YSM Issue 86.4

Established in 1894

THE NATION’S OLDEST COLLEGE SCIENCE PUBLICAITON

November 2013

Vol. 86 No. 4

BIRTH OF

A STAR

PAGE 8

MEDICINE CURRENT EVENTS BIODIVERSITY

Geography of a

Gene

Regional variations in the

MIF gene are linked to the

dual HIV/TB epidemic

Fighting for

Funding

Recent cuts in federal

spending take a heavy toll

on scientific research

Gut

Revelations

Analyzing DNA inside fly

guts grows understanding

of rainforest biodiversity

PAGES 15-17 PAGE 27 PAGE 31

everyday Q&A

Q&A

Almost everyone has struggled with jet lag, but what are the actual causes behind it?

After flying halfway around the

world, even the most seasoned

traveler will succumb to drowsiness,

disorientation, and a strong

urge to fall asleep in the middle of

the day. As we struggle to adjust

to new time zones, we cannot

help but experience the sensation

known as jet lag — the sun in our

new location tells us what time of

day it is, but our brains often do

not process the switch for several

days.

Normally, the body’s internal

clock is programmed to respond

to light as a stimulus that keeps

us alert and awake. But when the

body suddenly shifts to a different time zone, something occurs

at the molecular level that prevents light from having its immediate

effect. This “something,” recently discovered by a group of

Q&A

What Causes Jet Lag?

In high school chemistry class, we learned that absolute zero is

exactly what its name suggests: the lowest possible temperature

that can exist, the threshold at which atoms lose all their kinetic

energy and stop moving. However, physicists recently created

an atomic gas that exists below this threshold, or at negative

temperatures.

The term “negative” is actually a bit misleading. “The gas is

not colder than zero Kelvin, but hotter,” explained Dr. Ulrich

Schneider, the lead physicist of the project. “It is even hotter

than at any positive temperature — the temperature scale simply

does not end at infinity but jumps to negative values instead.”

To explain the idea of negative temperature, the researchers

describe their system in terms of hills and valleys. At absolute

zero, atoms have no energy, and they are all at the bottom of

the valley. As temperatures increase, some particles gain enough

energy to move up the hill, but most remain at the bottom.

A temperature of exactly infinity is the balancing point. Here,

enough particles have left the valley and spread out evenly along

the hill’s slope. But past infinity, more particles are on the hill

than in the valley — the exact opposite of the distribution in the

positive temperature realm; this is what physicists call negative

temperature.

In their experiment, the researchers forced a gas into its

highest possible energy state, achieving a temperature of a few

BY MARIANA DO CARMO

IMAGE COURTESY OF SCRIPPS COLLEGE

Researchers at Oxford University have found that a protein

called SIK1 is at contributor to symptoms of jet lag.

researchers at Oxford University,

is actually a protein called

salt inducible kinase 1, or SIK1.

The protein acts as a “molecular

brake” on the effect of light

in the human body, inhibiting

certain genes in our DNA that

are activated by light and that

help the body adjust to different

time zones.

By reducing SIK1 activity in

mice, the research team found

that animals acclimated to time

zone changes in only a few

hours, whereas untreated mice

required six days to adjust. This

newfound understanding of the

molecular basis behind jet lag may lead to drugs that could help

minimize SIK1’s effect on humans — and maybe help us all enjoy

the first few days of travel a bit more.

Can Temperatures Ever Drop Below Absolute Zero?

Physicists can now push temperatures below what has been considered the lowest energy minimum.

BY AHMED ANSARI

IMAGE COURTESY OF LMU/MPQ MUICH

Scientists were able to reverse the distribution of atoms

at positive temperatures (blue), resulting in a negative temperature

system (red).

billionths of a Kelvin below absolute zero. Their work opens

up possibilities for the study of other high-energy systems that

would otherwise collapse.

2 Yale Scientific Magazine | November 2013 www.yalescientific.org

NEWS

Letter from the Editor

Joan Steitz Receives the Grande Médaille

Disease-Detecting Biosensors

Q&A with Physics Professor Reina

Maruyama

contents

November 2013 / Vol. 86 / Issue No. 4

ON THE COVER

Q&A with Physics Professor Michel

Devoret

Illuminating the Circuitry of the Brain

Small Molecules Designed to Fight Heart

Ischemia

54-Year-Old Mathematics Conjecture

Proven

FEATURES

Current Events

The Impact of Sequestration on Research

Oceanography

An Undiscovered World of Ocean

Viruses

Geology

Mega-Canyon Uncovered in Greenland

Ecology

Fly Guts Reveal Rainforest Biodiversity

Environment

Mythbuster: The Great Pacific Garbage

Patch

Neuroscience

Debunking Science: Near-Death

Experiences

Undergraduate Profile

Jan Kolmas, TC '14

Alumni Profile

Yenyen Chan, SY '94, F&ES '01

Ecology

Urbanization Boosts Animal Brain Size

Trivia

Five Things You Didn't Know about

Black Holes

Book Reviews

-Brilliant Blunders

-The Eternal Darkness

-Packing for Mars

Why does the TB/HIV dual

epidemic pervade Sub-Saharan

Africa? Dr. Richard Bucala's

research suggests that

genetics holds the answer.

Astronomers Examine the Process of Starbirth

Yale Professor Héctor Arce and an international collaboration of

astronomers have obtained striking images of a protostar, providing a

new glimpse into the dynamics of star formation.

The Future of

Space

Exploration

The rise of the space industry

holds great promise for

exploration. From asteroid

mining to X PRIZE, rockets

are just the beginning.

HIV & TB:

Understanding

the Epidemic

Targeting

Diabetes at

Its Source

A clinical trial led by Yale

Professor Kevan Herold

may enable an effective new

type 1 diabetes treatment.

Solute Influence

on Enzyme 23

Motion

Small molecules from buffers

can alter millisecond motions

of enzymes. The Loria lab

demonstrates how buffers

can confound experiments.

Glia

IMAGE COURTESY OF ALMA/ESO

IMAGE COURTESY OF COLON-RAMOS

& Growth: Uncovering the

Architecture of Synapses

IMAGES COURTESY Of BARAN SARAC

Optimizing Microstructures to

Enhance Durability

More articles available online at www.yalescientific.org

www.yalescientific.org

November 2013 | Yale Scientific Magazine 3

the future of space

The last time man stepped on the moon

was over 40 years ago. With manned

missions rapidly losing popularity in

recent years, where is space exploration

headed?

pg. 12

rediscovering the earth

Although our eyes may be trained on the

skies and the deep seas as the frontiers

of exploration, the surface of our earth

still has secrets it is slowly revealing to us.

pg. 30

“

The day we stop exploring is the

day we commit ourselves to live

in a stagnant world, devoid of

curiosity, empty of dreams.

— Neil deGrasse Tyson

”

microscopic sea worlds

The murky, seemingly endless depths of the oceans have

mesmerized mankind’s imagination for all of time. Until now,

however, we have been overlooking some of the greatest

worlds of diversity — those invisible to the naked eye.

pg. 28

FRONTIERS of EXPLORATION

November 2013 Volume 86 No. 4

Editor-in-Chief

Publishers

Managing Editors

Articles Editors

News Editor

Features Editor

Copy Editors

Online Editor

Production Manager

Layout Editors

Arts Editor

Webmaster

Multimedia Editor

Advertising Manager

Distribution Manager

Subscriptions Manager

Outreach Chair

Staff

Zoe Kitchel

Brendan Shi

Elizabeth Himwich

William Gearty

Jiahe Gu

Contributing Writers

William Ge

Somin Lee

Taryn Laubenstein

Sophie Janaskie

Payal Marathe

Yale Scientific

M A G A Z I N E

Established 1894

Jessica Hahne

Karthikeyan Ardhanareeswaran

Stella Cao

Li Boynton

Renee Wu

Terin Patel-Wilson

John Urwin

Alyssa Picard

Rebecca Su

Grace Cao

Dennis Wang

Walter Hsiang

Chanthia Ma

Carrie Cao

Christina de Fontnouvelle

Nicole Tsai

Jeremy Liu

Seung Yeon Rhee

Aurora Xu

Alex Co

Deeksha Deep

Naaman Mehta

Kevin Boehm

Emma Graham

Tierney Larson

Blake Smith

Ahmed Ansari

Ariel Ekblaw

Ethan France

Cathy Ren

Stephanie Mao

Edward Kong

Advisory Board

Sean Barrett, Chair

Physics

Priyamvada Natarajan

Astronomy

Kurt Zilm

Chemistry

Fred Volkmar

Child Study Center

Stanley Eisenstat

Computer Science

James Duncan

Diagnostic Radiology

Melinda Smith

Ecology & Evolutionary Biology

Peter Kindlmann

Electrical Engineering

Werner Wolf

Emeritus

John Wettlaufer

Geology & Geophysics

William Summers History of Science & History of Medicine

Jeremiah Quinlan

Undergraduate Admissions

Carl Seefried 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

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Please send questions and comments to ysm@yale.edu.

F R O M T H E E D I T O R

Frontiers of Exploration

Exploration is without scope. It can encompass sparks of revolutionary invention

or revealing reexaminations of known fact. It can take us soaring up through clouds

and stars or deep down into the darkest depths of the ocean. It can be embodied by

Viking voyages hundreds of years past or even by a mission much closer to home: the

matriculation of modern-day university students.

On August 23, 2013, 1,359 Yale College freshmen bustled into new dorm rooms for

the very first time, greeted their suitemates, unpacked their suitcases, and settled in for

the long-haul. For many of these students, freshman year will be a bumpy ride. The

beginning of any journey can often be the longest, rockiest stretch of the road. But it can

also be an experience of excitement, of growth, and of great discovery.

Welcome to Issue 86.4 of the Yale Scientific. Thanks to our new freshman contributors

as well as our returning writers and artists, this issue’s articles will investigate a wide range

of scientific “Frontiers of Exploration,” from the microscopic inner workings of synapse

formation, to the far-away formation of stars. Two issues back, we published a collection

of articles on the theme “Limits and Breakthroughs,” focusing on the value of landmark

scientific discoveries. Our hope in this issue is to present a more panoramic perspective

on scientific research by covering news in science not just in terms of its end-results, but

in terms of the clever inquiry and exploratory work that goes into finding those endresults.

At a time when funds are few and far between in the United States, many scientists

who once had access to all the tools they needed to uncover and explore their way

to discoveries are starting to come up short. (See the article “Sequestration Cuts into

Scientific Research” on page 27). Now more than ever, the cost of scientific exploration

is steep. But its benefits are priceless, yielding improvements that sweep across society,

from cheaper health care alternatives to more efficient technologies.

Unexplored frontiers can be daunting, even for the boldest of explorers. Whether the

frontier in question happens to be a first year of college or a free market economy, it can

be difficult to maintain a steady direction forward in the face of obstacles. But science is

all about discovery through trial and error. With the common compass of science guiding

us onward, scientists and societies alike are empowered to strive toward discovery, to

delve into the unknown, and — perhaps most importantly — to find value in the process

of exploration along the way.

Jessica Hahne

Editor-in-Chief

About the Art

The cover, designed by Arts Editor Nicole Tsai, utilizes images

captured by the Atacama Large Millimeter/submillimeter

Array (ALMA), detailed in the article on page 8. A star chart

depicting the southern constellation of Vela (The Sails) was

overlaid on a second image of a rich region of dust clouds

and star formation in the southern constellation of Vela.

Images were provided by Yale Associate Professor Héctor Arce

and the European Organization for Astronomical Research in

the Southern Hemisphere. Contributing artists for this issue

were Rachel Lawrence (pages 4, 18), Lining Wang (page 12),

Lindsey Stavola (page 15), Nicole Tsai (pages 20-21), Casey

McLaughlin (page 23), Audrey Luo (page 25), Annelisa

Leinbach (pages 28-29), and Grace Pan (page 36). We would

like to correct the mispelling of an artist's name in Issue 86.3's

"About the Art": Kantiya Jindachomthong.

BIOCHEMISTRY

Joan Steitz Awarded the Grande Médaille

Joan A. Steitz, Sterling Professor

of Molecular Biophysics and

Biochemistry and Howard Hughes

Medical Institute Investigator, will

receive the 2013 Grande Médaille

from the French Academy of Sciences.

Each year, the Academy

bestows the Grande Médaille as its

highest honor to a French national

or foreign researcher who has

“contributed in some remarkable

and decisive way to progress in his

or her field.”

After obtaining her bachelor’s

degree in chemistry from Antioch

College in 1963, Steitz joined the

laboratory of James Watson at

Harvard University. There, she began her study of

ribonucleic acids (RNA). Throughout her career, she

has provided groundbreaking insights into the workings

of RNA. Most notably, since joining the faculty

at Yale in 1970, Steitz has shown that ribosomes bind

messenger RNA (mRNA) during translation through

BY CRISTAL SUAR

complementary base pairing and

that a class of non-coding RNA,

small nuclear ribonucleoproteins

(snRNPs), exists to splice

introns from mRNA following

transcription. With her group,

Steitz continues to discover what

she describes as “new, wonderful,

and sometimes bizarre

examples of how the power of

[RNA] base pairing controls and

sets the foundation for so many

things that go on inside cells.”

In addition to her pioneering

research, Steitz is also

recognized for promoting

the involvement of women

in science. When Steitz began her career, there were

few female role models in molecular biology. Steitz has

since become a prominent and respected leader in the SUBJEC

IMAGE COURTESY OF JOAN STEITZ

Sterling Professor Joan Steitz is

most recognized for her discoveries

involving RNA.

field. Regarding her Grande Médaille, Steitz hopes that

“whoever reads the publicity … sees that women are

making contributions just like men to science.”

ENGINEERING

Regenerative Biosensors Detect Disease Markers

The applications of nanosensors,

designed to identify target molecules

including disease markers, have

been limited by the fact that the

devices can only be used once. But

recently Dr. Mark Reed, Professor

of Electrical Engineering, has

led research creating electronic

biosensors that can be regenerated

and used repeatedly.

Biosensors, geared to detect

and measure disease markers

ranging from emergent cancer

signals to new types of infections,

are primarily used on blood and

water samples. Biosensors detect

particular indicators through

the binding of molecules onto

receptors that induce a change

in electric potential, allowing for rapid and accurate

medical diagnoses.

In traditional sensors, no further binding, sensing,

or usage is possible after a receptor has been bound.

However, Reed’s latest research, published in ACS Nano,

BY JONATHAN YU

introduces biosensors possessing

regenerative properties based

on a supramolecular approach,

in which a layer of receptors on

top of a sensor can be ripped

off through a “cleaning process”

and replaced by additional layers.

“[This] ‘Velcro’ layer system

allows for increased accuracy

and confidence in measurements,

since reusable biosensors can

be harnessed to run massive

multi-parallel experiments with

extreme precision,” said Reed.

The development of reusable

biosensors promises an

expansion in future applications

of biosensors, particularly in areas

involving continuous monitoring

and implantation. With contemporary improvements

unfolding in remote monitoring of toxins and biothreats,

regenerative biosensor technology holds the key

to even earlier and more accurate detection, diagnosis,

and treatment of diseases.

IMAGE COURTESY OF MARK REED

Biosensors detect disease by

sensing when certain molecules

bind to receptors. Traditional

biosensors can only be used once.

