YSM Issue 90.2


Yale Scientific

Established in 1894


MARCH 2017 VOL. 90 NO. 2 | $6.99


the invisible



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Yale Scientific Magazine



MARCH 2017







This recently discovered microprotein

has the ability to remove

excess genetic material in cells.

Researchers are only beginning to

explore its potential.

Using optogenetics, researchers

at Yale identified the region of the

brain critical for predatory hunting.

Using a laser, the researchers

could transform the docile mice

into voracious hunters.



Yale researchers are using fractals

to decode the signals planets leave

in their star’s light. The answer to

life, the universe, and everything?

Might well be hidden in the noise.





Until recently, very little has been

understood about fat cell growth

and maintenance. A new Yale study

shines light on the molecular mechanisms

behind these processes.




A special type of memory T cell could

be used as an immunotherapy tool to

efficiently eliminate tumors.

More articles available online at www.yalescientific.org

March 2017

Yale Scientific Magazine

q a



Honeybees are essential for American

agriculture, adding approximately

15 billion dollars worth of value to crops

each year via pollination. However, since

2006, bee colonies have been suffering

large losses in population. A combination

of factors, including pesticides, climate

change and diseases have been

thought to play a role. Now, a new study

conducted by researchers from Pennsylvania

State University and the US Department

of Agriculture has found that a

class of chemicals previously considered

inert may also share the blame. Called

organosilicone surfactants (OSSs), these

agrochemicals make pesticides more effective,

but they may also make bee larvae

more susceptible to viral pathogens.

“In California, OSSs are frequently

applied to blooming almond flowers

during the largest pollination event in

What’s killing our honeybees?


►Exposure to OSS results in blackened coloring

and kills honeybee pupae.

the United States. We knew that after

this event, honeybee larvae were dying,”

said Julia Fine, lead author of the

study. The researchers found that OSS

exposure reduced immunity and increased

levels of the lethal Black Queen

Cell Virus in larvae, indicating that

continued OSS use may be dangerous

for bee colonies nationwide.

Commenting on the research,

Graeme Berlyn, Yale professor of Forest

Management and Tree Physiology,

stated that while adjuvants may help to

grow more food, their continued use

puts valuable crop pollinators at risk. “In

the long term, we have to stop polluting

our soils and atmosphere,” Berlyn said.

Further research on OSS safety and

analysis of residue levels in bee environments

could be key in reversing

colony collapse.


Humans, pilot whales, and killer whales

are the only three species known to go

through menopause. It has long been a

mystery why menopause is evolutionarily

adaptive, but a recent study from Exeter

University suggests that menopause

may have evolved in killer whales because

of the reproductive competition between

mothers and daughters.

Killer whales live in family pods consisting

of a matriarch and several generations

of her offspring. As a result, older

females can ensure that their genes are

passed on by helping to raise their daughters’

calves, as well as by having their own.

But why do older females stop reproducing

altogether? According to the study,

when a mother and daughter each have

a calf around the same time, the older female’s

calf is 1.7 times less likely to survive

than the younger female’s calf. A matri-

Why do killer whales go through menopause?


►A young resident killer whale traveling with

group mates.

arch may be more successful at passing

on her genes if she helps her daughters

instead of competing with them.

Killer whales and humans have similar

family structures, so reproductive competition

may explain why they undergo

menopause. However, Stephen Stearns of

Yale’s Ecology and Evolutionary Biology

department cautions against jumping to

conclusions. “There are probably other

species in which degree of relationship

increases with age but menopause has

not evolved,” Stearns said. He notes that

scientists have not refuted other possible

explanations for the phenomenon.

The Exeter team hopes to learn more

about patterns of whale behavior using

drones. “How do individuals compete

with each other and help each other survive?”

asked Darren Croft, the paper’s

lead author.

Science and innovation surround every part of our lives.

From the production of the food you eat (pg. 7) to the creation of better phone

batteries (pg. 35), innovative design allows us to live better lives. We reap the

benefits from new advances in heathcare, whether that’s through a lung grown

in culture (pg. 8) or a smartwatch that monitors our health (pg. 26). But for all

that we pursue, there is so much that we still do not understand.

Journalism is perhaps best defined as the pursuit of truth above all else. That

is no different for scientific journalism, where we seek not only to discover new

truths about our universe, but also to make it accessible for everyone to understand.

We believe that there is beauty in a scientific story, whether that be how

the search for exoplanets has now come to depend on fractal structures (pg.

18) or how the complex relations between the brain and optogenetics give rise

to aggressive behaviors (pg. 12). In these endeavors to discover fundamental

truths about the universe, we come to find a better understanding of ourselves.

