makes checking for diseases before transport especially

important, according to Rosenblum.

The spread of the Bd pathogen has important implications.

They threaten the fragile biodiversity of ecosystems

through their decimation of amphibians, who sit

right in the middle of the food chain. They regulate insect

population and act as food for other predators. An

imbalance in an ecosystem can have a butterfly effect,

eventually hurting human health and agriculture.

HOW RESEARCHERS ARE TACKLING THE DEVASTATING BD PATHOGEN

26 Yale Scientific Magazine Decemberr 2019 www.yalescientific.org


P-CRAM

IN THE DATA

Technology

FEATURE

The advent of machine learning is increasing the demand

for data storage and computation. Today, we face

the challenge of the AI era: how to prepare the infrastructure

to reliably store big data and efficiently perform large

computations. This complex problem is at the intersection

of material science and engineering—one that the field of

phase-change memory aims to solve.

Modern computers are built using von Neumann architecture.

This setup has a central circuit, called the processor,

where instructions of the computer are carried out by performing

basic arithmetic and logic. Data is shuffled between

the processor and storage every time the computer performs

calculations. Because this shuffling is energetically expensive,

von Neumann computers waste about forty percent of their

electrical power by simply moving data around.

Phase-change memory offers promising alternative to overcome

this inefficiency. Phase-change memory provides a fast

and electricity-free method of storage by using “fifth-generation

materials”—which comprise of carbonites, tellurium,

germanium and antimony. These materials enable rapid, reversible

transitions between an amorphous phase that resembles

molten glass and an orderly, crystalline phase, analogous

to the 0s and 1s of a typical computer’s binary storage.

Perhaps even more promising is the capacity of phase

change memory to allow storage and computing to be

performed simultaneously, instead of separating the two

as discrete processes, in a process called neuromorphic

computation. As a result, the computer can minimize the

power lost because it no longer requires moving around

data to load memory to the processor. The processor and

memory are one.

“This is not just a dream, it is reality,” said Wei Zhang, a

professor of material science at Xi’an Jiatong University in

China. “Two companies are already selling phase change

memory products on the market. It has the potential to

revolutionize storage and memory technology, although

there is a lot of room for improvement.”

Yale professor of mechanical engineering Judy Cha,

whose research focuses on properties of phase-change materials

and nanomaterials, added, “We want the device to

be fast, but also reliable. It’s a tradeoff—sometimes these

are conflicting properties. If you optimize the speed, you

sacrifice the reliability,” Cha said.

Noisy data, or data that is distorted by erroneous, irrelevant

signals, is an obstacle to obtaining accurate computations

because the data we record is a combination of the

IMAGE COURTESY OF PIXBAY

Cha’s group identified one of the major limitations to the reliability of

phase change memory devices.

true signal and its noise. Since current phase change memory

devices are limited by noise and drift that damages the

precision and consistency of computations, Zhang and his

collaborators’ current research aims to address this problem

with a novel design called phase change heterostructure.

This design uses several layers of alternately stacked

layers of phase change materials and confinement materials

that limit how much phase change materials change

conformations, reducing the amount of noise in the device.

Thus, phase change heterostructure is a more reliable architecture

for data storage than the current commercially

available phase change memory devices. “We improved the

circuit performance without changing the circuit setup.

We were able to use one memory cell to significantly improve

overall performance of the whole chip,” Zhang said.

With advanced microscopy techniques, Cha and her collaborators

observed in real-time how phase change materials

convert between the materials’ amorphous and orderly

phases as the device operated. Antimony, one of the principal

ingredients of phase change materials, was found to

cause device failures due to dramatic fluctuations during

the process of morphing between the two phases.

“The material composition of the device influences its function

greatly,” Cha said. “We ultimately want to determine the

material composition that can optimize how fast you can encode

and read information while also stabilizing the device.”

These findings identify the root cause of device inefficiencies

and failures, bringing us a step closer to optimizing

phase change devices for commercial use. It is clear that the

computers of tomorrow could look and work nothing like

the computers we use today. The next generation may take

for granted terabyte-scale storage and nanosecond-speed

computation in portable devices, all without the need to

charge the device for weeks, or perhaps not at all.

IMPROVING MODERN STORAGE IN THE BIG DATA AGE

BY VIOLA KYOUNG A LEE

www.yalescientific.org

December 2019

Yale Scientific Magazine

27


FOCUS

Neuroscience

new insights provide critical clues into understanding sleep

Sleep has long been recognized as an

essential mammalian function that provides

crucial time for the brain to recover.

Learning and memory are bolstered by the

restorative capacity of sleep to change the

strength, form, and adaptability of synapses,

the structures which facilitate electrical and

chemical signaling between neurons, the

cells of the brain and nervous system. Sleep

loss, meanwhile, impairs general cognitive

ability and function.

Though the power of sleep to recharge

the brain is well-accepted, the mechanisms

underlying the need for sleep and its cyclic

nature are less clear. Most experts generally

believe that two principal forces interact

to regulate sleep. One is the body’s natural

chemical rhythms known as the circadian

clock. Among other profound effects on

physiological processes, the circadian

clock is the internal factor responsible for

maintaining the body’s preferred natural

sleep phase— nighttime for humans and

other diurnal species. The other component

of sleep regulation is known as the

homeostat, or the recurring pressure to fall

asleep based on time spent awake and the

quality of previous sleep cycles— something

we recognize this as fatigue. While these

two mechanisms are acknowledged as the

sources of sleep’s regulatory and fortifying

power, the way in which they interact

remains poorly understood.

The recent neuroscientific insights of a

European team of researchers, however,

could go a long way toward unraveling this

mystery and more precisely defining the

interdependence between circadian and

homeostatic factors in driving localized

control of sleep processes in the brain.