6 Yale Scientific Magazine | November 2013 www.yalescientific.org

q&a with

award-winning physicists

ECT

BY EDWARD KONG

Reina Maruyama, Assistant Professor of Physics, was

named June 2013 Woman Physicist of the Month by the

American Physical Society for her work in nuclear and

particle astrophysics and mentorship of young scientists.

What were your

thoughts when you

were named Woman

Physicist of the

Month?

I was nominated by

people I was mentoring,

so I felt honored that

those interactions I

had with students and

post-docs — that they

appreciated it, and that

they thought enough

to nominate me for this

award.

IMAGE COURTESY OF THE AMERICAN PHYSICAL

SOCIETY

How did you become

interested in research? Did you know what you wanted to

pursue early on, or did it take a lot of exploration?

I would say for me it was a journey. When I started undergraduate

studies I didn’t really know what I wanted to major in, so I pursued

physics as one option. I’ve always loved finding out how things

worked, and questions of why things are the way things are, how

we got here — that was always something that interested me.

What kind of advice would you give to undergraduates

interested in doing research, both in your field and in the

broader area of physics?

I would say, explore. Don’t be afraid to try new things; don’t be

afraid to fail. There’s so much cool stuff out there, and I really

encourage you to explore and see what gets you going.

What is it like to perform research internationally? Do those

roles and responsibilities ever make mentoring difficult?

A lot of neutrino and dark matter experiments are located in

remote locations such as underground laboratories. I think that

Antarctica has additional pull for students — just doing science in

crazy places. Having that extra motivation to get people interested

in what we do … I think that’s actually a plus. And if I can send

students there, that’s even better.

IMAGE COURTESY OF YALE APPLIED

PHYSICS

Michel Devoret is the

Frederick William Beinecke

Professor of Applied Physics

& Physics. He and Robert

Schoelkopf received the John

Stewart Bell Prize from the

University of Toronto for their

contributions to the field of

quantum mechanics.

What were your thoughts when you were awarded the John

Stewart Bell Prize?

This kind of recognition is always felt as a great honor, and a great

happiness to be admitted among physicists … it’s this feeling of

being included in a very interesting community.

What is it like to collaborate so closely with another researcher?

Rob is a wonderful criticizer. He’s pitiless and very harsh, and I

appreciate this very much. We collaborate in various ways, but this

kind of critical eye is very precious.

What made you interested in doing research? Did you know

early on that physics was the field you wanted to pursue?

I have known ever since I was 25 that I wanted to become a physicist

but prior to that, if I could have been a pilot, I would have. This was

my childhood dream. But then because my eyesight is rather poor, I

had decided to be an aviation engineer, but you see I ended up being

a physicist, because as you grow up you learn more about the world

around you, you understand better what science is, what the different

sciences are, and how you fit in.

What kind of advice would you give to undergraduates interested

in doing research?

Right now, we are not limited in my field by the laws of nature so

much as we are limited by our ability to interest young students to

join the field. So they can come en masse and there will be something

interesting for them to do.

What would you say is the coolest application of quantum

computing?

What’s interesting about quantum information [is] that it [can’t] be

copied … There will be more and more need for the privacy of

information as abuses are committed with information that circulates

on the web. There will be more and more desire to be able to control

where the information is going.

www.yalescientific.org November 2013 | Yale Scientific Magazine 7

ASTRONOMY

Yale Astronomers Take a Closer Look

at Star Birth

BY KAMARIA GREENFIELD

Earlier this year, Associate Professor Héctor Arce of Yale’s Astronomy

Department and his international collaborators were some of the first

to see two decades of collective scientific effort begin to bear fruit. Arce

and his team, which included Diego Mardones of the Universidad de

Chile and several others, studied the behavior of protostars and their

outflows using the Atacama Large Millimeter/sub-millimeter Array

(ALMA). Their discoveries about the dynamics of star formation were

only made possible by the new array. The conception of ALMA dates

back to before 2002, when the National Science Foundation (NSF) and

the European Southern Observatory (ESO) agreed to build an array

of unprecedented scale in Chile. Since then, the National Astronomical

Observatory of Japan (NAOJ) has also joined the coalition. This array

has been highly anticipated within the scientific community, with the

facility’s director comparing its inception to “opening a new window.”

ALMA, which detects radio waves instead of visible or infrared waves,

is ideal for studying dark parts of the universe where stars are in their

embryonic phase. Using the new technology, researchers were able to

obtain high-resolution images of the carbon monoxide gas streaming

away from a protostar. The particular region under scrutiny is located

in the constellation Vela, around 1,400 light years away.

The images led to two main developments in the understanding of

star formation: first, the ALMA images more clearly showed that star

growth occurs episodically (as opposed to constantly); second, the outflows

— ejected molecular material — have much more momentum

and kinetic energy than previously speculated. This particular outflow

and its collision with the surrounding atmosphere have been named

Herbig Haro 46/47. In general, Herbig Haro objects are small, volatile

regions closely associated with star formation. HH 46/47 stands out as

a significant discovery since its protostar is believed to typify protostars

of its kind and has a mass very similar to that of our own sun. There

are several ramifications of these discoveries. “We can assume that this

energy and momentum that we see will affect, for example, the timescale

that the star will take to form, [and] the amount of material that can be

around to form the star,” Arce said. “This implies that these outflows

have considerable impact on the ways that stars form.” The episodicity

of the growth, meanwhile, affects how the star’s gaseous building

IMAGE COURTESY OF ALMA/ESO

The antennas of the Atacama Large Millimeter/submillimeter

Array (ALMA) observatory stand out against the Chilean

night sky.

IMAGE COURTESY OF ALMA/ESO

The Herbig-Haro object HH 46/47, depicted with jets emerging

from a star-forming dark cloud.

blocks are gathered. “If we want to understand where we come from,

we need to understand how stars and solar systems form,” Arce added.

Since the images of HH 46/47 produced using ALMA were obtained

over a period of only five hours and by using only a quarter of the

full array, these findings represent only a small fraction of the new

technology’s capabilities. Based solely on the quantitative parameter of

collecting area — the array has 66 antennas ranging from 23 to 39 feet

in diameter — ALMA is at least ten times better than any of its predecessors.

Arce also noted a number of other advantages including its

improved technology and ideal placement. The array is located at over

three miles above sea level in northern Chile’s Atacama Desert — arid

conditions and high altitude.

The researchers have high hopes for future projects utilizing the new

technology. “You could do two things: you could do a more sensitive

project or observations with much higher resolution, or you could do

something similar in much less time,” Arce said. He anticipates that it

will also be possible to study numerous protostars at different points in

their evolution, creating a fuller picture of what was up until recently a

patch of the universe shrouded in mystery. Stuartt Corder, a researcher

at the ALMA Observatory and co-author of Arce’s recently published

paper on star formation, emphasized that ALMA is still in its infancy and

said that the technology is expected to provide “even better images than

this in a fraction of the time.” The team plans to expand their project

by eventually comparing their research with hydrodynamic models of

outflows and seeing how these outflows affect the surrounding gas cloud.

Arce, who came to Yale in 2008 and teaches a course called “Interstellar

Matter and Star Formation,” said that he has mentioned this part of

his research briefly to students before but plans to share this abundance

of new material with them. “I always try to incorporate my research in

my course,” he said. “Now that the results are out and the full analysis

is done, I can talk more about it.”

Already, other researchers have also used the revolutionary capabilities

of ALMA to further their own projects. In early September, it was

announced that a team had discovered a massive protostar developing

far closer to home in the Milky Way.

An Associated Foreign Press article from March states that all 66

antennas of ALMA should be fully operational by October.

8 Yale Scientific Magazine | November 2013 www.yalescientific.org

School of Medicine Professors Illuminate

the Language of the Brain

BY WILLIAM GE

Dr. Vincent Pieribone, Associate Professor of Neurobiology at Yale

School of Medicine, is currently submarine diving in the Solomon

Islands in search of shining proteins. If he finds them, it will mean

advancement for the entire field of neurology.

Understanding how

the brain works is

undeniably one of the

greatest challenges of

our time, and one that

dates back hundreds

of years. Although

scattered hypotheses

have long strained

for a coherent theory

of the brain, efforts

have been limited

by our ignorance

of the brain’s

labyrinthine circuitry.

“Traditionally, we

would rely on invasive

electrodes to sample

very limited areas of the brain, and only a few

neurons at a time,” Pieribone explained. A 2012

study at the University of California, Berkeley

characterized this level of imaging as akin to

viewing “an HDTV program by looking just

at one or a few pixels on a screen.” Imaging

technologies such as fMRI have improved our

historical myopia of the brain’s inner circuits, but

they are indirect methods which monitor areas

of high metabolism in the brain, as opposed to

actual neurons firing.

A collaboration between Dr. Vincent Pieribone and Dr. Michael

Nitabach of the Yale School of Medicine has produced a chimeric,

engineered molecule which has the power to illuminate the circuitry

of the brain. The molecule, dubbed ArcLight, has two functional

components. The first is a voltage sensor domain, a transmembrane

protein module containing positively charged amino acids. Voltage

changes across the membrane (in the case of neurons firing) cause a

change in the electric field in which these positive charges sit, and that

imposes a force on the positive charges and changes the conformation

of the domain. The second component, a mutated form of green

fluorescent protein (GFP), is fused to the voltage sensor domain. When

the sensor domain changes conformation, it also changes the shape

of the GFP, which affects the level of fluorescence. Thus, ArcLight

can be used to effectively map millions of neurons firing in real time

by the intensity of fluorescence each gives off.

The implications of this discovery are striking. “Behaviors and

biological processes can be associated with patterns of light,” explained

Pieribone. “For example, when people touch something, there is a

pattern associated with that action. We can ask: what does the brain

NEUROSCIENCE

do? Or, to add a twist, what happens if you lose your arms?” In their

study, Nitabach and Pieribone used ArcLight to demonstrate that

neurons involved in the circadian rhythm of a fruit fly were more

active in the morning than the evening. “This is something you could

only see this way,” said

Nitabach.

However, even this

new method of neural

imaging is not without

limitations. Current

efforts to improve the

protein probe include

increasing the intensity

of the fluorescent

signal in response

to smaller voltages

and increasing the

speed of response

(current lag time is

~20 milliseconds).

Moreover, the GFP

is limited to absorbing

blue light and emitting green light; if alternate

versions could be discovered that can absorb green

light (and thus emit red light), ArcLight could

be used in conjunction with other fluorescent

sensors (e.g. calcium detectors) which emit green

light to produce a system to investigate other

variables of brain activity. Finding these alternate

versions is one of the reasons why Pieribone is

diving in the deep Pacific. If the new proteins

are found, neural systems in which specific

processes can be excited by light (optogenetics)

Above: The mutant isolated from a fluorescent chordate, C. intestinalis (left), was

engineered into a molecule that can read a fruit fly’s (right) mind. Below: The lead

collaborators of the project, Vincent Pieribone (left) and Michael Nitabach (right).

IMAGES COURTESY OF YALE SCHOOL OF MEDICINE

IMAGES COURTESY OF ERIC GIBGUS/NUZRATH NUZREE

can be used concomitantly with ArcLight in order to selectively and

comprehensively decode the electrical circuits that lie at the heart of

neuroscience.

Last April, the Obama administration

unfurled a long-term scientific

effort to map the human

brain and its activity in the

Brain Research through

Advancing Innovative

Neurotechnologies

(BRAIN) Initiative. The

initiative is projected to

cost 300 million dollars

per year over a period

of the next ten years.

Here at Yale, in the

labs of Nitabach and

Pieribone, it looks like

it is already paying off.

IMAGE COURTESY OF

PROTEIN DATA BANK

A mutated form of the protein GFP

acts in ArcLight as the fluorescent

indicator of electrical activity.

www.yalescientific.org November 2013 | Yale Scientific Magazine 9

CHEMISTRY

Myocardial ischemia, or restriction of blood flow to the heart, can

cause serious and irreversible damage in cardiac tissue. Now, however,

an interdisciplinary team of researchers led by Yale Professor of

Medicine, Epidemiology, and Pathology Richard Bucala has developed

a group of small molecules that limit the damage that myocardial

ischemia causes. Bucala hopes to see these molecules developed into

drugs to limit ischemia’s detrimental effects.

Myocardial ischemia can have several causes. Heart attack victims

suffer from restricted blood flow, and surgeons sometimes intentionally

restrict blood flow to the heart during invasive surgeries like coronary

bypass. In either case, prolonged

ischemia can lead to cell death

and permanent damage of the

heart muscle, causing abnormal

rhythms and reducing the heart’s

ability to pump effectively. The

molecules designed and tested in

several studies by Bucala and his

colleagues could prevent some of

that damage.

Other members of the

research team include Yale

Sterling Professor of Chemistry

William Jorgenson and Yale

School of Medicine Professor

of Cardiology and Cellular and

Molecular Physiology Lawrence

Young. The team also includes

former Yale School of Medicine

faculty member Ji Li, an assistant

professor of pharmacology and

toxicology at SUNY Buffalo.

The molecules described in

the study target Macrophage

Migration Inhibitory Factor

(MIF), a cytokine cloned by

Bucala’s research group that

regulates inflammation pathways

found in macrophages, endothelial cells, T-cells, and cardiomyocytes. In

addition to being produced during immune responses, MIF production

is stimulated in the heart by lack of oxygen. Bucala and Young have

collaborated before to investigate the role of MIF in responding to

ischemic conditions. According to Bucala, Young “was very interested

to learn that we had mice in which we had genetically knocked out

the MIF gene. He was really interested in the role of AMPK [AMPactivated

protein kinase] in cardiac ischemia.” In his study, Young found

that mouse hearts missing the MIF gene were less able to overcome

ischemic injuries. MIF binds to the transmembrane receptor CD74,

which initiates a signaling pathway that leads to AMPK activation.

AMPK increases glucose uptake and limits apoptosis during ischemia,

thereby limiting damage to the heart.

Small Molecules Present Promising

Treatment For Ischemia

BY ZACHARY MANKOFF

IMAGE COURTESY OF THE PROTEIN DATA BANK

A rendering of Macrophage Migration Inhibitory Factor

(MIF), for which Bucala’s research group discovered small

molecule activators.

During the time he collaborated with Young, Bucala was also working

with Jorgensen to develop small molecule MIF inhibitors that could

be used to protect against autoimmune responses. As part of a study

originally published in Bioorganic and Medicinal Chemistry Letters in

December 2010, Jorgenson and his lab developed computer models of

several small molecules using the software BOMB (Biochemical and

Organic Model Builder), and synthesized the molecules in the lab. The

program, which was developed by Jorgenson, assists with designing

small molecules that fit with known structures of protein binding

pockets. When assaying the BOMB-designed molecules for MIF

inhibition, Bucala and Jorgensen

unexpectedly discovered that

some of the molecules increased

MIF activity. Bucala hypothesizes

that these small molecule agonists

induce conformational changes

that enhance binding between

MIF and its receptor.

More recently, Bucala’s team

assessed the potential for the

agonists’ therapeutic value by

assaying the molecules’ effects in

in vitro studies on cardiomyocytes

and ex vivo studies on mouse

hearts, as well as their effects on

living mice. Addition of MIF20,

the most potent of Jorgenson’s

small molecule activators, to

mouse cardiomyocytes in vitro

increased phosphorylation of

AMPK and other downstream

effectors. Furthermore, the

addition of MIF20 to an ex vivo

mouse heart before inducing

ischemic conditions allowed the

mouse heart to more fully regain

a normal heart rate after normal

conditions were restored. The

addition of MIF20 to the ex vivo heart also increased both glucose

oxidation and AMPK activity in postischemic conditions. Lastly, mice

treated with MIF20 and subjected to localized ischemia around the

heart showed less necrosis, or death, of heart tissue than mice not

treated with MIF20.