But only through thoughtful communication can we reach that kind of understanding;

a beautiful truth shrouded in confusion is no better than nothing at

all. Science is dependent on communication, and communication is dependent

on science.

Our cover article this issue focuses on the discovery of an entirely new class

of proteins called microproteins, tiny pieces of the human body that may allow

us to better understand human disease (pg. 15). These kinds of major breakthroughs

occur because they stand on the shoulders of giants, of the work that

thousands and thousands of scientists have dedicated their lives to. Every article,

whether on the evolution of fruit fly tolerance to alcohol (pg. 32), the use

of sea sponges to guide engineering design (pg. 28), or the discovery of more

complex chemical knots (pg. 30) are all firmly based on the same dedication to

the truth. We can’t afford to have anything fake in these pages, simply because

there is too much innovation at stake.

As our new 2017 masthead takes the reigns of the Yale Scientific, we are eager

to continue exploring the breakthroughs and discoveries with each of you.

Your dedication to seeing honest reporting of the facts energizes and inspires us,

leading our publication to continue a tradition of excellence. For all the science

and innovation that surrounds us, it’s time for us to understand these breathtaking

discoveries even better.

Yale Scientific

Established in 1894


MARCH 2017 VOL. 90 NO. 2 | $6.99


the invisible




Truth in Science


Chunyang Ding


The cover, designed by Arts Editor Catherine Yang, depicts

the DNA double helix. The image of the DNA double

helix became an icon the 1950’s and has since become

a centerpiece of scientific media. In this cover illustration,

the classic structure is front-and-center, bold in

magenta and cyan. Trailing down to the end of the double

strand, the DNA unravels completely, and other components,

the ribosomal RNA and tRNA, are pictured

beside the strands. The standout components of the illustration

are well-distributed in public media—but what

about the other players in genetics? The answer lies in

the cover story itself, which details the recent discovery

and analysis of “invisible” microproteins like NoBody.


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MARCH 2017 VOL. 90 NO. 2

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Mary Chukwu

Harold Dorsey

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Dhruva Gupta

Jessica Hong

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Noah Kravitz

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Grace Niewijk

Advisory Board

Kurt Zilm, Chair

Priyamvada Natarajan

Fred Volkmar

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Jakub Szefer

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William Summers

Scott Strobel

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Chunyang Ding

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in brief

Unlikely Friendships: Gut Bacteria Edition

By Matthew Hur


►Professor Serap Aksoy steps out of

the insect facility in her lab, in which

she studies the microbiomes of tsetse


Sometimes organisms can form unlikely

teams—imagine the Egyptian plover bird

cleaning the teeth of the Nile crocodile. Researchers

from the Aksoy Lab in the Yale

School of Public Health’s Epidemiology of

Microbial Diseases Department investigate

how gut bacteria “collaborate” with

their host insects. Recently, they published

a study linking gut bacteria in the tsetse fly

to the immune system’s first line of defense.

These researchers study insect microbiomes,

a collection of microorganisms in

the body, as a model for our own. Human

gut microbiota contain hundreds of bacterial

species that actively regulate bodily

functions. The insect microbiome operates

at a smaller scale, and researchers can utilize

the natural specificity of only a couple

bacterial species to investigate a small yet

mechanistically complex world.

The tsetse fly gut houses only two symbiont

bacteria species, Wigglesworthia and

Sodalis. Wigglesworthia stimulates the fly’s

cellular machinery to produce a molecule,

odorant binding protein six, associated

with the immune system’s first line of defense.

Notably, when researchers nurtured

the flies without Wigglesworthia, wounds

to the cuticles, or outer layers of the body,

failed to clot.

The symbiotic relationships between bacteria

and host organisms are intricate and

longstanding. Wigglesworthia has lived in

tsetse flies for approximately 50 to 80 million

years. In our own bodies, bacteria outnumber

our own cells by a factor of ten.

These incredible relationships have spurred

projects such as the Human Microbiome

Project, which will investigate the different

bacterial communities in the human gut.

The study from the Aksoy Lab represents

the start to finding the molecular mechanisms

by which symbiotic microbes affect

our health.

Skeletons in the Ice Age Closet

By Allison Cheung


►Insight into current mass extinction

may be hiding in the skeletons of our

Ice Age forbearers.

When predicting the future, there is no

better place to look than the past. Yale

researcher Matt Davis, a postdoctoral

fellow from the Department of Geology

and Geophysics, did just that in his recent

study on Ice Age mammal extinctions in

North America and their implications on

today’s extinction risks. In an incredible

study combining data and methods from

paleontology and ecology, Davis found that

our ecosystem stands at a critical point.