Led by professors Steven Brown and Shiva

Tyagarajan of the University of Zurich

and professor Maria Robles of the Ludwig

Maximilian University of Munich, the work

examines the area of the brain responsible

for learning, memory, and other cognitive

procedures affected by sleep loss in order

to model synaptic function across an entire

twenty-four-hour wake and sleep cycle.

mRNA transport responds to circadian

tendencies

IMAGE COURTESY OF FLICKR

Sleep is a crucial restorative process for the brain and body, but its molecular

underpinnings are still poorly understood.

The alteration of specific synaptic proteins

has previously been linked to induction of

sleep pressure in the brain. This process is

separated into two distinct steps, known as

transcription and translation. Transcription

is the first step in gene expression, whereby

a segment of DNA is copied into RNA, a

class of molecule that serves as the template

for protein production. This copy can then

be transported to other sites, including

28 Yale Scientific Magazine December 2019 www.yalescientific.org


Neuroscience

FOCUS

synapses, as messenger RNA (mRNA). The

next step is translation, where proteins are

created based on the RNA template. Once

these phases have been completed, some of

the new proteins undergo phosphorylation,

the molecular attachment of a phosphate

group that activates enzyme function. In

the course of conducting their research, the

investigators determined that these different

stages of the protein modification process,

essential to sleep cycling, are regulated by

separate procedures, and that circadian and

homeostatic effects are more pronounced

at various points in the process. “We hope

that it will lead both to a better knowledge

of why we sleep in the first place, and how

this sleep is locally regulated,” Brown said.

The investigators collected four mouse

forebrains every four hours over a twentyfour-hour

period to analyze the rhythmic

oscillations of mRNAs in synapses and in the

forebrain as a whole over the course of the

entire sleep and wake cycle. The control group

of mice was kept on a schedule consisting

of alternating twelve-hour periods of light

and dark laboratory conditions to simulate

daytime and nighttime. The researchers

found more oscillations in mRNA in the

synapses than in the entire forebrain—

revealing mRNA delivery is responsible for

such transcriptional oscillations in synapses.

Since mRNA oscillation intensity

heightens around the transitions between the

lights-on and lights-off periods analogous

to dawn and dusk, investigators sought to

confirm the hypothesis that such oscillation

is circadian-driven. They compared three

groups of mice under different laboratory

conditions: one group followed the

simulated day-night schedule, one was kept

in constant darkness, and the third was

composed of mice with their circadian clocks

genetically disabled. Results indicated stark

differences in oscillatory patterns for mice

lacking functioning circadian regulators,

indicating that the buildup of transcriptional

oscillations around such pivotal times is

generated by circadian effects.

In order to isolate the influences on

transcription brought about by circadian and

homeostatic rhythms, mice were deprived of

sleep for six hours prior to euthanasia. Levels

of sleep pressure are indicated by amplitudes

of electroencephalogram oscillations.

Testing over twenty-four hours with

sustained, elevated sleep pressure revealed

little difference in amplitude compared

to normal circadian phases, suggesting

that sleep pressure is not the key factor in

controlling synaptic mRNA oscillations.

A correlation between phosphorylation

and sleep pressure

Having guessed that post-transcriptional

oscillations are brought on by processes

involving protein modification rather than

those involving mRNA transport following

this data, the investigators pivoted to

explore which sleep-regulating method

most directly contributes to their presence.

Mice were once more kept on alternating

twelve-hour schedules and euthanized

every four hours. The team observed that,

similar to mRNAs, phosphorylated proteins’

oscillations cluster primarily around

simulated dawn and dusk, indicating the

role of sleep and wake pressure in shaping

synaptic phosphorylation processes.

Further analysis of kinases, the enzymes

that perform phosphorylation, revealed

that the types of kinases present at dawn are

associated with excitatory synaptic function

while those present at dusk are inhibitory.

Such insights reflect the buildup of sleep

and wake pressure, strengthening the claim

that the homeostat is largely responsible for

protein cycling independent of time of day.

To support these discoveries, the team

deprived the mice of sleep for four hours

prior to collecting brain samples and

measured phosphorylation. Whereas

one fourth of the effect of circadian

rhythms on mRNA were preserved

under sleep deprivation, a mere two

percent of oscillating phosphorylated

proteins remained. According to

Brown, this dissimilar

behavior under the

same conditions

was a profound

moment in the

research process. “The fact that synaptic

RNA and protein abundance responded

differently to sleep deprivation made

us realize that different steps in protein

production might be under different

control,” he said.

Sleep functions better-defined than ever

The mapping of the synaptic

phosphorylation process across an entire

sleep-wake cycle gives experts a clearer

understanding than ever before of how

circadian rhythms and homeostatic

pressures interact. The results indicate that

circadian cycles transport synaptic mRNAs

most heavily at dawn and dusk prior to the

first stages of protein modification, while the

phosphorylation that follows is modulated

by sleep pressure and homeostatic

regulation of the body. As characterized

by neuroscientist Robert Greene of the

University of Texas Southwestern Medical

Center, the brain prepares itself with

anticipatory circadian tendencies but only

follows through on such preparation as the

result of need-based sleep or wake pressure.

Though the insights offer exciting

delineation between the two interdependent

processes that govern sleep processes,

they remain largely theoretical. Brown

emphasized that the specific molecular

mechanisms underlying synaptic functions

are yet to be elucidated, and that his team’s

discoveries are merely puzzle pieces in

fully explaining the crucial role of sleep’s

restorative properties in daily function.

Nonetheless, they confirm long-suspected

procedural connections and leave little

doubt regarding the direction of future

research. “Even though they were done in

mice, the findings have implications for

promising avenues of research, drawing

the focus straight to events at the synapse,”

said neuroscientist Akhilesh B. Reddy of the

University of Pennsylvania. “This is just the

tip of the iceberg.”