Bucala is also working with Yale’s Neurosurgery Department to

investigate the use of these molecules to treat traumatic brain injury.

According to Bucala, “We are looking for partners now to develop the

agonists.” The group is also hoping in the near future to investigate

the small molecules’ therapeutic potential using large mammal models.

If they are developed into drug therapies after human trials, the small

molecules would have wide applications for limiting complications due

to heart attacks or restriction of blood flow during surgery.

10 Yale Scientific Magazine | November 2013 www.yalescientific.org

A team consisting of Adam Marcus, Daniel Spielman, and Nikhil

Srivastava has solved the 1959 Kadison-Singer Problem. Originally

posited by Richard Kadison and Isadore Singer, the problem is an

important cornerstone in the mathematics underlying quantum

physics, relating to the measurements of quantum properties.

Professor of Computer Science,

Mathematics, and Applied

Mathematics Daniel Spielman

explained that the Kadison-

Singer Problem has a long

history intertwined with many

Further Reading

• NASA, “Reduced Gravity Education Flight Program: Microgravity University.” Last

modified 2013. http://microgravityuniversity.jsc.nasa.gov/

14 Yale Scientific Magazine | November 2013 www.yalescientific.org

UNDERSTANDING

THE

AND ITS LINK TO

EPIDEMIC:

BY EMMA GRAHAM

HIV

There are few diseases that match

the persistence and pervasiveness

of tuberculosis (TB). Mycobacterium

tuberculosis, the bacterium that causes the

infection, resides in the bodies of one-third

of the human population. Most infections

are latent, meaning that they do not produce

any symptoms. In latent TB, the bacteria lie

dormant in the lungs, secluded from the rest

of the body and suppressed by immune cells

called macrophages. Latent TB, however, can

suddenly become active, causing symptoms

that include coughing, fatigue, and loss of

appetite. In healthy patients, dormant bacteria

have only a 10 percent chance of becoming

active. In immunocompromised patients,

however, the chance of reactivation is greatly

increased. Indeed, throughout the past ten

years, the number of patients infected with

both HIV and TB has increased dramatically.

Tuberculosis and HIV

Geographically, TB is prevalent

throughout Asia, Eastern Europe, Russia,

and Sub-Saharan Africa. With 24 percent of

the world’s TB cases, Africa has the highest

per capita mortality from the disease. The

region also happens to be the epicenter of

www.yalescientific.org

the HIV epidemic. HIV destroys the ability

of the human host’s macrophages to control

TB infection, a fact that explains the high

lethality of the disease in patients with both

TB and HIV compared to TB in otherwise

healthy individuals. This fact has exacerbated

the global TB epidemic, especially in regions

of the world where TB and HIV are most

prevalent.

Why Sub-Saharan Africa?

While the despairingly high prevalence of

TB and HIV in Sub-Saharan Africa could

once have been attributed to the lack of

public health initiatives and infrastructure in

the region, researchers have now pinpointed

a more basic reason for the disease’s

ethnocentricity (meaning its high incidence

among specific populations). Our genetic

makeup has long been known to play a

role in our susceptibility to tuberculosis

and its progression. Researchers including

Dr. Richard Bucala, a professor at the Yale

School of Medicine, are examining the

genomes of different human populations

in an attempt to identify small differences

that might make certain populations more

susceptible to diseases such as tuberculosis.

Specifically, Bucala’s research investigates

how genes can influence the body’s response

to different pathogens. Bucala’s lab recently

discovered a functional polymorphism in a

gene that strongly influences our response

to TB. This gene is called macrophage

migration inhibitory factor (MIF), and the

immune protein it encodes is produced by

agents of the immune system (macrophages,

leukocytes, and pulmonary epithelial cells)

upon infection. The MIF gene has a common

polymorphism in its promoter region that

results in two main variants: a low-expressing

variant and a high-expressing variant.

The difference between these variants,

or alleles, lies in the different number of

short DNA repeats in the promoter. The

low-expressing variant has five repeats of

a tetranucleotide regulatory sequence while

the higher-expressing variants have more

than five repeats, leading to correspondingly

greater expression. After discovering this

polymorphism, Bucala started measuring

the distribution of these variants in human

populations within the United States.

In nursing home studies carried out

previously by other researchers, African-

American patients had been shown to

be more susceptible to developing more

November 2013 | Yale Scientific Magazine 15

MEDICINE

lethal tuberculosis than Caucasian patients.

Interestingly, Bucala found that while the

low-expressing variant is expressed by 65

percent of African Americans, it is only

expressed by 45 percent of Caucasians.

Noticing this trend, Bucala then sequenced

the MIF gene in different populations from

around the world. The low-expressing variant

was most prevalent in Sub-Saharan Africa,

with 78 percent of Zambians, for instance,

possessing the low-expressing variant.

ESTIMATED TB INCIDENCE RATES, 2010

MIF and Malaria

The prominence of the low-expressing

MIF variant was not the only genetic

discovery within the Zambian population.

Unlike their counterparts in Northern

African and Mediterranean countries,

populations in Southern Africa were known

to lack the sickle cell gene, a variant in the

hemoglobin gene that confers malarial

immunity in heterozygous individuals at

the cost of anemia and shortened lifespan

in homozygous individuals. Realizing this,

Bucala hypothesized that the low-expressing

MIF gene helps provide immunity against

malaria, as it suppressed the excessive

inflammatory response that often kills

malaria-infected children. The group studied

African children with malaria and found

that a low-expression MIF allele was indeed

associated with less severe disease.

Mouse models of malaria or TB infection

performed by Bucala confirmed that having

IMAGE COURTESY OF RICHARD BUCALA

The areas with the highest TB incidence rates correspond to populations with

predominantly low-expression MIF alleles, suggesting that having the low-expression

allele makes you more susceptible to TB infection.

a low-expression variant of the MIF gene

correlates with both less severe malaria

but higher likelihood of developing TB

pathology. Accordingly, it was predicted that

TB patients with low MIF would be more

susceptible and less able to fight off TB

infection. Rita Das, a graduate student and

infectious disease fellow in the Bucala lab,

found evidence for this in humans as HIVpositive

Ugandan patients with disseminated

(widespread) TB were 2.4 times more likely

to have a low-expressing variant of the MIF

gene than those without bacteremia.

The low-expressing form of MIF is a

double-edged sword. The low-expression

variant, by preventing a full immune

response, protects people from the lethal

inflammatory complications of malaria. Yet

at the same time the variant can increase

susceptibility to TB and act as a marker for

poor prognosis of disease progression.

Population Stratification of the MIF locus

Low-expressing MIF alleles occur

disproportionally in Africa. Bucala

postulates that this stratification of the MIF

locus occurred when a small population of

individuals migrated out of Africa about

100,000 years ago. As this population

reached colder climates with less malaria and

encountered new, life-threatening pathogens,

the benefit of the low-expressing allele was

lost in favor of the higher-expressing allele.

IMAGE COURTESY OF RICHARD BUCALA

While HIV is prevalent throughout the world, the epidemic is at its highest incidence

rates in Southern Africa. In this region, it is estimated that 50 percent of new TB

patients are also infected with HIV.

You Take the High Road and I’ll Take the Low

Road

While the prevalence of the low-expressing

form of the MIF gene in Sub-Saharan Africa

can be explained by the immunity it confers

to lethal malaria, its prevalence in areas

such as North America and Europe cannot

be explained as easily. Common diseases in

these regions include community-acquired

pneumonia, a disease that can lead to sepsis

(a state of overwhelming infection) and

death if not treated. Community-acquired

16 Yale Scientific Magazine | November 2013 www.yalescientific.org

MEDICINE

hogen

55/GG

56/GG

56/GC

66/GG

66/GC

bia

ambia

sor

logy

ine the

ibility

ons.

his

overy

ning

has

sor

yses of

ttings.

57/GC

VISUAL APPEARANCE OF INDIVIDUAL BIOCHIPS, which measure only 1 square cm, showing every possible

above combination left: of MIF Rapid allele (5, determination 6, 7, and 8 repeat) together of MIF with a allele related in single areas nucleotide without polymorphisms genomic (G or analysis C) technology is now available with biochips,

Pictured here are biochips showing every combination of MIF allele (5, 6, 7 or 8 short DNA repeats) and a single nucleotide

individuals who have more repeats produce more enables direct visualisation of a patient’s MIF

polymorphism. above right: Dr. Richard Bucala (left) and Dr. Rita Das (right) in front of the Botswana Ministry of Health.

MIF. “Depending on the individual,” continues genotype without the need for sophisticated

Bucala, “this repeat can be present in five to eight instrumentation. “All too often,” says Bucala,

pneumonia is the leading cause of noncardiac

First, inexpensive techniques are needed to this global epidemic.” Bucala is currently

copies; the more copies that are present, the more “exciting discoveries or technologies are

the gene

intensive

that is expressed

care unit

and

deaths

the greater

in the

the

U.S.,

developed

determine

that

each

are not

individual’s

economically

MIF

practical

variant. working with Dr. William Jorgensen in the

simply inflammatory because response of how during easily an infection.” sepsis can By be for widespread To this application. end, Witness rapid the and problem affordable Yale Department of Chemistry on ways to

triggered. extending this The DNA-sequencing low expressing analysis MIF to allele a few has in providing diagnostic adequate methods care for have patients been infected developed increase MIF action in low MIF-expressing

been hundred shown individuals, to not the team only found exacerbate that people TB in with using HIV or biochips, tuberculosis.” small silicon chips with individuals. Supplementing MIF would

African of African-American populations, ancestry but to are lead more to likely reduced to The oligonucleotides benefits of being able attached to genotype to patients the surface provide an important adjunct to the current

survival have a low rates number from of sepsis repeats in in Americans their MIF gene with at the that bedside light are up clear: when as bound well as the to a cost specific method of combating resistant TB strains,

and as a result, to produce less MIF protein during

community-acquired pneumonia. In these being sequence. very low, the Using methodology this technology is robust, to the detect which involves taking multiple antibiotics for

an immune response. This work led directly to the

cases, the high-expressing allele is clearly needs which for training patients and are laboratory more facilities susceptible are

hypothesis that these low-expression variants

to many months, a difficult and costly treatment

minimised, and patients can be quickly identified

beneficial. of the MIF gene, or alleles, offer a selective malaria or TB infection will allow doctors to and one being circumvented by the everincreasing

drug-resistance of TB strains.

and ‘stratified’ according to their susceptibility

advantage Bucala’s to people clinical living expertise in Africa and there is in to lethal spend disease. more This time enables with quicker their cases, referrals whether

rheumatology exposed chronic and infections, autoimmune the most prevalent diseases. to that hospitals involves for monitoring longer hospitalizations, and aggressive more The discovery of geographic and

These and lethal diseases being malaria. are caused by excess treatments, antibiotic such use, as or blood an individually transfusions optimized and ethnocentric polymorphisms in the MIF

inflammation, Bucala notes that highlighting the human population an important has antibiotics, treatment which plan. saves lives and conserves gene led to a new understanding of the HIV/

context co-existed for with favoritism malaria for of the longest low-expressing period precious According medical resources. to Bucala, “we are slowly TB epidemic. No longer is geography simply

allele of time in Africa, North suggesting America. that Studies low-expression showed LOOKING developing TO THE new FUTURE antibiotics for TB, but an additional fact about the epidemic; it now

MIF alleles were favoured and selected for

that the low-expressing form of MIF is Given we the desperately central role need of MIF new in the tools immune to combat offers a unique explanation of its cause.

in order to allow individuals to escape the

associated with less severe rheumatoid response to malaria, the rapid genotyping of MIF,

lethal inflammatory consequences of malaria

arthritis, infection. “We systemic modelled lupus this idea erythematous, in a controlled and or other genetic polymorphisms of interest may

prove useful in field studies of malaria vaccines to

other laboratory inflammatory infection and disorders. found that geneticallyengineered

arisen mice to combat lacking the different MIF gene infections show

Genes that

different antigens. Such genetic information

have About may the Author

help to predict vaccine responsiveness in different

also enhanced have survival the ability during to lethal worsen malaria,” autoimmune Bucala

populations, Emma as Graham candidate vaccines is a sophomore progress in Trumbull College majoring in Molecular

inflammation, explains. His team emphasizing since verified the this balancing idea

through

by completing a genetic epidemiology study Biophysics clinical trials. and “Although Biochemistry. we developed

act that our immune system plays to keep us this biochip methodology specifically to allow for

in a malaria-susceptible population in Africa,

healthy.

the genotyping of MIF variant alleles,” continues

observing a significant protective effect of lowexpression

MIF alleles in the development of

Bucala, “it Acknowledgements

is broadly applicable to any genetic

polymorphism

Individualized severe malarial Treatment

The author of interest, would and like there to is thank ongoing Professor Richard Bucala for taking the time to share

anaemia.

work to his adapt research. this technique for the study of

RAPID GENOTYPING

other genes, both for malaria and other prevalent

Knowing what variant of the MIF

Genotype determination normally requires costly infectious diseases such as leishmaniasis.”

gene a person has can lead to a greater

and sophisticated analytical instrumentation Low-expression

Further

MIF

Reading

alleles are associated in

understanding that is available in of only that a few person’s specialised disease, centres and Western • populations Das R, Koo with M-S, protection Kim B-H, against Jacob ST, Subbian S, Yao J, Leng L, Levy R, Murchison

inflammatory C, Burman diseases WJ, Moore such C, as Scheld WM, David JR, Kaplan G, MacMicking JD,

how in Africa. best Ordinarily, to treat samples it. Those would suffering have to be from autoimmune

TB collected, and having shipped to a low-expression a laboratory for processing, MIF allele arthritis, asthma, Bucala and R. 2013. inflammatory MIF is a Critical bowel Mediator of the Innate Immune Response to M.

theoretically analysed by a genetic could analyser, receive and supplemental

the results disease. Investigation tuberculosis. of a polymorphic Proc Natl Acad genetic Sci USA 110;2997-3006.

MIF then reported to reset back their to the immune healthcare response providers. to locus that appears to have evolved in response

This is a process that normally takes many to lethal malaria infection therefore also

combat TB more effectively. However, as is • Bucala R. 2013. MIF, MIF Alleles, and Prospects for Therapeutic Intervention in

days to weeks, even in developed countries. provides one explanation for susceptibility to

the case with many infectious diseases, the

But Bucala’s team has developed a facile and the development

Autoimmunity.

of autoimmune

J Clin Immunol.

disorders

33;S72-S78.

epicenter inexpensive of ‘biochip’ the HIV/TB that, within dual two epidemic hours, is prevalent in many Western countries.

in a part of the world where analysis of each

person’s genome may not be cost-effective.

www.yalescientific.org

67/GC

67/CC

77/CC

78/CC

IMAGES COURTESY OF RICHARD BUCALA

November 2013 | Yale Scientific Magazine 17

TARGETING

Diabetes Diabetes

at its

Source

preserving insulin production in type 1 diabetes

Source

By Grace Cao

For many, a diagnosis of diabetes

carries with it a lifelong sentence

of glucose monitors and insulin

injections. Although associated technology

has improved, the essential nature of

treatment has not changed since the discovery

and subsequent commercial production

of insulin in the 1920s. However, a recent

clinical study led by Dr. Kevan Herold, Yale

Professor of Immunobiology and Medicine

(Endocrinology), aims to improve treatments

for patients with type 1 diabetes.

