YSM Issue 92.4
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
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
published by Yale College students, and Yale University is not responsible
for its contents. Perspectives expressed by authors do not necessarily
reflect the opinions of YSM. We retain the right to reprint contributions,
both text and graphics, in future issues as well as a non-exclusive right to
reproduce these in electronic form. The YSM welcomes comments and
feedback. Letters to the editor should be under 200 words and should
include the author’s name and contact information. We reserve the right
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
Interested in writing for
Contact us at
yalescientific@yale.edu
AD_Yale_SC_ENG_half_FALL_10_19qxp.qxp_8 10/7/19 12:05 PM Page 1
Welcome to Yale!
The Yale Science and Engineering
Association is here for you.
Founded in 1914, the YSEA is one of the oldest university student/alumni
organizations in the world with a focus on STEM.
Whether near or far from New Haven, we help our members realize their
goals and to connect in ways that strengthen the Yale science and
engineering community.
We are excited to be a part of your Yale journey, and we look forward to
supporting you at Yale and beyond!
Join us at: ysea.org