BY NICHOLAS ARCHAMBAULT

ART BY ANTALIQUE TRAN

www.yalescientific.org

December 2019

Yale Scientific Magazine

29


FOCUS

Molecular Biology

By Britt Bistis

PROBIOTIC

PLANTS

Newly

Discovered

Protein

Regulates

the Plant

Biome

A new gene cluster discovered by professor

Konstantin Severinov’s lab at Rutgers encodes a

peptide that provides legumous plants with extra

power. This peptide acts as an antibiotic that

endows the plants with enhanced resistance to

certain harmful bacteria—leaving room for bacteria

which promote health. Probiotic bacteria

support their host organism’s health in two main

ways: first, they produce compounds necessary to

the organism’s fitness, and, secondly, they protect

against harmful bacteria. Probiotic bacteria called

Rhizobium are nitrogen-fixing bacteria that exist

in a symbiotic relationship with many plants,

helping them by converting free atmospheric nitrogen

into necessary nitrogen compounds that

plants can uptake and use. Severinov’s lab discovered

that Rhizobium also acts as a probiotic by

producing a protein that targets harmful bacteria.

By characterizing a new gene cluster, the lab discovered

a new protein that is thought to have antimicrobial

and anticancer effects.

Severinov and his colleagues used cutting-edge

genetic data processing to identify this new gene

cluster. Before the age of bioinformatics, the classic

forward genetic screen was, and still is, prevalent in

research. This approach entails randomly mutating

DNA and subsequently carefully characterizing

random mutations that affect the model system,

allowing researchers to screen for the desired phenotype

being studied and trace the phenotype back

to the random mutation made. However, in some

cases, this is rather slow and inefficient, often returning

previously discovered hits.

30 Yale Scientific Magazine December 2019 www.yalescientific.org


Molecular Biology

FOCUS

The researchers screened for new proteins

belonging to the family of peptide regions

called Linear Azol(in)e-containing Proteins

(LAPs), which have several common

sequences in the DNA that encode them

and are of particular interest to researchers

because of their antibiotic effects. LAP regions

contain a few key genetic elements.

First, these gene clusters encode enzymes

which facilitate the modification of proteins,

such as the addition of chemical functional

groups required for the protein to function.

In addition, they need an ABC transporter,

a type of transporter that facilitates the secretion

of the mature protein. Lastly, they

include the sequence of the core peptide

itself. Using bioinformatics, Severinov and

his colleagues were able to circumvent the

challenges of traditional genetic screens and

efficiently screen for novel gene clusters.

Having discovered a novel LAP gene cluster

that fit their research criteria, the team

then needed to purify and characterize this

new central protein. However, it is difficult

to purify an unknown protein whose properties

have not yet been classified. The Rutgers

lab had some sense of the polarity of

the protein, and so they used a process that

separates proteins based on this characteristic.

Then, using knowledge of the optical

properties of the protein family, they were

able to find and further purify the fraction

of their new protein. To analyze the structure

of the purified protein, they used a

variation of mass spectrometry, a laboratory

technique that allows researchers to

determine the exact molecular weight and

atomic composition of a compound.

Severinov and his team called the new

protein phazolicin (PHZ). PHZ is produced

by the species Rhizobium Pop5 and belongs

to the LAP family, which contains a five-atom

ring in their structure with one nitrogen.

PHZ has more of three specific amino acids

(protein building blocks)—serine, cysteine,

and threonine—all strategically placed to

allow the mature PHZ protein to form a

cycle. These LAPs belong to an even larger

family of proteins called Ribosomally-synthesized

and Post-translationally modified

Peptides (RiPPs). The PHZ protein, like

all peptides in this family, is synthesized

at the ribosome and undergoes significant

post-translational modifications, which, for

Art by Jennifer Yoon

PHZ specifically, involves cyclization. Empowered

with the knowledge of what type

of motifs the LAP-encoding gene cluster

would have, Severinov and his colleagues

used genome-mining techniques to screen

the genome for these motifs.

To determine which pathway PHZ inhibits,

researchers investigated whether

PHZ’s mode of bacterial targeting involves

inhibiting the DNA replication or protein

synthesis machinery in bacteria. To

accomplish this, they used two different

fluorescent proteins. One fluorescent protein

is expressed when DNA replication is

lowered, and the other fluorescent protein

is expressed only in the presence of translational

inhibitors. They then looked for

processes which caused the fluorophore to

fluoresce. They found that functional PHZ

protein inhibits protein translation.

The next step was to determine the exact

binding sites of PHZ to further elucidate

the role of this antibacterial protein

in blocking translation at the ribosome. To

this end, the researchers first attempted to

crystallize the ribosome and its associated

proteins, including PHZ. They then used an

advanced imaging technique called x-ray

crystallography to determine the three-dimensional

structure of the complex. However,

the ribosome with associated proteins

proved a poor candidate for crystallization.

Severinov and his colleagues also used

cryo-electron microscopy to confirm the

structure predicted by x-ray crystallography.

In contrast to x-ray crystallography,

cryo-electron microscopy allows for precise

determination of structure without crystallization.

“Cryo-EM is a new technology,

which is very powerful and doesn’t need

crystals. Essentially, you simply look at

molecules lying on an electron microscopy

grid, average tens of thousands of molecules

at different angles lying on the surface, and

then make computers make three dimensional

models at high resolution,” Severinov

explained. This technique revealed that PHZ

binds the protein-ribosome complex in the

narrowest part of the peptide exit tunnel,

through which newly formed protein leave

the ribosome, and blocks it, thereby blocking

translation. This eventually stops protein

synthesis and results in bacterial death.