Most people are familiar with type 2

diabetes, a disease associated with poor diet

and excess weight; however, type 1 diabetes

is a more severe form of the illness, which

is most often diagnosed in children and

represents up to ten percent of all diabetes

cases. In this condition, immune cells

known as T cells attack insulin-producing

beta cells in the pancreas, which leads to

decreased levels of insulin production.

While a concrete cause for type 1 diabetes is

unclear, there is evidence for strong genetic

and environmental factors. As the disease

progresses and the death of beta cells results

in falling insulin levels, patients need to

deliver the insulin their body cannot supply

through injection or insulin pumps.

Though researchers and clinicians have

expanded their knowledge of the disease in

recent decades, options for treatment are still

limited. Diagnosed individuals must carefully

and constantly monitor their blood glucose

levels, then administer insulin at several

points throughout the day. Furthermore,

as Herold explained, since the advent of

insulin, “there has never been another

treatment that fundamentally changed the

natural history of the disease.” Even with

appropriate management, a significant

fraction of type 1 diabetes patients today

develop complications that include kidney

failure, blindness, and various neuropathies.

A Potential Treatment

Herold’s study may foreshadow a new

treatment that could change how patients

IMAGE COURTESY OF UCSF DIABETES TEACHING CENTER

In Type 1 diabetes, insulin production is

insufficient, decreasing glucose uptake.

manage their condition. In this clinical

trial, patients were treated with the drug

Teplizumab, a monoclonal antibody which

binds to a specific region of the CD3 receptor.

This receptor is found on the surface of

all T cells, including the ones responsible

for beta cell destruction in type 1 diabetes,

and helps T cells recognize their target

antigen. The reason that binding to the CD3

receptor reduces attacks on beta cells is as

of yet unknown. Unlike other CD3-targeted

antibodies, Teplimuzab does not simply

deplete T cells from the body. Research

by Herold and Richard Flavell, Sterling

Professor and Chair of Immunobiology at

Yale, suggests that the drug “causes cells to

migrate to the gut, where they may acquire

a regulatory function,” said Herold. These

induced regulatory T cells can then suppress

the immune response.

In the study, two groups of patients, all

of whom were within eight weeks of their

initial diagnosis, were treated, either with

Teplimuzab or with nothing as a control.

One year later, the patients were again treated

for two weeks with the same substance.

Throughout these years, the patients’

insulin production and consequently beta

cell function were monitored by measuring

levels of C-peptide, a short protein found in

a precursor to insulin.

What the researchers found was extremely

promising. In patients receiving the drug, the

18 Yale Scientific Magazine | November 2013 www.yalescientific.org

average decline in C-peptide was 75 percent

less than the control group after two

years, meaning there was

a 75 percent improvement

in insulin production.

However, not all the treated

patients responded similarly,

leading to a second critical

question: Why did some

patients respond better than

others?

Identifying Responders

To understand the

answer to this question, it

is important to first define responders and

non-responders. According to Herold, the

distinction is straightforward: “We looked

at the decline in C-peptide in the control

group after two years. Drug-treated subjects

who had the same level of decline are nonresponders,

and those with less decline

are responders.” Based on this criteria, of

the 49 treated subjects who completed the

study, 27 were non-responders and 22 were

responders. Examining the C-peptide levels

over time within these groups revealed

that non-responders actually had similar

levels of C-peptide as the control group. In

patients who responded to the treatment,

C-peptide levels remained at or above the

initial baseline for an average of 18 months,

and the level of C-peptide was almost three

times higher than the control group at this

time.

After discovering this drastic difference,

the team was very interested in determining

what caused it. “We thought for sure that

there were going to be big immunologic

differences, but [the distinctions] were fairly

subtle,” Herold said. Rather, “the major

difference seemed to be that the responders

used less insulin going into the trial than

IMAGE COURTESY OF HEALTH MEDIA

Patients with Type 1

diabetes require multiple

doses of insulin daily.

the non-responders, and also had better

glucose control.” While this initially seemed

counterintuitive, as one might

expect that responders would

end up with lower blood

glucose levels rather than the

other way around, the team

found the same trend when

they reevaluated previous trials.

One potential explanation is

that glucose levels may affect

immune responses or beta

cells directly. Herold’s lab is

interested in investigating

the links, as he believes

that “there’s an interesting

interrelationship between metabolic control

and immunologic effects that really has not

been addressed at all.”

Hope for the Future

The success of the trial has not stopped

Herold from looking toward improvements

and future applications. He is continuing to

track the response of patients in the trial to

see how long their C-peptide levels remain

stable. He has also continued to investigate

basic immunological questions about type 1

diabetes and Teplimuzab, including defining

biomarkers for the disease and investigating

the role of the microbiota in regulating

the differentiation of regulatory T cells

in the digestive tract. By improving our

understanding of the disease pathology and

interaction with the drug, more effective

interventions can be developed.

About the Author

MEDICINE

IMAGE COURTESY OF YALE IMMUNOBIOLOGY

Kevan Herold, Professor of Immunobiology.

In addition to these studies, Herold

is enrolling patients for an even more

ambitious trial, one which aims to prevent

or delay the onset of type 1 diabetes. “We

know from monitoring relatives of people

with type 1 diabetes that those who have

autoantibodies and altered glucose monitor

tests have a greater than 75 percent risk

of getting diabetes in five to seven years,”

he said. “The question is, if you come in

much earlier, does the drug prevent the

disease altogether?” If the trial shows that

Teplimuzab has an effect in preventing

type 1 diabetes, it could lead to a major

advance in patient care, as those at risk for

can currently do little to stop disease onset.

Together with Herold’s other ongoing

research, the study represents a longawaited

hope for improved type 1 diabetes

treatments.

Grace Cao is a sophomore Molecular, Cellular and Development Biology major in

Timothy Dwight College. She is a Yale Scientific copy editor and works in Professor

Carla Rothlin’s lab in the Immunobiology Department.

Acknowledgements

The author would like to thank Professor Herold for his time and enthusiasm in explaining

his research on type 1 diabetes.

Further Reading

• Daifotis, Anastasia G, Scott Koenig, Lucienne Chatenoud, and Kevan C Herold.

2013. “Anti-CD3 Clinical Trials in Type 1 Diabetes Mellitus.” Clinical Immunology.

IMAGE COURTESY OF BIOTUESDAYS

An insulin pump delivers insulin without

requiring multiple injections.

• Daneman, Denis. 2006. “Type 1 Diabetes.” Lancet 367 (9513) (March 11): 847–58.

doi:10.1016/S0140-6736(06)68341-4.

www.yalescientific.org November 2013 | Yale Scientific Magazine 19

uncovering

the

architecture

of our

synapses

20 Yale Scientific Magazine | November 2013

www.yalescientific.org

BY SOMIN LEE

Imagine a production of all 38 of Shakespeare’s plays,

performed back-to-back, complete with over one

thousand characters and nearly a million words. The

success of the production depends critically on each

character saying the exact right words at the exact right

times. Although the flawless execution of such a play seems

daunting, the human brain orchestrates a similar task in the

formation of 100 trillion synapses between over 100 billion

neurons during development.

Synapses are the connections neurons use to communicate

with one another, and the proper creation and maintenance

of these connections are necessary for normal brain

function. Exactly how the brain manages such complexity

has been an interest of Professor Daniel Colón-Ramos of

the Yale School of Medicine for nearly a decade. As we

grow, our brains increase nearly fourfold in volume. The

mechanism behind the maintenance of synapses during such

dramatic growth is one of his lab’s primary interests. Current

research in his lab has now uncovered that the regulation

of a cell type called glia during growth may hold the key to

synapse regulation.

C. elegans as a Model Organism

Due to the overwhelming complexity of working with the

human brain, Colón-Ramos studies synaptic connections

in Caenorhabditis elegans (C. elegans), a small roundworm

about one millimeter in size. C. elegans is well-suited for

neurodevelopmental research in several ways. One major

advantage of C. elegans is the ease of genetic manipulation in

the species. Scientists in recent decades have also constructed

the entire C. elegans connectome, which means that we now

know the identity, morphology, and connectivity of each

of the 302 individual neurons in C. elegans. Colón-Ramos

described working with an organism with a completed

connectome as “a bit like having an answer key. We know

this is what a proper nervous system looks like so it’s much

easier to notice when things go wrong.”

Discovery of cima-1

The majority of synaptic connections form in the

embryonic stages, and these connections remain as the

animals grow into adults. To address the question of how

C. elegans maintains embryonically specified synapses, the

Colón-Ramos lab searched for genes involved in synapse

maintenance through a process known as forward genetics.

In the forward genetic approach, random mutations are

chemically induced in the DNA of the organism, creating C.

elegans with a wide array of abnormal features. These mutant

organisms are then screened for particular characteristics of

interest. To target genes involved in synapse maintenance,

the Colón-Ramos lab isolated mutants exhibiting normal

synapses as larvae but misaligned synapses as adults.

To uncover the exact genes and proteins malfunctioning

in the mutants, the lab conducted genetic fingerprinting on

the mutants’ DNA, a process similar to paternity tests in

humans. The test pointed to a mutation in a gene called cima-1

as the cause of the abnormal synaptic connections. Prior to

this study, cima-1 had never been investigated in C. elegans.

To further confirm that cima-1 acts critically during growth,

the lab created mutations in the cima-1 genes of abnormally

21 Yale Scientific Magazine | November 2013 www.yalescientific.org

NEUROBIOLOGY

IMAGE COURTESY OF MIT

C. elegans, a common model

organism.

small and large

worms. “It

was a really fun

experiment,”

Colón-Ramos

noted. “We

had these

really giant

worms and

really tiny worms, and exactly as we predicted,

the small worms were less affected by cima-1

mutations and the giant worms were much

more affected. It’s fun when science works

like that.”

Glia and cima-1

Because mutations in cima-1 cause abnormal

neuronal connections, the logical prediction

would be that cima-1 acts in neurons.

Surprisingly, the Colón-Ramos Lab found

that cima-1 was found not in neurons but in

epidermal cells, which make up the outermost

layer of the skin. So how does a gene found

only in epidermal cells affect synaptic

connections between neurons? The answer,

as it turns out, lies in glial cells.

IMAGE COURTESY OF COLON-RAMOS

Epidermal cells (green) are in close contact

with glia (red) which are close to neurons

(green).

Glia often act as translators between

epidermal cells and neurons. Although

previously believed to be nothing more than

“glue cells” of the brain, we now know that

glial cells have an array of important functions

including supplying nutrients, providing

structural support, and fighting pathogens.

Furthermore, recent research has implicated

glial cells in a variety of neurodevelopmental

activities, including synapse formation. In the

neurodevelopment, epidermal cells position

the glia, and the glia in turn position neurons

and synapses. cima-1 mutants exhibited glial

cells with abnormal shapes, suggesting that

mutations in cima-1 interfere with proper

communication between epidermal cells and

glia, resulting in abnormal synaptic growth.

An analysis of the various molecules

involved in sending signals between epidermal

and glial cells identified a receptor regulated

by cima-1, suggesting that communication

through this receptor was the mechanism

behind synaptic maintenance.

From C. elegans to Humans

Although humans and round worms seem

to share very little in common with each other,

evolution has ensured that even the most

disparate of species share similar roots and,

consequently, genes. The human equivalent

of cima-1 is called sialin, and mutations in

sialin result in a neurological condtion known

as Salla disease. The defective sialin in Salla

patients results in a dangerous build-up of

a metabolic byproduct called sialic acid.

Build-up of sialic acid causes brain atrophy

and leads to an array of neurological problems

including mental retardation. Patients also

often suffer from motor control problems

such as reduced muscle strength, loss of

muscle coordination, and speech difficulties.

There is currently no cure for Salla disease,

and symptoms can be managed only to a

limited extent through medications and

therapy. Although Salla disease is relatively

rare, mutations in genes related to sialin

cause other human diseases such as gout and

congenital deafness. The Colón-Ramos lab

hopes that further investigation of cima-1

and its related mechanisms will result in the

discovery of novel therapeutic targets.

In addition to bettering our understanding

of various diseases, glial signaling may offer

insight into the evolutionary origins of the

human brain. Colón-Ramos pointed out that

the epidermal-glia-neuron signaling network

is reminiscent of the human blood-brain

barrier. During times of high activity, neurons

need more energy. Neurons communicate

this energy need through glial cells that are

in contact with epithelial cells of blood

capillaries. The result is increased blood

flow to the brain. The presence of the

epidermal-glia-neuron unit in C. elegans, as

well as the endodermal-glia-neuron unit in the

blood brain barrier of humans, suggests an

evolutionarily conserved role for glia in linking

epidermal (or endodermal) cells and neurons.

Future Directions

IMAGE COURTESY OF COLON-RAMOS

cima-1 (red) is found surprisingly not in

neurons, but in epidermal cells.

Although the discovery of cima-1 and its

role in neurodevelopment is a big step in

understanding synapse regulation, Colón-

Ramos noted that there are still many gaps left

to be filled. The implication that C. elegans and

humans may share the same fundamental glialneuron

unit also raises questions regarding the

evolutionary roots as well as functions of glia.

Although not all of these questions are ones

Colón-Ramos plans on pursuing, he hopes

that “our research will influence the way other

people and labs think about the role of glia

in neurodevelopment and maintenance of

neuroarchitecture”

About the Author

Somin Lee is a junior in Branford College majoring in Molecular, Cellular, and

Developmental Biology. She currently works in Professor Marvin Chun’s lab

investigating neural representations of sustained attention.

Acknowledgements

The author would like to thank Dr. Colón-Ramos for his time and insights, and

John Urwin for his clear explanations of complex topics.

Further Reading

• Ryan Christensen, Zhiyong Shao, Daniel A Colón-Ramos, The cell biology of

synaptic specificity during development, Current Opinion in Neurobiology,

Available online 6 August 2013, ISSN 0959-4388, http://dx.doi.org/10.1016/j.

conb.2013.07.004.

22 Yale Scientific Magazine | November 2013 www.yalescientific.org

So, what’s in your buffer

DOES matter!

Loria Lab Detects Solute Influence on Enzyme Motion

By Jayanth Krishnan

Professor Patrick Loria has always

been fascinated by the fundamentals

— internal motions in proteins and

the functions of those proteins in the body.

Enzymes, the proteins that work to catalyze

reactions, are certainly not static. The Loria

lab investigates the internal motions of

biological enzymes, an area of study that

is crucial to drug discovery efforts. Using

nuclear magnetic resonance spectroscopy

of proteins (protein NMR), the Loria lab

studied how phosphate, sulphate, and acetate

buffers can influence motions and illuminate

the functions and allosteric regulation of

enzymes.

Allosteric enzymes are proteins that

change their conformation when bound

to an effector protein. This change in

www.yalescientific.org

IMAGE COURTESY OF PATRICK LORIA

The Loria lab at Yale, with Professor Patrick

Loria standing third from the right.

conformation can either activate or inactivate

the enzyme. Although functional allosteric

enzymes regulate many classic pathways, the

biochemical mechanism of action of most

of these enzymes is still very unclear. The

Loria lab works in collaboration with Yale

Chemistry Professor Victor Batista, who

is an expert in computational chemistry,

to understand and rationally alter allosteric

enzymes.