Functional diversity describes the

role and impact an animal plays in an

ecosystem. Davis examined the roles of Ice

Age mammals like the Shasta ground sloth

and deduced that the extinction of some of

these mammals did not impact functional

diversity as much as previously thought

due to the later introduction of European

domestic animals. The missing gaps in

diversity created by the extinctions were

filled by animals with similar diets and

body masses. In addition, species did not

go extinct just because they had the same

functions as other species.

However, today’s ecosystem would not

be as lucky. Fewer species have redundant

functionality, so it would be harder to

restore roles lost in potential extinctions.

For instance, no animal could replace

the environmental role played by the

endangered polar bear in the Artic. Now,

the stakes are higher because if we lost a

mammal, we would also lose its role in the

ecosystem, causing significant ecological


Davis’ research has won him the prestigious

Deevey Award from the Ecological Society

of America, and he is collaborating with

ecologists around the world to establish a

better understanding of today’s functional

diversity losses. “We won’t know what we’ve

lost unless we know what we had before,”

Davis said. “By understanding our past

through paleontology, we’ll have a much

better chance of preserving our future.”

6 Yale Scientific Magazine March 2017 www.yalescientific.org

in brief


What Woodpeckers Can Teach Us

By Meital Gewirtz

A truly customizable education may soon

become a reality. Amin Karbasi, assistant

professor of Electrical Engineering and

Computer Science, recently received the

prestigious Young Faculty Award from the

Defense Advanced Research Projects Agency

(DARPA), a branch of the Department of

Defense. The award recognizes his project,

“Efficient Learning of Human Intent from

Observations,” where Karbasi developed a

computer program that teaches individuals

to differentiate between three different

kinds of woodpeckers.

This new program is unique in its teaching

style—while most online training programs

teach to one specific level, Karbasi’s

program is personalized to the student.

His program automatically monitors the

student’s progress and then adjusts its

teaching approach to fit the student’s needs,

capabilities, and learning style, enabling each

student to be taught in the most efficient

way possible. Using previous responses, the

machine tries to understand why the student

is making mistakes and adjusts its approach

accordingly. It customizes new examples and

then monitors the student’s progress.

Professor Karbasi would like to extend his

research project beyond teaching users to

distinguish between types of woodpeckers.

He explains that the importance of the

program lies in its crafting of humanmachine

interactions. DARPA intends

to use this method to train people to

understand human behavioral cues. This

requires the machine learning system to

learn about human behavior and understand

different cues for use in teaching. Using

Karbasi’s promising research, DARPA aims

to develop programs to more efficiently

train people with different learning styles.

Hopefully, the same technology can make

it into educational software for all students,

regardless of subject.


►Karbasi’s computer program,

originally designed to teach individuals

about woodpeckers, can be used

to teach individuals a wide-range of


Mega-Cities, Mega-Problems

By Allie Forman

Growing cities may precede an uncertain

and sobering future for the planet. A new

international study coauthored by Yale

School of Forestry and Environmental

Studies professor Karen Seto suggests that

urban expansion will result in the loss of

vast areas of cropland by 2030.

The findings, published in Proceedings of

the National Academy of Sciences, estimate

that approximately two percent of global

cropland will be lost. Much of this land is

highly productive, producing yields far

above the global average. Moreover, a large

proportion of the cropland at risk belongs

to some of the poorest, most vulnerable

regions in the world, particularly developing

countries in Asia and Africa. Climate change

will pose an additional challenge to tropical

regions, as rising temperatures and sea levels

alter landscapes and crop viability.

These researchers found that large

portions of cropland is currently located

near urban areas. They then used urban

expansion projections to analyze possible

cropland loss.

Seto was surprised and alarmed to find

that the regions predicted to lose the largest

percentage of cropland tend to have weaker

government institutions, higher corruption,

and less rule of law. This instability, combined

with crop shortages and high unemployment

should farmers and pastoralists lose their

lands and livelihoods, would potentially spur

food riots and social upheaval.

To avoid such conflict in the future,

Seto believes that governments must

think beyond city boundaries and make

regionally beneficial decisions. “Sustainable

urbanization and development has to take

into consideration all of these places that

are not urban. We have to think about

preserving and being stewards of the larger

ecosystems,” Seto said. Seto hopes the study

highlights the role that decision-making in

cities ultimately plays in sustaining other

types of ecosystems.


►Researchers working with Professor

Karen Seto investigated the potential

loss of cropland under urban



March 2017

Yale Scientific Magazine



biomedical engineering


New bioreactor system allows crucial oxygen exchange


Science fiction movies always show brains, hearts, lungs,

limbs, and eyeballs in jars lining the shelves of mad scientists’

labs. These organs are all dead and preserved. But what

if they didn’t have to be dead? Imagine growing live organs

in a glass jar. Turns out, this isn’t a far-fetched idea at all. A

group of researchers at Yale, led by Dr. Laura Niklason, are

exploring ways to improve bioreactors that can keep organs

alive in culture.