Like many other proteins altered by

post-transcriptionally modifications, PHZ

has the strongest activity in bacteria closely

related to the bacterial species that produce

the PHZ protein. Specifically, PHZ has the

most antibiotic activity in Rhizobium and

significantly lower antibiotic activity in E.

coli. A likely evolutionary explanation for

IMAGE COURTESY OF XIONGWU WU AND BERNARD R. BROOKS

This shows a protein model (not PHZ) generated

via computer modeling using input data from cryo-

EM (left) and the same protein modeled using x-ray

crystallography (right). Recent advances in cryo-EM

have further enhanced the resolution that can be

achieved using this technology.

why PHZ has strong antibiotic effects in

similar bacteria is that the molecule is made

for a competitive advantage over those in a

similar niche. “It needs to take care of its

competing bacteria that live in the same

habitat in the soil, and E. coli is not one of

them as it lives in human intestines” Severinov

explained. The Rutgers team found

that the Rhizobium Pop5 are immune to

the PHZ they produce due to another gene

in the cluster they called phzE that confers

self-immunity to the bacteria. PhzE encodes

an exporter pump that enables Pop5

to efficiently excrete PHZ upon entry into

the cell, thereby immunizing the bacteria to

its harmful effects.

In the near future, Severinov and his colleagues

project that PHZ-like proteins could

be used in agriculture and employed as biocontrol

agents. Understanding the antibacterial

mechanism of PHZ will enhance our

understanding of how antibacterial LAPs

function, as many protein members of this

family induce antibiotic effects via significantly

different mechanisms, which makes

them an excellent candidate for antibiotic

research. Investigations into this class of

proteins can further inform bacterial immunobiology

studies and aid research and medicine

in the quest for new antibiotics.

www.yalescientific.org

December 2019

Yale Scientific Magazine

31


FOCUS technology

E L A S T I C

Electronics

32 Yale Scientific Magazine December 2019

As robotics has

blossomed in the

past decade, some

robots have been

perfected and implemented

into daily life or

put to use in factories for

manufacturing goods. However,

this is just the tip of the

potential of modern robotics.

Through implementing

more human-like properties

as well as developing artificial

intelligence, researchers are

continuously working to make

robots better and enabling

them to act on their own. Significant

progress has already

been made in making robots

closer to resembling humans,

allowing them to be more easily

integrated into society.

One step that researchers

have taken to give robots

more human-like properties

is through developing soft robots.

As opposed to conventional

robots, soft robots have

a soft structure usually consisting

of one complete system

that moves by hydraulics

or pneumatics. Soft robots are

superior to conventional linkand-joint

robots in many ways.

First, they are softer and safer

around humans than the hard

metal frames of conventional

robots, which can be rather

dangerous. In addition, the

manufacturing of soft robots is

often more efficient and cheaper

than that of conventional

Creating Flexible Materials

with Conductive Properties

BY CATHERINE ZHENG | ART BY LAWRENCE WANG

robots, which have many individual

pieces that need to be

crafted separately. Soft robots

can be produced all at once.

In order to create a soft robot,

the material used must be

soft or malleable, as the name

suggests. Previously, soft materials

like elastomers (rubber

compounds), gels, and fluids

were used to create various soft

electronics. Liquid crystal elastomers

(LCEs), polymers with

crosslinked liquid crystals dispersed

throughout, have been

especially promising for soft

electronics. Specifically, they

allow for more elasticity than

traditional elastomers while

maintaining conductivity.

When these polymers are exposed

to heat, they display a

shape-memory effect so that

they contract back to their

original shape when heated.

When the polymer is cooled,

it expands, whereas heating

causes it to contract. With this

material, the shape-memory

effect can also be achieved

through a photochemical transition,

meaning that when it is

exposed to light, the shape of

the elastomer is also affected.

LCEs are a special type of

IMAGE COURTESY OF MJ FORD

The structure of the shape-morphing elastomer contains

liquid metal droplets within a polymer network.

polymer that, in one state, are

made up of molecular units

forming an almost crystal

structure with the molecules

organized into layers. When

heated, those molecules become

disordered, so the material

goes from behaving

more like a crystal to a fluid.

To make this an elastomer,

meaning that it behaves more

like a rubber, polymer chains

are added to those molecular

units. Thus, even when the

material is heated and the molecules

are distorted, the polymer

chains still connect them

together and the material still

stays intact and rubbery.

A downside of most materials

like LCEs and rubbers,

however, is that they are not

electrically responsive, magnetically

responsive, and/or

photoresponsive. This means

that they are not responsive

to stimulation by electrici-


IMAGE COURTESY OF MJ FORD

The elastomer has a shape-memory

effect, as when it is cooled back

down after heating, it returns to

its original shape. This figure also

shows the elastomer’s durability as

it is holding up a 100 gram weight.

ty, magnetism, or light—limiting

their uses. In addition, they

are mostly thermally insulating.

“Once you heat it up, it takes a

long time for the material to cool

down and return to its original

shape,” explained Carmel Majidi,

a professor from Carnegie Mellon

University. The other issue is

that, because LCEs are not electrically

conductive, they cannot be

heated through electric current

flow. To raise their temperature,

the researchers had to use a heat

gun or a hairdryer instead of using

a direct source of electricity.

In order to make LCEs more

conductive and responsive, some

tried adding metal filler particles.

However, these particles made the

polymers stiff and brittle, detracting

from the elasticity that makes

LCEs desirable as a soft material.

In order to resolve these issues,

researchers from the University of

Texas at Dallas and Carnegie Mellon

University—including Majidi—created

a material that incorporates

a liquid metal alloy made

of gallium and indium into LCEs,

giving the polymer conductivity

without sacrificing elasticity. Gallium

and indium on their own are

solid at room temperature, but

when mixed in just the right ratio,

form a liquid alloy that is an

ideal elastomer. “By adding these

little microscopic droplets of the

liquid metal to any kind of polymer,

plastic or rubber, we can

tune their thermal and electrical

properties,” Majidi explained.