Techniques and Tools of the Loria Lab

The Loria lab used NMR spectroscopy

extensively to analyze the influence of buffers

on enzyme motions. In NMR, the nuclei of

atoms, depending on whether they possess an

intrinsic form of angular momentum (spin

property), behave like small magnets.

Upon immersion of these atoms into

a static magnetic field of the NMR

spectrometer while maintaining exposure

to a secondary oscillating magnetic field,

an NMR signal is produced. This is a

physical phenomenon in which nuclei

in a magnetic field absorb and re-emit

electromagnetic radiation at a specific

resonance frequency. The chemical shift

of a nucleus is the difference between

the resonance frequency of the nucleus

and a standard reference compound

(e.g. tetramethylsilane, which is assigned

a chemical shift of zero). This quantity is

reported in parts per million (ppm) and

given the symbol delta, Δ. The chemical shift

differs for the various amino acids (residues)

of an enzyme. The protein NMR signal

helps scientists classify the protein and better

understand its dynamic properties.

The Loria lab measures spin-spin

relaxation times using relaxation dispersion

experiments, which are pulse sequences

applied during spectroscopy. The term

relaxation describes several processes by

which nuclear magnetization prepared

in a non-equilibrium state returns to the

equilibrium distribution. In other words,

relaxation describes how fast spins “forget”

the direction in which they are oriented.

Spin-spin relaxation is the mechanism

by which the transverse component of

the nuclear spin magnetization vector

exponentially decays towards its equilibrium

value of zero. The metric (R ex

), which is

commonly used to analyze results from the

relaxation dispersion experiments, depends

on conformational exchange parameters ϕ ex

and k ex

. The parameter ϕ ex

takes into account

the equilibrium population of a pair of

inter-converting conformers as well as the

difference in chemical shift between the two

conformations. The parameter k ex

is the sum

of the forward and reverse rate constant of

the conformational states.

November 2013 | Yale Scientific Magazine 23

BIOCHEMISTRY

IMAGE COURTESY OF MICHIGAN STATE UNIVERSITY CHEMISTRY DEPARTMENT

An NMR spectrometer: in the continuous wave method,

the sample is spun between poles of a powerful magnet. A

spectrum is acquired by varying the magnetic field.

Investigations at the Loria Lab

Imidazole glycerol phosphate synthase

(HisF), an allosteric enzyme needed

for the survival of plant pathogens and

some pathogenic bacteria, has been

studied extensively in the Loria lab. If the

mechanistic properties of this enzyme

are better understood, scientists could use

small molecules to inhibit the enzyme and

eventually provide a therapy for those affected

by the pathogen. Using protein NMR on

HisF, the team noticed chemical shifts that

changed based on the buffer being used. In

literature, the lab found research on the pH

dependence of atomic resolution structures

that complemented the solution NMR

experiments but found

very little work that

investigated how solute

and buffer molecules

interact to change

enzyme conformation.

The lab then embarked

on control experiments

to illustrate the

importance of choosing

the most appropriate

buffer as common

solute molecules can

alter observed enzyme

millisecond motion.

In a study led

by Madeline Wong ’13, the Loria lab

implemented solution NMR to examine the

effects of different functional groups in

the enzymes HisF, ribonuclease A (RNase

A) and triosephosphate isomerase (TIM).

Phosphate, sulfate, and acetate were used as

buffers as these functional groups have shown

a number of ways to interact with proteins of

interest. The effects of these buffers on the

chemical shift perturbation and millisecond

conformational exchange motions of the

enzymes were compared to the effects of

reference buffer systems HEPES and MES.

When the NMR experiments were performed

to examine chemical shifts and dynamics of

the three enzymes, the scientists kept the pH,

ionic strength, and temperature constant so

that the buffer was the only independent

variable. The researchers subsequently

performed relaxation dispersion experiments,

which showed significant solute-dependent

changes for all of the enzymes. Lastly, when

the X-ray crystal structure for all three

enzymes was analyzed, there was a significant

presence of phosphate ions at the enzymes’

active sites, clearly illustrating that an anionic

buffer could alter conformational dynamics

of enzymes. In future research, the lab will

perform enzyme assays with and without

different buffer components to see if buffers

can inhibit enzyme function.

Through the results of this study, the Loria

lab has illustrated the importance of buffers,

and how buffers can confound biochemical

experiments. “Typically buffers for

biochemical studies are chosen as a matter of

experimental convenience. What Madeline’s

experiments show is that buffers can play a

more active role, often altering the function

and dynamics of the system under study,”

stated Loria. Although addressing this issue

in the lab may be difficult, as even the best

buffers could affect enzymatic conformation,

these results have highlighted an important

procedural issue.

On a local scale, the results of Wong’s study

continue to inspire current Yale students. Tim

Caradonna ’15 is now starting his second

year in the Loria lab. When asked what drives

scientists such as himself in this type of

basic research, Caradonna stated, “The goal

of basic research is to solve fundamental

problems, which can provide an established

context for more applied research in the

future. Experiments such as Madeline’s are

important controls; if the buffer has changed

the dynamics of a protein, you’ve potentially

affected its function or activity.” On a larger

scale, knowledge of how buffers can affect

enzyme activity offers important insight into

the future of drug development and other

fields of biochemical experimentation.

About the Author

Jayanth Krishnan is a junior Molecular, Cellular, & Development Biology

major in Morse College. He is the journalism chair for the Synapse program of Yale

Scientific Magazine Outreach and works as a remote affiliate in Professor Kellis’ lab

at MIT.

Acknowledgements

The author would like to thank Professor Patrick Loria for his time and his enthusiasm

for his research.

IMAGE COURTESY OF PATRICK LORIA

Millisecond motion in the enzyme RNase

A. Amino acid residues with Rex ranging

from 0 (gray) to 40/s (red, see color bar)

are shown on a diagram of RNase A for

MES reference (A) and phosphate (B).

Further Reading

• Wong, Madeline, Gennady Khirich, and Patrick J. Loria. “What’s in Your Buffer?

Solute Altered Millisecond Motions Detected by Solution NMR.” Biochemistry

[http://pubs.acs.org/doi/pdf/10.1021/bi400973e]

24 Yale Scientific Magazine | November 2013 www.yalescientific.org

A Shattering Discovery:

Optimizing Microstructures

TO ENHANCE DURAB ILITY

BY DEEKSHA DEEP

Picture your ideal mobile phone — it

probably has a sleek design with a

polished screen and a slim but fragile

body. Now imagine that phone falling: either

off the edge of your bed, out of the car as

you open the door, or even clumsily out of

your hand as you pull it out of your pocket.

The sound and sight of a shattered screen

that would likely follow are all too familiar,

but what if there were a way to alter the

properties of the materials used in our devices,

our buildings, and the very infrastructure on

which our lives are based? Yale researchers

Professor Jan Schroers and Dr. Baran Sarac

have tackled this question by developing a

process to enhance the physical properties of

a material utilizing “artificial microstructures.”

The Importance of Microstructures

Every material has measurable physical

properties, such as tensile strength, ductility,

and plasticity. These properties can be

improved if a compatible microstructure

is coupled with the desired material.

Microstructures, which can only be seen using

optical microscopes, can function to absorb

stress, thus increasing a material’s strength and

durability. The key features of microstructures

include shape, size, volume, distribution, and

spacing between each individual element. If a

microstructure can be altered in a controlled

manner to produce a structure analogous to

a particular material, the material’s quality and

www.yalescientific.org

durability can be greatly improved.

An example of the utility of microstructures

is their role in improving the quality

of refractory materials. Useful for the

construction of industrial equipment such

as kilns, incinerators, and reactors, refractory

materials can withstand heat while retaining

durability. Embedding microstructures in these

materials greatly enhances their refractory

properties. Furthermore, increasing the

efficiency of materials decreases consumption

and costs. For example, since 1970, the US has

decreased its consumption, and by extension

waste, of refractories by over 64 percent.

Applications of microstructure biomaterials

used in hip replacements are not refractory

materials, they match in elasticity with the

body and are biocompatible. For example,

biomaterials (ex. hip replacements) to be

used in vivo need to match in elasticity with

the body parts they replace. The desired

mechanical properties can be achieved via

directed construction of microstructures.

With such drastic improvements in sight, there

is clearly incentive to further study and apply

microstructures to more materials.

Introduction to the Project

Professor Schroers and his team used a

class of material called Bulk Metallic Glasses

(BMGs) for their study on microstructures.

These materials mimic many properties

of metals but are far more resilient and

IMAGE COURTESY OF BARAN SARAC

Dr. Baran Sarac (left) and Professor Jan

Schroers (right) are the co-authors and

main researchers in determining the

optimal microstructure for BMGs.

surprisingly plastic, or moldable. This unique

conglomeration of properties makes BMGs

promising in many areas of application

from large structures down to nano-scale

projects. Unfortunately, there is a barrier to

the implementation of BMGs in improved

materials: They have a gaping lack of

tensile ductility, which prevent them from

being worked into a desired shape without

significant stress. This issue with what would

otherwise be a perfect candidate for the

future reshaping of materials was the focus

for the “artificial microstructure” approach

implemented by Schroers and his team.

November 2013 | Yale Scientific Magazine 25

MATERIALS SCIENCE

The Process of Discovery

Schroers’ “artificial microstructures”

approach is universally applicable to the study

of all microstructures, and not only to BMGs.

It strives to control individual characteristics

of the microstructure independently, allowing

isolated study and optimization of the

properties of each microstructure within the

overall material.

The technique of “artificial microstructures”

has both a distinct process of generation and

a unique method of implementation. Usually,

microstructures are applied onto the material

during the casting or heat treatment of the

IMAGE COURTESY OF BARAN SARAC

The tensile testing machine utilized to

determine the tensile ductility by which

the effectiveness of the artificial microstructures

can be quantified is shown in

the picture above.

material. However, artificial microstructures

are generated in a controlled manner on a

template, and are then transferred to the

metallic glass by reheating and pressing

the material. This method of applying

microstructures is more precise and efficient.

Schroers and his team analyzed the resulting

heterostructure using three different methods:

finite element simulation, a bending test, and

heat treatment. The finite element simulation

proved useful in modeling the mechanical

behavior under stress. The bending test

involved testing the behavior of the material

in the elastic to plastic strain region and

subsequently examining how the material

changed in bending ductility in a range of

strains. The heat treatment involved studying

the heterostructure under varying annealing

conditions and embrittlement to analyze

thermal and structural properties for elevated

temperature applications.

The project’s goal was to use the “artificial

microstructures” technique to determine the

factors in the microstructure that could imbue

the BMGs with tensile ductility. The BMGs

were studied in the soft, cellular phase, but the

technique’s effect on the hardened, composite

phase was also examined. By applying varying

parameters to the microstructures, Schroers

and his team found that the shape, volume,

and interfacial strength projected qualities

on the soft second phase that decreased

shear stress in the material. Furthermore,

the spacing of the microstructures and

relative size of the overall material were also

important in optimizing the tensile ductility

and toughness of the BMGs. Overall,

Schroers and his team were able to identify a

heterostructure that conferred tensile ductility

onto the BMGs.

Implications and Further Studies

Materials are an integral part of everyday

life, from the steel infrastructure of buildings

and bridges to the polymer plastics that are

used for garbage bins and kitchen appliances.

The cost of production and waste from such

usage of materials is also a significant part of

daily life. The work of Schroers and Sarac has

provided the industry with a new technique

for improving the efficiency and quality of

materials in a way that can be applied to

decrease waste and increase cost-effectiveness.

Not only are BMGs now more practical

for use, but this technique of microstructure

analysis can also be readily applied to other

materials. Microstructures can be designed-toorder

depending on the desired qualities in the

material, which opens up a wide horizon for

future applications of the technology. Sarac,

who co-authored the paper, recently obtained

his PhD from Yale with the completion of this

project and is continuing his study on BMGs

and their properties in Germany. At Yale,

Schroers and his team are investigating flaw

tolerance of metallic glass heterostructure

as an analogous system to microstructures

found in nature. Studying optimization

of microstructures via the novel artificial

microstructures technique in a lab setting

could reveal new information about how

nature optimizes its microstructures.

This research, uniquely situated in the

intersection of the artificial and the natural

and past and future of materials, has the

potential to change materials from being

limiting factors for innovation to being in

the forefront of innovative construction and

production.

About the Author

IMAGE COURTESY OF BARAN SARAC

Professor Jan Schroers’ lab, including

the equipment necessary to to construct

these artificial microstructures.

Deeksha Deep is a sophomore Molecular Biophysics & Biochemistry major in

Morse College. She works in the Spiegel lab studying cell surface reconstruction in

bacteria and vaccine design and is on the Yale Scientific Magazine business team.

Acknowledgements

The author would like to thank Dr. Baran Sarac for his time and for his enthusiasm

about his research.

Further Reading

Sarac B. and Schroers J. Designing tensile ductility in metallic glasses. Nat. Commun.

4:2158 doi: 10.1038/ncomms3158 (2013).

26 Yale Scientific Magazine | November 2013 www.yalescientific.org

CURRENT EVENTS

Sequestration Cuts into Scientific Research

BY ALEX CO

FEATURE

On March 1, 2013, the federal budget sequestration went into effect,

implementing the automatic spending cuts that the Budget Control Act

of 2011 had created two years ago. This fiscal year, reductions across the

board will total approximately $85.4 billion, with a $9.3 billion decrease

in federal R&D funding alone.

While the cuts spare no public sector, medical research is among the

hardest hit. The National Institutes of Health, the largest financier of

biomedical research in the world, was forced to make a five percent ($1.7

billion) budget cut by the end of September. It expects to fund only 15

percent of proposals received this fiscal year, a historic low from down

from its peak of 37 percent in 2001. Defunding such vital research and

development may threaten the quality of human health, curtail training

of the next generation of researchers, and jeopardize the United States’

position as one of the world’s leaders in science research.

A nationwide survey conducted by the American Society for Biochemistry

and Molecular Biology (ASBMB) asked more than 3,700 scientists

across a range of disciplines about the effects of the sequester on their

research. 80 percent of respondents indicated that they spend more

time writing grants than in 2010, while 67 percent receive less total grant

money than before. “The biggest time commitment now for investigators

is trying to get funding,” said Dr. Paul Lombroso, Director of the

Laboratory of Molecular Neurobiology at the Yale School of Medicine.

Lombroso also highlighted the dramatic increase in competition, with

many outstanding proposals competing for fewer funds. With less time

and fewer resources devoted toward conducting research, projects that

have been underway for years may be forced to end.

Because sequestration has only existed for several months, the

short-term effects have not been too substantial. Major agencies and

individual researchers report having

a slight cushion of funding for

the time being. But the future of

science research that looks solemn

if sequestration continues.

The lack of grant money will also

affect jobs, with many researchers

unable to hire new staff or

even keep current lab members.

Meanwhile, in a time of general

economic austerity, foreign governments

including those of the

United Kingdom, Sweden, and

Australia, among others, have committed

funds and political backing

to science. Thus, current and future

researchers in the United States

may soon have to make important

choices. Faced with ongoing funding

shortages, they may choose to

leave the country for greener pastures

— those nations with money

for research funding, and perhaps

more importantly, job security.

With dwindling job opportunities, the possibility of a so-called “brain

drain” is becoming more of a reality. Eighteen percent of respondents

in the ASBMB survey considered continuing their careers in another

IMAGE COURTESY OF DAILY KOS

While funding applications are on the rise, acceptance rates are

decreasing as the sequester reduces money to fund research.

IMAGE COURTESY OF CHECK KENNEDY

President Obama, a vocal opponent of sequestration, speaks at

Argonne National Laboratory outside Chicago. With Congress

unable to produce a budget and prevent a shutdown, the sequester

remains in place, spelling more trouble for the future.

country, where research jobs are more stable. For others who have yet

to select a career path, the prospect of science research has lost some of

its appeal, and the number of students who enroll in graduate programs

each year has declined sharply. As a result, projects with the potential

to change the lives of citizens across the country and around the world

may not be fully realized. With the threat of scientists leaving the United

States and the risk of students defecting to other, more stable professions,

the position of the United States’ leverage in science is precarious.

In light of federal funding cuts, researchers have turned to other tactics

for money. Researchers can seek “bridge funding” to tide themselves

over, and some have resorted to

especially creative means. HIV

researcher Yuntao Wu of George

Mason University is receiving

money from an online charity

drive set up by a non-profit organization.

But Wu, like some other

desperate colleagues, has also

taken out a $35,000 personal loan

to keep his lab open and continue

projects that he has worked on for

years. For others like Wu, options

are decreasing all around and the

state of future science research in

America remains unknown.

In light of the government shutdown

on October 1, the sequestration

will remain in place until

Congress passes a new budget that

explicitly redefines agency funding.

While sequestration is hurting science

now, the impact will be much

greater in future years if these cuts

in research funding continue and

researchers must continue and perhaps even intensify their austerity. It

remains to be seen if America’s quality of research will remain at its

influential level if money is not there to support it.

www.yalescientific.org

November 2013 | Yale Scientific Magazine 27

FEATURE

OCEANOGRAPHY

A Whole New World

Scientists Discover Abundant Viruses Living Under the Sea

BY PAYAL MARATHE

A single drop of seawater contains nearly ten million viruses.

But despite their strength in numbers, marine viruses failed for

decades to win the attention of most researchers. Scientists believe

that only one percent of all saltwater virus species have been identified

to this day.

Recent discoveries in this branch of microbiology are finally shedding

light on just how intriguing and powerful these viruses can be.

In fact, there are ten times as many saltwater viruses as there are all

other saltwater microbes combined, and their sheer number makes

them an incredibly powerful ecological force. By controlling bacterial

populations, marine viruses determine how much energy is available

for plants and animals in the world’s oceans. They can also benefit

research in agriculture, medicine, and evolution.

One significant breakthrough in the field came in February, when

Nature published a study led by Oregon State University microbiologist

Stephen Giovannoni. Giovannoni’s team identified a new species

of marine virus that attacks SAR11 bacteria, the most abundant

marine bacteria worldwide. This discovery might not come across as

astonishing. After all, 99 percent of marine viruses are still floating

around unidentified; ecologists who sift through saltwater are likely

to find something new eventually. And yet these new viruses, which

Giovannoni has found are the most abundant saltwater viruses in

the world, managed to escape discovery for decades.

The new viruses, dubbed “pelagiphages,” play a critical role in the

ecology of marine ecosystems, making it even more remarkable that

they remained hidden from the scientific community for so long. By

regularly attacking and killing SAR11, the pelagiphages prevent the

bacterial population from overrunning an entire ocean ecosystem.

Paul Turner, a Professor of Ecology and Evolutionary Biology at

Yale, explained that bacteria like SAR11 are extremely efficient at

using their resources. Without marine viruses to kill as much as 50

percent of saltwater bacteria every day, rampant bacterial growth

would quickly deplete the ocean’s resources.

SAR11 also happens to be a major player in the carbon cycle. The

bacteria absorb organic carbon from the environment in order to

produce energy, releasing carbon dioxide in the process. Although

each individual bacterium consumes a small amount of carbon,

the entire population uses up a tremendous amount of the organic

carbon molecules dissolved in seawater. Given carbon’s essential

role as a biological building block — it is a component of proteins,

lipids, carbohydrates and nucleic acids — it is crucial that plants and

animals have access to organic carbon from the environment. When

pelagiphages penetrate and kill the bacteria, this captured organic

carbon becomes available to other plants and animals in the water.

The inner workings of the pelagiphage resemble those of most

other viruses. Technically, the virus is not alive — instead, it relies on

a host cell to function and reproduce. It attacks its host, SAR11, by

penetrating the bacterial cell and inserting its own viral DNA. Once

it has control of the cell, it uses the cell’s machinery to make copies

of itself. The SAR11 host cell eventually bursts and dies, releasing

new copies of virus that are free to scatter and infect new hosts.

More importantly, when SAR11 bursts it releases carbon, among

other essential nutrients, into the environment.

In addition to uncovering the new virus’s role in the ecosystem,

These “peliphage” viruses hold key roles in marine ecology.

An electron micrograph of SAR11 bacteria.

28 Yale Scientific Magazine | November 2013 www.yalescientific.org

OCEANOGRAPHY

FEATURE

Stephen Giovannoni, the lead researcher of the Oregon State University team

that identified the most abundant marine viruses.

Giovannoni’s research highlights an ongoing evolutionary arms race

between SAR11 and marine viruses. Because of their fast life cycles

and quick reproduction, both microbes are able to evolve rapidly, and

according to Turner, they are the “champions of adaptive change.”

With each generation, the viruses are responding to SAR11’s evolutionary

advantages with changes of their own; meanwhile, SAR11

bacteria quickly adapt to any adjustments made by the viruses.

This evolutionary process is extraordinarily rapid. Viruses proceed

through an average of 1.2 generations per day. By contrast, observing

evolution in humans is impossible, because it takes decades for

multiple generations to elapse.

The arms race between SAR11 and its viral predator has been

used by scientists to explain the great diversity of marine microbes.

For instance, as SAR11 adapts to the virus, perhaps by developing

a less penetrable nucleus or establishing a counterattack, the single

strain could potentially diverge into multiple species.

Luckily, for each new bacterial strain that emerges, there are dozens

of viruses that have yet to be revealed. In July, researchers at the

University of Arizona identified twelve new types of bacteria-killing

saltwater viruses. “Studies like this convince us that we only know

the tip of the iceberg when it comes to the diversity of viruses in

natural environments,” said Turner.

Several months earlier, researchers at Cornell University added to

the growing list of discoveries in marine virology. The team identified

a species of saltwater virus that attacks crustaceans called copepods.

These crustaceans feed on photosynthetic phytoplankton, and the

pellets they release sink to the ocean floor. But these pellets are not

entirely waste — they include large amounts of locked-up organic

carbon that came from the phytoplankton. Once again, marine

viruses come to the rescue by controlling copepod populations and

maintaining suitable levels of organic carbon in the ecosystem.

Given the great variety of marine viruses, cataloging these species

is a tremendous step in revealing the diversity within underwater

ecosystems. “One of the ultimate goals for ecologists is to eventually

describe all the creatures on the planet,” said Turner. With such

vast quantities of marine viruses, it is impossible to pursue this goal

without exploring and identifying pelagiphages.

Of course, most people outside the field of ecology are not quite

so passionate about cataloging every creature on

earth, understanding the carbon cycle, or testing

evolutionary theories at high speed. However,

these newly discovered marine viruses have a

profound impact on other aspects of research.

For example, studying new viral specimens gives

scientists a better understanding of how viruses

can easily penetrate a host cell and navigate a

victim’s immune system. By studying this process,

researchers can potentially develop better antiviral

treatments to human and animal diseases.

Turner explained that other advantages of

marine viruses are less obvious, but just as

exciting. “We tend to only focus on viruses that

make us sick,” he said, “but, if we look at specific

viruses and at the specific genes that make

those viruses successful, we can take advantage

of viral functions for our own applications.”

IMAGE COURTESY OF KARL MAADSAM According to Turner, recent research has shown

that certain plants can grow more efficiently at

high temperatures when infected by a virus. This

ability can be harnessed to support plant growth

even as global warming threatens agriculture.

As research in marine viruses accelerates, Turner said he is optimistic

about where the field will go. There is still much work to be done

in cataloging the diversity of these saltwater viruses, and along the

way scientists can continue investigating the impact viruses have on

medicine, agriculture and biodiversity. Much remains to be explored

in that single drop of seawater containing ten million viruses.

www.yalescientific.org

November 2013 | Yale Scientific Magazine 29

FEATURE

GEOLOGY

Hidden Beneath the Ice

scientists discover mega-canyon in greenland

BY SOPHIE JANASKIE

In the past century, scientists and researchers have

explored the depths of the ocean, landed rovers on

Mars, and developed a deeper understanding of the

human brain and body. In the wake of these discoveries

and in the age of Google Maps and GPS,

one would think that we have explored all there is to

explore. However, a new finding suggests there may

be more left to discover than we originally thought.

A research group led by Jonathan Bamber of

Bristol’s School of Geographical Studies has recently

uncovered a never-before-seen mega-canyon in

northern Greenland. This massive geological feature,

which measures about 460 miles in length and up

to 2,600 feet in depth, stretches from the center of

Greenland all the way to the Petermann Glacier fjord

on the northern coast.

But how did this enormous canyon, which in

some locations is comparable in scale to the Grand

Canyon, escape our notice for so long? Simple: It is

buried under more than a mile of ice.

Most glacial researchers study coastlines, where the ice is most

unstable and most likely to affect the global sea level. Bamber’s team,

however, did not limit their scope so narrowly. Their study encompassed

the entire island of Greenland, drawing from the data of prior

studies across a 40-year period.

In the beginning, Bamber’s team had simply hoped to investigate

the portion of Greenland’s landscape that was hidden by ice. From

previous investigations, researchers knew that ice-covered geological

features were important, though unseen. Topography below glacial ice

affects the flow and path of meltwater, which are key in understanding

glacial movements and global sea level rise. In addition, landscape

features that predate the ice sheet can reveal important insights into

the history and geology of the region.

But when the team set its sights on Greenland, it certainly did not

expect to find anything of this magnitude. “You know, it’s not every

year, it’s not every decade, it’s not every five decades that you discover

IMAGE COURTESY OF NASA

NASA’s Operation IceBridge used an airborne radar to collect data

on the topography hidden beneath the ice sheet.

IMAGE COURTESY OF JONATHAN BAMBER

Radar data enabled Bamber’s team to produce a three-dimensional map of the

canyon’s topography.

something quite as substantial and extensive as a feature like this, so it

was a big surprise for us,” Bamber said in an interview with NPR. It

was not until they analyzed a significant portion of the data that they

noticed a large anomaly in the center of Greenland.

One of Bamber’s major data sources was NASA’s IceBridge, a sixyear

mission that monitored how Earth’s polar ice caps were changing.

IceBridge researchers employed an instrument called a multichannel

coherent radar depth sounder to carry out their survey. This device

emits ice-penetrating radio waves, enabling it to measure geological

characteristics of the bedrock beneath the glacier. Using this data,

Bamber’s team was able to generate a 3D map of the canyon’s landscape.

He found that over this area, radio waves took a much longer

time to bounce back to the radar device, indicating a large depression

in the topography.

Unlike valleys formed from glacial erosion, this mega-canyon is

not U-shaped. Rather, its sharply-defined features, meandering path,

and steep slopes suggest that a river once carved its way through the

bedrock. These characteristics place the canyon’s age at over four

million years old — the last time period when Greenland was not

covered in glaciers. These days, the canyon seems to play a key role in

the transport of the ice’s meltwater to the ocean.

The team’s discovery is a huge step for geological research because

it demonstrates that there is still much to explore on Earth. “One

might assume that the landscape of the Earth has been fully explored

and mapped,” said Bamber. “Our research shows there’s still much

left to discover.”

What else might be left? Although Bamber expressed doubt that

another geological feature of this magnitude remains hidden, he did

not rule out the possibility. Many landscapes hidden by ice sheets

remain unexplored and unstudied, as do other areas of our planet.

Whether it is the deep sea, ice sheets, remote islands, or high mountaintops,

this discovery leaves no doubt that we still have much left

to learn about our planet.

30 Yale Scientific Magazine | November 2013 www.yalescientific.org

ECOLOGY

FEATURE

Fly Guts Reveal Rainforest Biodiversity

BY WILLIAM GEARTY

A recent study lends truth to the saying that “you are what you eat.”

Dr. Sebastien Calvignac-Spencer, an evolutionary biologist at the Robert

Koch Institute, has found that the gut material of flies may be the key

to understanding the biodiversity of rainforests. By analyzing the DNA

in the digestive tracts of carrion flies, he has developed a new method

of monitoring and assessing mammalian biodiversity.

About one year ago, Calvignac-Spencer began studying sick chimpanzees

that were dying from a strain of rainforest anthrax in the Tai

National Park of Côte d’Ivoire. Since fly gut bacteria are known to

cause other strains of rainforest anthrax, he hypothesized that a similar

culprit was responsible for carrying and spreading this new strain. While

investigating the contents

of the suspect fly guts,

Calvignac-Spencer noticed

that 40 percent of the flies

yielded mammalian DNA.

This key observation

is what led to Calvignac-

Spencer’s latest study. As

scavengers, carrion flies

eat dead animals that have

fallen to the rainforest

floor. While the organisms

soon decompose,

fragments of their DNA

accumulate in the guts of

the flies. Unlike humans,

flies do not possess highly

acidic stomachs that they

churn their food in. Therefore,

the DNA will often

remain unbroken for long

periods of time. This DNA

can easily be recovered

from the captured flies

and matched with the species that it came from. “[The DNA is] not

gorgeous, but still usable,” he explained to Nature.

Calvignac-Spencer collected 201 carrion flies from his field sites in Tai

National Park, Côte d’Ivoire, and Kirindy Forest, Madagascar. His team

then extracted the DNA from the tropical flies, selecting the portions

containing sequences that most mammals are known to have. Finally,

by comparing the selected DNA sequences to libraries of animal DNA

sequences, Calvignac-Spencer was able to identify the various species

that the flies feasted on.

The list of species was surprisingly diverse. The flies from the Tai

National Park carried DNA from 16 mammal species, including local

primates, bats, a porcupine, a hippo, a shrew, and an extremely endangered

antelope. The search in Madagascar was also successful, yielding

four of the 31 total mammalian species on the island.

Although the group only gathered 201 flies, increased sampling could

produce higher recovery of mammalian DNA, increasing the percentage

of mammal diversity that these DNA censuses can account for.

To monitor animal populations, researchers usually have to spend

several years out in the field, counting specimens by direct observation.

It is time-, resource-, and labor-intensive. Furthermore, results of traditional

censuses can often become out of date very quickly, especially

taking into account the amount of time that is required to collect and

assess the data.

Calvignac-Spencer’s new method makes the process much more efficient.

Carrion flies are everywhere, and getting enough DNA samples is

far quicker than trekking through the rainforest in search of an elusive

species.

In addition to assessing a region’s overall biodiversity, Calvignac-

Spencer believes that analyzing fly guts can also be used to gather detailed

information on a single species.

For instance, by collecting

a large enough sample

of flies from a wide enough

range, this method could

potentially help researchers

determine the species’

distribution in the area.