With these elements incorporated

into the polymer, this research

combines the best of both

worlds—the thermal and electrical

properties of metals and the

elasticity, shape memory, and mechanical

properties of these LCEs

and soft polymers.

The end goal is to create a material

that can “think” on its own, in

that it can move and change shape

based on its environment rather

than direct simulation. The electrical

conductivity of this material

allows it to respond to external

electrical stimuli in an active

way. “For example, we could kind

of create this composite so that

when you punctured it or if you

damage it and tore it, the material

would basically sense that damage,

and then cause electrical signals

and current within the material

to flow in a certain way, so

that the material would suddenly

contract or undergo some type of

shape change in response to that

mechanical damage,” Majidi said.

Thus, this liquid metal elastomer

would be ideal for soft robots

since it stretches, bends, moves,

and responds to stimuli as a result

of the liquid metal microdroplets

incorporated into the polymer

network. Some think this elastomer

could be used as a rubber

skin for robots, replicating the

capabilities of nervous tissue or

muscle and allowing them to better

sense their environments.

One additional benefit of these

polymers or elastomers is that

they all work well together. Since

their chemistry is very compatible,

it is easy to mix and match

materials with different uses for a

common purpose. Therefore, all

of these polymers that researchers

have been developing can

eventually be combined, each

serving a different purpose.

The excitement of soft robots is

starting to spread into industry.

A startup company called Arieca,

co-founded by Majidi, produces

and sells rubber composites

filled with little drops

of metal alloy. “It’s nice

to explore commercial

translation of academic

research. So, not just do

stuff that is interesting scientifically,

but also has commercial,

real-world, industrial

applications,” said Majidi.

This technology lends itself

well to a wide variety of applications.

Polymers and materials

science are a hot topic of

research in the soft robotics field,

especially with regards to

creating new “robot skins.”

In the future, researchers

are hoping to create materials

that are more responsive

and perform even better,

as well as looking into additional

applications of this elastomer

in prosthetic devices or

wearable electronics.

IMAGE COURTESY OF MJ FORD

This shows the elastomer in an electrically conductive

state. The LED light on the opposite end turns on in

response to touch stimuli.

technology

FOCUS

December

Yale Scientific Magazine

33


COUNTER

PLANETS HARBORING

LIFE-SUSTAINING FLUID

BY YU

JUN SHEN

POINT

COUNTER

Exoplanets capture our imagination, and recent missions have

discovered thousands more around neighbouring stars. However,

even when discovered, the compositions of exoplanets are difficult

to study because of the sheer distance away from us. A recent

paper by Harvard University astronomer Li Zeng and his team

challenges the conventional belief that many intermediate-sized

exoplanets—between one and four Earth radii—are gas dwarfs.

Instead, they suggest many such exoplanets are watery worlds,

migrating towards their central stars over time and hinting at the

prevalence of water in the universe.

Li’s team started by considering a data set of over four thousand

confirmed or candidate exoplanets measured by NASA’s Kepler

space telescope mission and refined by the

European Space Agency’s Gaia astrometry

mission. While larger exoplanets generally

ATER,

ATER

VERY-

have greater mass, Li and his team studied a

gap in the data between 1.8 to 2 Earth radii;

exoplanets detected generally cluster either

below this range (rocky worlds called super-

Earths) or above (lower density worlds called

sub-Neptunes). Previously, most scientists

thought sub-Neptunes had to be dwarf

gases, since ice could not coalesce during

planetary formation at such close distances

to the star. The role of this temperature

boundary—termed the “snowline”—is key

to the model Li’s team proposes.

Li’s team modelled the dynamics of

HERE

exoplanet formation using equations of state, generating different

results by considering various starting conditions. For instance, an

exoplanet may or may not have an atmosphere, depending on whether

the core contains metals like magnesium silicates versus iron. This

includes how water behaves in the high-pressure core. From these

simulations, Li’s team concluded that many observed exoplanets

within the two to four Earth radii range should have over one quarter

of their mass as water. In contrast, the Earth, despite water covering

over seventy percent of the globe, is only 0.05 percent water by mass.

If watery, how did these sub-Neptune exoplanets appear within

the snowline? The paper’s simulations would suggest the icy sub-

Neptune exoplanets formed beyond the snowline, but migrated

inwards over time driven by collisions between planets. While

rocky proto-planets would likely not survive collisions between one

another, icy bodies may instead merge and continue their advance.

So, icy planets would get bigger and bigger as they approach the

central star, generating a peak in the exoplanet mass data. Such

a theory could explain the gap in exoplanet radii/mass observed.

Our solar system, with Earth as the only planet harboring much

surface liquid, may not be so typical after all. “Generally speaking,

this type of planetary system architecture with close-in rocky

super-Earths and water-rich sub-Neptunes may be found more

common than in our own solar system, in the Milky Way galaxy,”

Li explained. Since all life on Earth as we understand developed

dependent on water, astronomers today regard the discovery of

liquid water as a crucial pre-requisite to the possibility of life. This

approach guides modern scientific exploration of our solar system.

Debora Fischer, an astronomer from Yale University, commented,

“I think this work is very interesting and Li Zeng is carrying

out exciting simulations to better understand the composition

of exoplanets. The one caveat is that there may be uncertainties

in the measurements of planet radius and mass that exceed

our estimates,” Fischer said. Conventionally, astronomers find

exoplanets by detecting faint changes in star light, either as a result

of a direct transit, the planet blocking the star, or radial velocity

shifts, frequency changes via the Doppler effect. Yet all along the

central star fluctuates in brightness, adding noise to the data.

There are other potential concerns with the conclusions drawn in

this paper. “The implicit assumption is that the long-term energy

budgets of the planets depend strictly on the amount of energy they

get from their parent stars,” said Yale astronomer Gregory Laughlin.

In particular, “tidal heating, somewhat analogous to that observed on

Jupiter’s Moon Io, where intense volcanism is driven by tidal heating”

may question the abundance of water worlds, according to Laughlin.