Likewise, sampling over

a period of several years

could provide information

about the population’s

change over time, detecting

population crashes or

booms that would otherwise

be undetected by

conventional monitoring

methods.

In a discussion with

IMAGE COURTESY OF JJ HARRISON

Calliphora vomitoria: a type of meat-eating blowfly that Calvignac-Spencer

used in the 2013 study.

National Geographic,

Calvignac-Spencer cited a

case in 2002 when thousands

of gorillas were killed

by the Ebola virus in the

Republic of Congo. Standard monitoring only discovered 44 carcasses.

“Flies could really be precious in this context,” said Calvignac-Spencer.

Flies are not the only animals that can help monitor biodiversity. In

2012, Thomas Gilbert from the University of Copenhagen conducted a

similar study using leeches in Vietnam. Gilbert’s team was able to find six

mammal species including an extremely rare deer and a rabbit that had

never been seen in the area. Studies such as these, using new methods

of detection, may be the next step in understanding remote regions with

undiscovered life. “Unlike camera trapping and dung-searches,” Gilbert

told National Geographic, “leech data collection is simple, inexpensive

and can be conducted by untrained personnel.”

Calvignac-Spencer and Gilbert’s studies are part of the growing

research movement in environmental DNA (eDNA), the genetic litter

that animals spread throughout their surroundings. Since the early 2000s,

scientists in this new field have studied scraps of DNA that accumulate

in soil, water, air, and more recently, fly guts. While these methods are

still being fine-tuned, they may bring us closer to fully understanding

the scope of Earth’s biodiversity.

www.yalescientific.org

November 2013 | Yale Scientific Magazine 31

FEATURE

ENVIRONMENT

Mythbuster: The Great Pacific Garbage Patch

BY TARYN LAUBENSTEIN

IMAGE COURTESY OF CHARLES MOORE

This bird’s stomach contents are almost entirely composed of

plastics, which were the likely cause of its death.

From above the Pacific Ocean, all is calm. Blue water meets

blue skies, each reflecting the other’s pure, infinite depths.

But now a white scrap meanders by; not the reflection of a

cloud, but a bobbing Styrofoam cup. Soon it is joined by two,

now three, now ten, now fifty others, all jostling for space.

They start to stack, forming hills, mountains. They support

their plastic brethren: discarded bottles, packaging materials,

webbed fishing nets. Worn-out tires pile atop one another

forming rubber towers, while flimsy shopping bags flutter

like flags in the breeze. It is an island of plastic the size of

Texas, floating in the middle of the Pacific.

This is the image that comes to mind when people hear

of the Great Pacific Garbage Patch: a massive, floating heap

of debris. However, while it is true that trash does find its

way into the oceans, the Great Pacific Garbage Patch is not

a floating island in the traditional sense. Instead, the Garbage

Patch is composed of tiny plastic bits that linger unseen

beneath the surface, ranging in size from a few square inches

to barely visible specks.

Captain Charles Moore was the first to notice the Great

Pacific Garbage Patch in 1997. Then a racing boat captain, he was sailing

from Hawaii to southern California when he stumbled upon “plastic …

as far as the eye could see.” In an article he wrote for Natural History,

he described “plastic debris floating everywhere: bottles, bottle caps,

wrappers, fragments.” Seeking to quantify the extent of the debris, he

towed fine-mesh nets behind his boat, collecting the plastic bits along

with plankton in the water. He found that the mass ratio of plastic to

plankton was an astonishing 6:1.

Moore explained that the garbage patch was formed by a system of

ocean currents. In large ocean basins between continents, currents tend

to move in a circular pattern, known as a gyre. These wind-driven currents

push water towards the center of the basin. This means that any

pollution that enters the Pacific will eventually be pushed to the center

of the gyre, where it begins to accumulate. Of course, the Pacific gyre

is not the only ocean gyre — all of the world’s oceans have circular

currents like these. This means that there is not just one garbage patch,

but many; the two next-largest ones are found in the Northern Atlantic

and the Indian Ocean.

IMAGE COURTESY OF CHARLES MOORE

Captain Moore poses with a water sample taken from the Great Pacific

Garbage Patch.

While Moore’s description of ocean gyres holds true, his initial

description of the Great Pacific Garbage Patch has recently come into

question. He claimed to “never [have] found a clear spot” in the ocean,

perhaps leading to the hyperbolic tale of the floating island of garbage.

In 2008, seeking to debunk the myth, Dr. Angelicque White of Oregon

State University set off on a voyage through the heart of the Great

Pacific Garbage Patch. White’s team towed nets behind their boat, just

as Moore had, but their data told a different story. Yes, tons of plastic

were floating in the Pacific, but the vast majority of these plastic bits

were tiny, with 90 percent of them spanning less than 10 millimeters

in diameter. The Great Pacific Garbage Patch, therefore, is less of an

island and more a whirlpool filled with plastic confetti.

Despite the small size of the plastic bits, they can still have hugely

negative impacts on the marine ecosystem. While larger plastics like sixpack

rings can strangle marine animals, smaller plastics harm animals

from the inside. The plastic waste is small and transparent, and it floats

in the water column — just like plankton, which is a vital food source

for fish and marine mammals alike. Animals cannot digest plastic, and if

enough of it accumulates in their stomachs, they can die. Plastic can also

contain toxins like DDT and PCBs. Once ingested, these chemicals do

not break down, but build up in an organism’s body fat. As these organisms

are consumed by larger and larger organisms, the levels of toxins

increase dramatically, until those at the top of the food chain, including

humans, are eating fish and fowl with dangerously high levels of toxins.

Although the myth of the Great Pacific Garbage Patch as a floating

plastic island has been busted, the remaining facts are grim. Three ocean

basins are rife with plastics, marine organisms consume plastic instead

of plankton, and toxins climb up the food chain to humans. Is there a

solution in sight? Scientists like Moore and White hope so. Researchers

are currently working to understand the full scope of the garbage patches.

Still, consumers should take note: It is only by drastically reducing plastic

waste that the ocean gyres can hope to be cleaned for good. By choosing

products wisely and recycling, consumers can take small steps to make

the Great Pacific Garbage Patch into the Pacific that it should be: calm

and quiet, where blue water meets blue skies.

32 Yale Scientific Magazine | November 2013 www.yalescientific.org

NEUROSCIENCE

FEATURE

Debunking Science: Near Death Experiences

BY CATHY REN

IMAGE COURTESY OF SELF OBSERVED

Those who claim to have had near-death experiences often

report seeing a tunnel of bright light.

“On April 10, 2010, I was rushed to the hospital … I flat-lined …

my heart would not restart … It was during this time that I experienced

one of the most incredible phenomena that can be experienced

in one’s lifetime.”

This account is just one of many stories posted on the Near Death

Experience Research Foundation website. About twenty percent of

patients who survive cardiac arrest report having a near-death experience

(NDE) — they often recall seeing a tunnel of light, having

out-of-body experiences, being in a state of euphoria, or experiencing

other dreamlike events. Some who claim to have NDEs attribute

them to religion or the supernatural, but could there be a scientific

explanation for experiences like Cherie’s?

A new study conducted by Dr. Jimo Borjigin, Associate Professor

of Neurology at the University of Michigan, presents a possible

answer. In a previous project, Borjigin had noticed a neurochemical

spike in rats’ brains in the moments before their deaths, and she

became interested in what occurred in the brain at that particular

moment.

NDEs have long baffled scientists, who assumed that brain function

ceased during cardiac arrest. Previous hypotheses about the causes

of NDEs included hormone and neurotransmitter release, abnormal

activation of certain lobes of the brain, lack of oxygen in the brain,

and side effects of drugs. However, prior to Borjigin’s study, which

was published in August, the neurophysiological state of the brain

immediately following cardiac arrest had never been formally studied.

Borjigin and her team implanted six electrodes each into nine rat

brains in order to record brain activity at the brink of death. The rats

were anesthetized, and cardiac arrest was induced with injections of

potassium chloride. In the critical thirty seconds between the last

heartbeat and the shutdown of all brain activity, the team used a

device called an electroencephalogram (EEG) to record the frequency

at which the rats’ brain cells fired electrical signals. Immediately after

the rats entered cardiac arrest, overall brain activity decreased, but

the EEG detected an increase in a particular type of high-frequency

signal known as the gamma wave. “We weren’t surprised that we

www.yalescientific.org

found brain activity but we were surprised by the high degree of it,”

said Borjigin in an interview with National Geographic.

EEGs generally measure waves of five different frequencies: alpha,

beta, gamma, delta, and theta. Each wave is associated with a different

state of consciousness. Strikingly, gamma waves are correlated with

extreme focus, whole brain activity, and sudden insight — qualities

which may have been present in the near-death rats.

Along with an increase in gamma wave activity, the researchers also

noticed information transfer between neurons in the front and back

of the brain. They interpreted this activity as a possible sign that the

rat brains were forming organized thoughts. Furthermore, the EEG

detected organized activity among other brain wave frequencies.

Though not as prominent as the gamma waves, these suggest that

the near-death brain activity included different levels of consciousness

and was even more complex than that of a normal brain. This

extraordinary electrical commotion during cardiac arrest may serve

to explain these accounts of NDEs.

Borjigin’s results are certainly interesting, but there are still limitations

and confounding variables in the experiment. For one, the

anesthesia performed on the rats may have affected brain activity.

Furthermore, physician Sam Parnia doubts that researchers can

directly make the jump from signs of consciousness in rat brains to

near-death-experiences in humans. “There is no animal model of a

near-death experience,” he said in an interview with Science.

Though the findings are preliminary, researchers hope that the

outcomes may lead to future studies on the human brain. Borjigin

suggests monitoring EEG activity in patients undergoing brain surgery,

a procedure which has led to NDEs in the past, to see if the

findings from studies in rats can be applied to humans.

Whether or not near-death experiences are actually caused by

heightened brain activity in humans is yet to be determined. However,

the results of the study open the doors to further investigations in

the field. Perhaps we will soon find the answer to a question that has

long been shrouded in mystery and enigmatic anecdotes.

IMAGE COURTESY OF TRANSCENDENTAL MEDITATION

Electroencephalograms (EEGs) record waves of different

frequencies, including alpha and gamma waves. Gamma wave

activity spiked in the tested rats’ brains after cardiac arrest.

November 2013 | Yale Scientific Magazine 33

FEATURE

UNDERGRADUATE PROFILE

Out of this world: Jan Kolmas TC ’14

BY ELEANOR SUN

For many of us, the phrase “mechanical engineering” evokes images

of complicated diagrams and dreadfully hard physics problems. For

Trumbull senior Jan Kolmas, however, engineering embodies not just

an academic subject but also a lifelong passion.

Hailing from the Czech Republic, Kolmas became interested in

engineering in middle school, where he displayed a natural aptitude

for quantitative sciences. “I always liked making things,” said Kolmas,

“and I always liked math and physics in high school. That sort of led

me to consider mechanical engineering because it’s a form of ‘very

applied physics.’”

To Kolmas, one of the most irresistible things about mechanical

engineering is its role in aerospace. During his freshman year, Kolmas

found a creative way to compensate for Yale’s lack of an aerospace

major by co-founding the Yale Undergraduate Aerospace Association

(YUAA). Through the YUAA, undergraduates interested in aerospace

can work on projects that they design themselves. “For two years, we

were building high altitude balloons, taking pictures from near space,”

recalled Kolmas. “Last year, we transitioned to building rockets and

UAVs [unmanned aerial vehicles]. This year we’re expanding on a

rocket experiment and doing more advanced rockets and propulsion

research.”

Although the YUAA was founded less than four years ago, Kolmas

and his teammates have already met with great success. In addition

to being one of the largest engineering student-run organizations at

Yale, the YUAA team also won the Astro-Egg Lander event in the

Battle of the Rockets Competition this year.

Outside of aerospace, Kolmas has explored other aspects of

mechanical engineering through research. During the summer after

his freshman year, he worked in the GRAB Lab at Yale, a group that

specializes in robotics. “Imagine someone who had an accident or

who is rehabilitating from an injury,” said Kolmas. “I was helping

build an exoskeleton, or a brace for the knee, that would help you

walk without placing stress on the knee.” This past summer, Kolmas’

research took him all the way to Delft University in the Netherlands,

where he studied mission reports from small satellites. By determining

which components of small satellites were most vulnerable to failure,

he worked to find troubleshooting and repair methods that would

minimize satellite failures in the future.

In addition to research, Kolmas developed his interest in aerospace

by participating in the 2013 Caltech Space Challenge, an event that

brings the world’s top engineering students together in a competition

to design the best space mission. “I think there was a poster on campus

that first caught my attention, and I thought, ‘Hey, this is something

I’d be really interested in,’” said Kolmas. After undergoing an intensive

application process, he was selected as one of the thirty-two competitors

and placed onto Team Voyager with fourteen others.

Under the guidance of Caltech professors and NASA professionals,

Kolmas and his teammates drafted a research proposal for NASA on

a human mission to a Martian moon. The proposal, completed in

just five days, encompassed research goals in astronomy and biology.

Some of these goals included determining the origin of the Martian

moons, testing food cultivation in a different gravitational setting,

and investigating the effects of radiation exposure and stress on

the human system. After presenting its plan to a grand jury, Team

IMAGE COURTESY OF JAN KOLMAS

The launch of the 2013 Astro-Egg Lander winner, the rocket

YSS Eli Whitney.

Voyager emerged victorious. “I met a lot of interesting people

from the field that I want to work in,” said Kolmas. “I made lots of

contacts at different schools, so I have more of an insight on what

I want to do.”

Besides being a brilliant engineer, Kolmas is also a sports enthusiast.

He swam all four years at Yale on the club team, serving as captain

for two years. Additionally, he spearheads Trumbull’s IM endeavors

as the volleyball and water polo captain. “I would say that water polo

is my favorite sport because it’s so unusual,” said Kolmas.

Currently finishing up his last year at Yale, Kolmas plans to obtain a

master’s degree in aerospace engineering after graduation but is open

to accepting a job offer if the circumstances are right. His dream job?

“Probably ground control for a space station,” said Kolmas.

IMAGE COURTESY OF JAN KOLMAS

Kolmas, an enthusiastic and accomplished athlete, has run a

Half Ironman Triathlon.

34 Yale Scientific Magazine | November 2013 www.yalescientific.org

ALUMNI PROFILE

FEATURE

At Home in the Wilderness: Yenyen Chan SY ’94, F&ES ’01

Yenyen Chan fell in love with Yosemite National Park

while exploring its wilderness and vistas during a high

school field trip. Now, after graduating from Yale College

and the Yale School of Forestry and Environmental

Studies, she has returned to the place where it all began:

As a United States Park Ranger in Yosemite, Chan works

to pass her knowledge and enthusiasm about the natural

world on to the next generation of park visitors.

Before coming to Yale, Chan was already interested

in environmental studies. Her courses in environmental

history and policy only solidified this focus. “Professor

John Wargo, who later became my advisor at the Forestry

School, really opened my eyes to the environmental policy

issues facing the country,” reflected Chan.

After a summer internship with the Natural Resources

Defense Council, Chan spent a few years at an

environmental consulting firm in Hong Kong. By working

in a region undergoing rapid development, she gained a

more global view of topics such as waste, water and air

pollution, and corporate environmental stewardship.

Looking back on her time at the Forestry School, Chan’s

recollections mirror the giddy faces of most students in

Kroon Hall today. “I loved it,” she said. “All of us in

this field want to do this work because it’s something

we love and because it’s critically important, both

socially and environmentally.” After gaining a Masters in

Environmental Policy and Resources Management, Chan

landed a position with the Yosemite Institute as a field

science instructor, and became a park ranger a year later.

Now, even after ten years of working in Yosemite,

Chan’s life as a park ranger is never dull. “There is no typical day,” she

said with a laugh. Her activities range from leading visitors on full-day

hikes to giving star and campfire programs at night, and she spends

much of her time teaching visitors about the rich history of Yosemite.

While Chan works much of the year in Yosemite Valley, she spends

the summer months in her favorite part of the park, Tuolumne

Meadows. Open to visitors from June to October, the meadows are

nestled in the Sierra Nevada mountain range at 8600 feet above sea

level, and characterized by breathtaking sub-alpine meadows and

peaks. To nature-enthusiasts like Chan, the beauty makes up for the

accommodations. “I live in a rustic tent cabin,” she explained. “Cold

running water, electricity, and a tarp roof over my head — it’s pretty

primitive.”

In addition to working in the field, Chan conducts educational

programs pertaining to subjects such as geology, history, resource

conservation, and climate change. For instance, in 2011 she created

a project that chronicles the history of Chinese laborers in Yosemite.

“There wasn’t much research about the topic,” Chan explained, when

she was asked to teach visitors about early Chinese contributions to

the park. Eventually, she co-produced a short park video on the topic.

Chan is also one of several park rangers participating in a multi-year

collaborative project between NASA, the Fish and Wildlife Service,

and the National Park Service on communicating climate change

science to park visitors.

BY ZOE KITCHEL

IMAGE COURTESY OF YENYEN CHAN

As a field science instructor and park ranger, Chan leads long, full-day

hikes and educates visitors on the history of Yosemite National Park.

Chan, a strong advocate of environmental consciousness, believes

that one of the parks’ most important roles is to educate visitors.

“The environment is important for our health and the health of the

planet,” she said. Her mission as a park ranger is two-fold; she strives

not only to share the beauty of the park with visitors, but also to make

them aware of the various threats that endanger its survival—invasive

species, habitat changes, diminishing snowpack, and wildfires, to name

a few. “To experience nature is both inspiring and humbling, and it

helps people take into account how important it is to have places like

this,” said Chan.

Although her work is primarily as a naturalist and educator, Chan’s

interests also lie in of environmental policy, especially the intersection

between public and environmental health. “Working with a national

environmental organization such as the Natural Resources Defense

Counsel or the Environmental Defense Fund still potentially lies in

my future,” she said. But for now, she is content to share one of the

country’s most beautiful places with visitors from across the world.

According to Chan, “It’s wonderful to see them experience it all.”

The temporary closure of National Parks this October due to the

government shutdown reminded the country how, as Chan explained,

“We depend on Congress to fund these places.” However, government

support is supplemented and shaped by public support. The recent

celebration of Yosemite’s 123rd birthday brings another statement of

Chan’s to mind: as she put it, “It’s a park for everyone.”

www.yalescientific.org

November 2013 | Yale Scientific Magazine 35

FEATURE

ECOLOGY

Urbanization Boosts Brain Size in Animals

BY STEPHANIE MAO

From day-to-day observations, the environmental impacts from

human activity are not so obvious. However, a collection of satellite

images from 1984 to 2012 speaks volumes: in the course of only three

decades, much of Earth’s verdant landscape has gradually given way to

gray cities, marking the long-term impact of urbanization. For better

or for worse, humans have distinctly altered their natural surroundings,

forcing other species to either adapt or go extinct.

It is not easy to develop new habits for a new environment. Many

animals have been compelled to adjust their behavior, gradually learning

to avoid, outsmart, or even befriend their new urban neighbors. Now, a

recent study conducted by University of Minnesota biologist Emilie C.

Snell-Rood and undergraduate Naomi Wick suggests that some animals

have adapted to the presence of humans by developing bigger brains.

In their study, Snell-Rood and Wick focused on local animal specimens

collected at the University of Minnesota Bell Museum. By measuring

the breadth, width, and height of various mammal skulls, they were

able to estimate the size of the species’ brains. Remarkably, in the

IMAGE COURTESY OF M. L. CAMPBELL

A white-footed mouse is one species in the study that displays

a difference in brain sizes between urban and rural populations

of animals.

white-footed mouse and the meadow vole, they found that specimens

from the city displayed a 6 percent increase in brain capacity over their

rural counterparts.

Snell-Rood provides two possible explanations for these findings. An

increase in nutritional quantity and quality, which urbanization provides

to some extent, may give animals the energy required to maintain larger

brains. However, the increase in skull size was not accompanied by an

increase in body size, making this theory less likely. A more probable

and interesting hypothesis is that adapting to human activity places a

larger demand on cognitive skills, such as foraging for food and interacting

with humans.

The growing impact of city environments on animal behavior, a

trend dubbed “synurbanization,” is well-documented. By destroying or

radically transforming natural habitats, cities create new, unfilled niches

and force local species to adapt. Studies of resulting animal behavior

report changes such as increased friendliness toward humans, new

nesting preferences, and longer waking hours. For some city-dwelling

animals, humans have also become a primary supplier of food. As human

metropolises continue to grow, the effects of synurbanization have been

conspicuous and profound. Snell-Rood’s study, however, is the first

that points to a possible link between behavioral change and brain size.

An additional finding in the new study suggests that the influence of

IMAGE COURTESY OF JENNIFER SIMONSON

Evolutionary biologist Emilie Snell-Rood examines shrew

specimens at the University of Minnesota Bell Museum.

human activity extends beyond cities as well. According to Snell-Rood’s

measurements, four rural species exhibited a boost in brain size, revealing

that they, too, may have been affected by changing environments. For

instance, an impact like deforestation may force bats in the countryside

to change their feeding and roosting habits.

Snell-Rood’s discovery is not the first time scientists have found evidence

of human activity driving animal evolution. In London, industrial

pollution gave dark peppered moths an advantage over the lighter ones,

enabling them to blend in with layers of soot. By contrast, the white

peppered moths, which once blended in with tree bark and lichens,

lost their evolutionary advantage and became less common. A second

example of human-driven evolution is a type of anole lizard, which

developed shorter legs to adapt to urban areas in the Bahamas. While

long legs are suitable for perching on wide surfaces, shorter legs better

equip the lizard to climb the narrow stalks that are typical of urban plants.

While Snell-Rood’s findings are significant, additional research needs

to be conducted on other specimens to determine whether the trend

continues in other regions. The age of the museum collections is also

an important factor, as the Minnesota researchers could only study

specimens from the past century — the brain sizes of animals that lived

before major industrialization remain unknown.

Still, the results are striking in their implications. The evolution of

bigger brains in animals sheds new light upon how deeply our actions

affect the surrounding ecology. We humans are not the only ones who

have adapted to our environment, developing tools and technology to

master nature. It turns out that the animals around us are adapting too

— and some in unexpected and surprising ways.

36 Yale Scientific Magazine | November 2013 www.yalescientific.org

TRIVIA

FEATURE

Black Holes Are Bright

The phrase “black hole” is both dramatic and memorable,

but it is not entirely accurate. Black holes are not the shadowy

voids portrayed in science fiction — in fact, they produce tremendous

amounts of radiation. This is because black holes act more like drains

than like magnets. Matter caught by their pull is not pulled directly

inward; instead, it circles around as if caught in a whirlpool. This swirling

process traps large amounts of stellar gas, spinning it around the

black hole at high speed. The result is an accretion disk: a rotating field

of imprisoned gas particles whose movement produces great friction

and strong magnetic fields. In turn, these forces produce X-rays which

we can detect on Earth with our instruments. These X-rays allow us

to see “black” holes, bright and clear.

Black Holes Are Loud

To our instruments, black holes are far from black, and

research suggests they are also far from silent. Black holes

exert an incredibly powerful gravity field, which pulls in stellar matter

at nearly the speed of light. Such fast-moving matter gains a tremendous

amount of energy, and this energy does not vanish past the event

horizon. Instead, as an object is pulled into a black hole, the energy

of its motion is

transformed

into sound. We

cannot hear

these sounds,

as space is

silent, but we

can “see” them

with our telescopes.

Sonic

waves emerging

from a black

hole produce

ripples in the accretion disk, and by analyzing these ripples, we can

determine their frequency. Incredibly, black holes produce the deepest

“notes” in the universe — 57 octaves beneath middle C.

Black Holes Are Messy Eaters

The pull of a black hole is commonly believed to be inescapable.

To some extent, this is true — once past the event

horizon, even light cannot emerge. But material circling the hole is not

always doomed. In fact, over 99 percent of it may escape. Why? Some

black holes, it seems, “spit out” their food. Our galaxy’s core contains a

massive black hole, one that behaves in unusual ways. Most large black

holes are constantly growing and emitting massive amounts of light. By

contrast, the Milky Way’s resident black hole is surprisingly dim. The

Five Things You Didn’t Know

IMAGE COURTESY OF NASA

X-ray image of a black hole’s sonic vibrations.

About Black Holes

By Ethan France

You’ve heard of black holes. They’re massive, they’re dense, and they can be inescapable

even at the speed of light. But did you know that they sing, glow, and spit

out their food? If not, read on!

cause is gas ejection — instead

of absorbing the stellar clouds

that circle it, the black hole is

launching most of them back

into space. Thus, while the hole

should be swelling and radiating

light, it has instead begun

to “starve.”

Black Holes

Are Cannibals

Because they need

“food” to survive, black holes are far from picky eaters. Their gravitational

fields attract anything with mass, and nothing is more massive

than other black holes. When two of these giants collide, neither is consumed.

Instead the two merge and become even larger. This kind of

fusion produces the greatest black holes of all, the behemoths we call

“supermassive.” These black holes are so large and their gravitational

fields so strong, that their accretion disks spin like particle accelerators.

Matter whirls around the event horizon at half the speed of light.

Black Holes Have Earthbound Relatives

Thankfully for us, black holes are restricted to deep space,

not on or near Earth. But the oceans produce surprisingly

similar phenomena known as eddies. Formed when currents bend back

on themselves, eddies are

“islands” of water swirling

in the middle of an

ocean. Small eddies, like

the “whirlpools” formed

by a canoe paddle, last

only a few seconds. The

largest can be hundreds

of kilometers wide and

may survive for years at

a time. Like black holes,

these gigantic eddies draw

in and collect anything

that approaches, trapping

it until they disintegrate

months later. Eddies also

create their own “accretion

disks” of water spray,

which floats above the current

but does not fall in.

IMAGE COURTESY OF STARDATE

A star feeds gas into a nearby

black hole’s accretion disk.

IMAGE COURTESY OF NASA

Satellite image of a massive eddy

near Japan.

www.yalescientific.org

November 2013 | Yale Scientific Magazine 37

FEATURE

BOOK REVIEWS

Brilliant Blunders:

From Darwin to Einstein — Colossal Mistakes by Great

Scientists That Changed Our Understanding of Life and the Universe

BY ZACHARY MILLER

We are apt to think that science proceeds as a steady, unceasing succession of “Eureka!” moments.

But as Mario Livio reveals in his wide-ranging and fast-moving book, Brilliant Blunders: From Darwin to

Einstein, even the most celebrated minds in history fumbled on a regular basis.

Livio’s book is adequately written, impressively researched, and surprisingly broad in scope — though

sometimes so broad as to seem haphazard. He begins by skimming through some of history’s most

interesting blunders and blunderers, from Aristotle and Marx to the Nazi High Command. This introduction

is followed by an in-depth exploration of the great mistakes committed by five scientists better

known for their groundbreaking intellectual successes. For instance, we learn about how Darwin’s theory

of inheritance came close to undermining his theory of evolution and about how Linus Pauling failed

to remember basic chemical principles in his model of DNA.

But far from just cataloguing scientific slip-ups, Brilliant Blunders is largely devoted to praising their

worth. Livio shows us that mistakes often fuel progress, just as Lord Kelvin’s erroneous estimates of

Earth’s age still succeeded in raising the bar for scientific rigor.

Along the way, Livio probes some deeper issues in the philosophy of science and establishes himself

as a skilled storyteller. The balance is decidedly in favor of the trivial over the profound, though, and

for this reason Livio’s book can end up feeling hollow. Still, it is an entertaining read and a unique and

more human perspective on some of the loftiest figures in science.

Rating: &&&&&

The Eternal Darkness

Packing for Mars

BY AVA MARIE HUNT

Rating: &&&&& BY MADELINE POPELKA Rating: &&&&&

From our earliest days to our more recent Star Trek TNG marathons,

the mysterious realm of outer space has held us earthlings in its thrall.

However, it is not necessary to board a spaceship in order to access an

unknown world. To this day, the depths of the earth’s oceans remain

just as enigmatic as any distant nebula. Robert Ballard captures this

alien landscape in his book The Eternal Darkness: A Personal History of

Deep-Sea Exploration.

Ballard’s work does not fit any conventional

definition of genre. It is at

once a memoir, a history, and a call to

action. In it he describes the history

of ocean exploration, beginning with

the invention of the earliest diving

craft. As he works his way through

more recent endeavors, Ballard also

includes his own adventures in the

field, such as his personal accounts

of mapping the Mid-Atlantic Ridge

and retrieving an inactivated nuclear

bomb off the coast of Spain, which

are richly imbued in narrative form.

Although much of his work reads

like an adventure story, Ballard does include sobering reflections on

the dangers inherent in ocean exploration. He challenges the reader

to weigh the benefits of scientific advancement against its potential

risks, calling for a paradigmatic shift in how we approach exploration.

Despite brief moments when the text borders on being overly technical,

the book is overall a fast-moving read. Ballard weaves his own

journey, from boyhood daydreaming to his famous discovery of the

Titanic wreckage, together with the stories of other intrepid pioneers,

creating an intimate picture of our quest to understand the oceans.

In Mary Roach’s Packing for Mars, the life of an astronaut is surprisingly

unglamorous. From embracing minuscule living spaces for

months on end to accepting the horrors of zero-gravity showers,

Roach illustrates the fascinating trials that intrepid space explorers

must learn to overcome. With entire chapters devoted to motion sickness

and astronaut hygiene, she describes the dark details involved in

each step of getting to space.

While the book has Mars in the

title, the bulk of Roach’s writing

actually summarizes trips to the

Moon and the International Space

Station, as well as isolated simulations

on Earth. Only briefly does she

cover the current efforts to transport

humans to Mars.

Nevertheless, Roach’s descriptions

of space travel are nauseatingly

effective. She drifts into lurid detail

when she describes the psychological

challenges of life on a space shuttle,

for instance citing the story of a

deprived astronaut who smuggled

casks of vodka into space.

Packing for Mars is not a how-to manual on traveling to our red

neighbor. Rather, it is an attempt to humanize a profession shrouded

in legend. For the most part, it succeeds. Roach occasionally stumbles

by fixating on scandal over substance; however, even the bizarre case

of the astronaut who drove across the country in diapers to accost her

lover does not detract too much from Roach’s message. The majority

of the book remains packed with humorous and enlightening insights

on life away from Earth.

38 Yale Scientific Magazine | November 2013 www.yalescientific.org

CARTOON

FEATURE

Frontier’s End

BY CELINA CHIODO

www.yalescientific.org

November 2013 | Yale Scientific Magazine 39

YSM Issue 86.4

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