Nonetheless, Li is optimistic that next-generation telescopes can

deliver even more accurate mass and orbital radial measurements

for stronger simulations. NASA’s follow-up to Kepler, the

Transiting Exoplanet Survey Satellite (TESS), will discover

more super-Earth range exoplanets. If those masses can be

more accurately determined with ground-based spectrographs,

researchers will have stronger confidence in the conclusion that

watery worlds truly flourish in our galaxy.

34 Yale Scientific Magazine October 2019 www.yalescientific.org


URIOUS

METHODS

THE COOLING PROPERTIES OF ELASTIC FIBERS

In the early nineteenth century, an English scientist reported

that releasing stretched rubber bands could make them a few

degrees cooler. While the idea of elastic cooling was novel

at the time, it was overshadowed by vapor-compression

methods that would eventually form the basis of modern

refrigerator technology. However, a team of researchers led

by Ray Baughman of UT Dallas and Zunfeng Liu of Nankai

University recently discovered that they could use rubber

fibers to make fridges even more efficient than their vaporcompression

counterparts by adding an extra step: twist.

Baughman and his colleagues first came across twist-based

cooling while using coiled fishing line to make artificial

muscles. They realized that the energy absorbed by these fibers

during the untwisting process could be harnessed not only

for mechanical purposes, but also for thermal cooling. Since

then, they have found that other kinds of fiber can produce

even greater temperature changes when untwisted—a natural

rubber fiber can decrease its maximum surface temperature

by 15.5°C, and a nickel-titanium wire can decrease its

maximum surface temperature by 17.0°C. “Everything from

the very beginning was unexpected,” Baughman said.

According to Baughman, the temperature changes in the

fibers occur because of changes in entropy—a measure of

disorder in any system. When the fibers are twisted, their

polymer chains form helices, moving from a high-entropy to

low-entropy state. This change in entropy requires work and

releases heat into the environment. Conversely, untwisting the

fibers restores the polymer chains to their disordered state,

which requires them to extract heat from their immediate

surroundings. Because the polymers near the surface of a

twisted fiber have a more helical configuration than those in

the core, the outside of the fiber experiences a greater degree

of cooling during untwist.

The researchers found that they could increase this cooling

effect by releasing stretch after untwisting. Elastocaloric

cooling also operates through changes in entropy—relaxing

a rubber band brings its polymer chains to a higher entropy

state and cools the surrounding environment. In combining

the two processes, the scientists were able to maximize the

BY MIRILLA ZHU

increase in entropy and thus maximize cooling. However,

they came across a surprising finding: twisted fiber has a

natural tendency to coil in the same direction as the twists,

but coiling the twisted fiber in the opposite direction reverses

the temperature changes caused by stretch and stretch release,

resulting in a material that has the strange property of cooling

when stretched.

Not only is releasing twist a more effective form of cooling

than releasing stretch alone—the maximum change in surface

temperature of a twisted and stretched natural rubber fiber

was 5.4 times that of the untwisted fiber—but twisted fibers

are also more compact than stretched ones. Using these rubber

fibers, the researchers demonstrated that a twist-based cooler

could be two-sevenths the length of a stretch-based cooler

while still providing 2.3°C greater average surface cooling. By

flowing a stream of water over three twisted nickel-titanium

wires while unplying them, they were able to transmit the

surface cooling of the wires to the water, decreasing its

temperature by up to 7.7°C in one cycle. This process could

be repeated over many cycles of twisting and untwisting to

create a steady supply of cooled water.

Having filed a patent on their findings, Baughman and his

team are now working to commercialize this technology.

Given that typical vapor-compression refrigerators are not

optimally efficient and often use chemicals that contribute

to global warming, twist-based cooling could be a significant

step towards environmentally sustainable refrigeration. “In

practical devices, we expect to be able to exceed the efficiency

of a conventional refrigerator,” Baughman said. “We want to

make refrigerators cheaper, smaller, and lighter.”

Because of the variety of fibers that change temperature

with twist, their discovery could have many applications

beyond traditional refrigeration, such as cooling circuit

boards and other small electronic devices. Baughman’s team

has even demonstrated that the fibers could be coated with

thermochromic paint to create mechanical strain sensors and

fabrics for color-changing clothing. It remains to be seen how

exactly this technology will be commercialized over the next

few years, but there will certainly be exciting twists to come.

www.yalescientific.org

December 2019

Yale Scientific Magazine

35


TIGER ZHANG (JE ‘20)

BY: JULIA ZHENG

COURTESY OF BRIDGE

Murmurs of delighted background conversation

permeate the JE Common Room as Tiger Zhang

(JE ‘20)—chemistry major, Phi Beta Kappa academic

honor society member, and undergraduate

researcher—speaks about what drew him to the

realm of science research in the first place. “The

idea of finding something new has always excited

me. Getting into research felt natural. I wanted

to apply what I had learned in the classroom and

try to see how science really worked through the

process of discovery,” Zhang said.

Zhang’s journey along this path of discovery has

been an eventful one. This past summer, Zhang

completed an immunology research project at the

Memorial Sloan Kettering Cancer Center (MSK), a

project which earned him the first place in the hard

science and medicine category at the recent 2019

Yale Undergraduate Research Symposium. His MSK

research originated from a long-standing interest

in immunology. “I had always been interested in

viruses and bacteria and parasites. Early on, I remember

reading a book called Parasite Rex by Carl

Zimmer about how certain parasites can do really

weird things,” Zhang said. Zhang recalls a certain

species of parasitic worm that, if eaten, could ease

the symptoms of autoimmune diseases. “I thought

anything that was really weird was really cool.”

In taking part in immunology research at MSK,

Zhang had the chance to explore a new area of

science. He studied a type of immune cell called a

natural killer cell. When body cells become infected

with a virus, natural killer cells proliferate at

an accelerated rate, combatting the invading virus

by killing infected cells. Zhang was interested in

investigating if there were other cells aiding natural

killer cells in their accelerated division. He and his

fellow researchers ultimately identified CD8+ T

Cells, a different type of immune cell, as one such

helper. Importantly, natural killer cells also have

the ability to kill tumor cells. “A better understanding

of natural killer cells could, in turn, lead to the

development of a natural killer cell immunotherapy,

where natural killer cells could be harnessed to

UNDERGRAD

PROFILE

target cancer cells. We might be able to treat cancer

that way,” Zhang said.

Currently, Zhang is a member of the Miller Lab at

Yale, a chemistry laboratory whose main research

focus is studying how we can expedite chemical

reactions through the addition of certain substances,

called catalysts. Zhang joined the lab following

his sophomore year, a decision which stemmed

from his interest in organic chemistry. “I always

liked chemistry, but I liked organic, in particular,”

said Zhang. He was drawn to organic chemistry’s

intuitiveness—it allows us to explain how reaction

mechanisms work, step by step, and rationalize

behaviors of tiny molecules based on just a few

concepts. His current research with Margaret Hilton,

a postdoctoral fellow in the lab, relates to the

development of peptide catalysts. The implications

of his research at Miller Lab are significant. “They

could, potentially, be used to develop more effective

antibiotics or anti-cancer drugs,” Zhang said.

When asked about his plans for the future, Zhang

said “hopefully, graduating.” He also hopes to

eventually pursue an M.D. or combined M.D./PhD

degree. Long term, he is considering engaging in

the research and development of cures for different

autoimmune diseases that, currently, don’t have

very effective treatments.

For future researchers, Zhang notes the importance

of being driven by true interest in your

research topic. “The research process can be very

tedious, but if you’re passionate about, curious

about your research topic, you’ll be more likely

to persevere and follow through.” He adds that,

for him, the most motivating aspect of research is

the process. “The process is what leads to understanding—the

process of trying to figure out what’s

going on, trying to understand the mechanisms of

the natural world better and more deeply.”

For Zhang, the most rewarding aspect of research

is the path toward discovery. Driven, fundamentally,

by personal interest and curiosity, Zhang hopes

to be but a small part of a larger scientific endeavor

to tackle disease.

36 Yale Scientific Magazine December 2019 www.yalescientific.org


ALUMNI ALUMNI

PROFILE

Dean Kelsey Martin (MD/PhD ‘92) never planned

to become a physician, let alone the dean of UCLA’S

medical school. In fact, as an undergraduate at Harvard,

she majored in English and American Language

and Literature. After graduating in 1979, she decided

to serve as a Peace Corps volunteer in Zaire, known

today as the Democratic Republic of Congo.

It was Martin’s time as a Peace Corps volunteer that

ignited her passion for medicine. Concerned by the

alarming rate of child mortality, Martin began working

on a variety of public health projects, ultimately

setting up an education and vaccination program to

help prevent measles in over 30,000 children. The program

was so successful that Martin was motivated to

do even more. “For me, it was absolutely the right way

to get inspired by medicine,” Martin said.

Upon her return to the United States, Martin began

working in the laboratory of George Miller at

Yale, studying HIV transmission. Martin was originally

drawn to the project’s ties to public health, but she

spent most of her time working at the bench. “I really

loved my work there. I loved working at such a basic

science level, but on a project that had so much public

health and clinical relevance,” Martin said. The Miller

Lab, which focuses on primarily a molecular virology,

turned Martin onto the kind of biomedical science research

she would continue for the rest of her career.

In 1984, Martin became a Yale student, eventually

graduating in 1992 with an MD and a PhD in Molecular

Biophysics and Biochemistry. She completed

her graduate work in the laboratory of Ari Helenius,

where she studied influenza virus-host cell interactions.

Afterwards, Martin began her clerkships at

Yale-New Haven Hospital with the full intention of

pursuing a career as a physician—that is, until she

stumbled upon psychiatry. On the wards, she was

struck by the limitations psychiatrists faced when it

came to our understanding of the brain. The more she

saw of this enormous need in the behavioral sciences,

the more she wanted to contribute to the field.

After Martin graduated from Yale, instead of going

on to complete a medical residency training program

as most students do after medical school, she

COURTESY OF ALICE TAO

decided to continue research, completing her postdoctoral

training in neurobiology with Eric Kandel

at Columbia University. There, she became interested

in figuring out how experiences change the neuronal

connections in our brains and how our brains store

long-term memories. “I completely fell in love with

what I was doing in the lab. After staying there for a

long post-doc, I knew I wanted to continue neuroscience

research,” Martin said. And so, she did.

In 1999, Martin joined the faculty at the David Geffen

School of Medicine at UCLA. Today, the Martin lab

seeks to understand how gene expression is spatially

and temporally regulated during the formation of longterm

memories. She says this is an exciting time to be

studying a project like this. “The tools we use to ask

molecular cell biology questions about memory are becoming

more and more exciting,” Martin said.

Martin was named dean of UCLA’s medical school

in 2016. She is proud to be a medical school dean

whose career has been so focused on basic biomedical

research. “The main reason I am so motivated

as dean is because I believe so deeply in the synergy

of discovery science and clinical medicine,” Martin

said. “There is so much promise in curiosity-driven

biomedical research to make discoveries that transform

how we understand and treat disease.” Martin

is especially motivated to ensure that medical schools

continue to support this crucial interface between innovative

new knowledge and clinical medicine.

The first woman to serve as dean for UCLA’s medical

school, Martin is also one of only a few women

leading a medical school in the United States. “My

main advice is to follow your dreams,” Martin said

when asked if she had any advice for young women

pursuing careers in STEM. “There isn’t only one way

to pursue a career in medicine as a woman. You need

to find the right path for yourself.”

In 2018, Martin won Yale’s Wilbur Lucius Cross

Medal for her excellence in scholarship, teaching, academic

administration, and public service. In the coming

years, Martin will undoubtedly continue defying

stereotypes, pushing medicine forward, and inspiring

us all to pursue our own unique goals in life.

BY: ALICE TAO

KELSEY MARTIN (MD/PHD ‘92)

www.yalescientific.org December 2019 Yale Scientific Magazine

37


THE SCIENTIFIC ATTITUDE

BY ARIANNA LORD

Creationists, climate deniers, and anti-vaxxers are united by their skepticism of science. Science is under attack from those who claim to

simply be skeptical, but why should they believe in science? What is it that distinguishes

science from other disciplines? In his book The Scientific Attitude, philosophy

of science scholar and Boston University professor Lee McIntyre posits that it

is the attitude of the scientific discipline—the willingness to change one’s mind and

adjust theories on the basis of new evidence—that makes science special.

Science deniers often hinge their arguments on a lack of definitive proof.

“All of us, not just scientists, can learn to fight back against science denial,”

McIntyre said. He explains that, instead of defending science as objective fact,

perhaps we should foster the understanding that science is justification based

on the available evidence. Science itself exemplifies how beliefs can be adjusted

in a rational way based on new information.

It is not reasoning or methodology that makes science distinctive, but

a community that embraces the evaluation and criticism of one another’s

work. “Through the scientific attitude we have found a way to make our beliefs

better by constantly comparing them to evidence,” McIntyre said. In the

book, McIntyre discusses a blog called retractionwatch.com, which reports

on the retractions of scientific papers. Willingness to admit one is wrong

or to publicize the retraction of research is in no way universal. Retractionwatch.com

exemplifies how the scientific community holds one another accountable

and values the fluidity of knowledge.

McIntyre also points to the rise of modern medicine as an example of the

field-transforming power of the scientific attitude. “Medicine underwent a revolution

in its scientific attitude in the nineteenth century. This transformed it

into a prime example of what is so reliable about science.” The book acknowledges

that some may cast Alexander Fleming’s accidental discovery of penicillin

as good fortune. However, McIntyre counters this by pointing out that the

understanding of the empirical evidence, subsequent large-scale experiments,

and development into a life-saving drug, were certainly not by chance.

McIntyre makes a convincing case that it is mindset rather than method that

distinguishes science from other disciplines. McIntyre’s argument is both appealing

and an informative call to arms. The philosophical discussion of demarcation

and the scientific method in the early chapters helps to establish the

basis of his argument. He thoughtfully convinces the reader to appreciate the examples of failure, fraud, and transformation in the

history of science. Furthermore, his contribution “provides the tools for scientists and others who care about science to fight back.”

His writing is thoughtful, logical, and accessible to scientists, philosophers, and others. This book provides a foundation for

understanding how science is carried out. Not only does this book present arguments in the defense of science, but perhaps more

importantly, it celebrates and exemplifies the features that make science so special.

SCIENCE IN TH

38 Yale Scientific Magazine December 2019 www.yalescientific.org


THE OTHER SIDE OF MARS

BY NITHYASHRI BASKARAN

Behind me, a path of tracks imprints the trail that I’ve trekked. Ahead, tawny slates and crumbled dunes stretch on. Though I

stand alone in the valley of Dingo Gap on Mars, I fear no evil, for the desert

is a planet away, and my presence is but an illusion.

Throughout her film The Other Side of Mars, Minna Långström incorporates

stunning images captured by NASA’s Curiosity Rover to give the viewer

the sensation of stepping into the Martian landscape. Interspersing these

with opinions from interdisciplinary experts, Långström explores not only

how NASA uses photographs to advance scientific discovery, but also how

these photographs reflect and define reality. The audience meets a roboticist

peering into visuals with a concern for the rover’s safety, a geologist recounting

the sentiment behind the photograph of Dingo Gap, and a media theorist

explaining science fiction writers’ desire to experience the new space in

the images. “My goal was to somehow take the viewer through this journey

where, in the end of the film, she or he would be thinking of the image almost

as a three-dimensional, spectral object that can be so many different things at

the same time,” Långström said. She argues that the same photograph, viewed

through different lenses, can yield multiple interpretations of reality.

Moreover, the same photograph can itself be altered in an attempt to better

appeal to viewers, but this process is controversial. In one clip, a sociologist

describes that as the aesthetic quality of scientific photographs increases, so

does the public’s suspicion of them. Yet Långström’s film illustrates the black

holes of information missing in individual images and elucidates why NASA

must stitch scenes. “Scientists alter the images so that they can see more; they

use filters and spectroscopes and all kinds of ways of getting more information,”

Långström said. This manipulation is not malevolent. Rather than to

persuade, it aims to extract sensory details, such as infrared wavelengths that

our eyes cannot discern unless color-coded by computer.

Such relationships between subjective perception and objective representation

underlie the film. After all, Långström chooses photographs to impart

her interpretation of how photographs, themselves, craft perception. Wielding

creative direction, she alludes to Sara Ahmed’s essay “Orientations Matter”

to hint at the broader power of narrative in scientific communication.

“We have a perspective of history that is very exclusive… when white male

perspectives are much more represented than others, their version of reality, however sharp imagery they are using, is not

reflecting reality anyway,” she said. The historical exclusion of women from film has affected Långström’s own experience of

discomfort in her field, but she believes we can address inequality by involving a broader spectrum of people in all discussions.

In fifty-five minutes, The Other Side of Mars beautifully advocates for the melding of diverse perspectives, in terms of field

and background, to create a more complete portrait of Earth, Mars, and the infinity beyond.

www.yalescientific.org

December 2019

E SPOTLIGHT

Yale Scientific Magazine

39


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