Bioreactors allow for the growth and study of cellular systems,

tissues, and organs in an environment outside of the

living organism from which they were derived. Currently,

scientists are capable of controlling the environment of cellular

bioreactors with regard to temperature, fluids, pH, nutrients,

and gas exchange. However, in full-organ bioreactors,

the major difficulty is maintaining efficient gas and nutrient


Specifically, Niklason’s research focuses on the levels of dissolved

oxygen in whole-lung bioreactors. Past studies have

shown that if the cells have too much or too little oxygen,

they become damaged or die. Therefore, Niklason aimed to

create a whole-lung bioreactor that can successfully monitor

and adjust levels of dissolved oxygen, enabling the successful

growth of a whole lung.

Niklason described her newly-designed bioreactor as an

artificial organism, supporting the growth of the organ inside.

“My lab really does ‘applied biology.’ We take what is

known and what we can learn about how tissues and organs

develop and about their composition, and then we use that

knowledge to try to recapitulate those factors in the laboratory.

In this way, we attempt to turn the laboratory bioreactor

into an artificial organism, which can grow and nurture a

functional tissue,” Niklason said.

The path towards developing this dissolved oxygen maintenance

and delivery system had four main steps. First, the

researchers physically constructed the gas exchange system.

Then, they mathematically analyzed the gas transfer within

the system by measuring the relationship between the system

inputs and the resulting oxygen gas outputs. Next, they

mathematically compared the rate of oxygen delivery by the

system to the rate of oxygen consumption in native rat lungs.

Finally, they confirmed their mathematical models by testing

rat lungs in the bioreactor under various system parameters.

The results of their research showed that the mathematical

model derived indeed reflected the real-life interaction of the

rat lungs in the bioreactor system. Additionally, the study of

the bioreactor system revealed insights on the nature of oxygen

absorption in the rat lungs. When there was enough dissolved

oxygen, the rat lungs were observed to intake oxygen

at a constant rate proportional to the percent of cells capable

of aerobic metabolism. Conversely, when the dissolved oxygen

was below a given threshold value, the lungs slowed the

oxygen consumption rate. This relationship gives direct insight

into the cellular behavior of lungs in the bioreactor under

different oxygen conditions.

The research team faced many challenges while developing

this system. For instance, lung engineering often involves the

use of stem cells. “For our work with stem cell differentiation,

identifying the key factors that drive specific fates from

primitive stem cells, for both vascular and lung engineering,

was one of our key challenges,” Niklason said. Despite these

challenges, the research culminated in a system that measures

dissolved oxygen levels in real time, and consequently

enables the constant estimation of oxygen consumption rates

and cell number in engineered tissue.

The development of bioreactors has many future medical

implications. Whole-lung bioreactors enable more cost-efficient

studies on lung stem cells and regeneration. Additionally,

lung bioreactors may contribute to the successful bioengineering

of new lungs and preservation and recovery of

damaged lungs for transplants.

Specifically, the bioreactor system constructed by Niklason’s

lab allows improved maintenance of lungs outside of

the body, therefore widening the field of opportunity surrounding

organ transplants. This system brings a positive

outlook to the future of organ engineering, specifically vascular

engineering, which involves the growth and study of

blood vessels. “For vascular engineering, we hope that the

technologies my group has developed may one day provide

engineered arteries for patients with vascular disease who

need arterial grafts or replacements,” Niklason reflected. The

future of organ and tissue engineering may lie in constantly

improving bioreactor systems, such as with Niklason’s pioneering



►Immunofluorescence was performed with PCNA (Proliferating

Cell Nuclear Antigen) and TUNEL (Terminal deoxynucleotidyl

transferase dUTP Nick End Labeling) for analysis of cell

proliferation and death, respectively.

8 Yale Scientific Magazine March 2017 www.yalescientific.org




Healing patients with a stroke of genius



►A study conducted at Yale University found that the TGF-β1

signaling pathway helps the brain recover following a stroke.

Intracerebral hemorrhage (ICH), a form of stroke, is characterized

by rupturing blood vessels in the brain. Along with a mortality

rate of 40-50 percent, there is no current treatment. Following

the break in blood vessel, the battle is only half over. The immune

system is activated, and macrophages, a form of white blood cells,

rush to the job. Microglia, the resident macrophage, act as the

main defenders and gobble up unwanted particles in the brain.

However, once activated, the microglia can respond in two possible

ways. The classical response is the release of pro-inflammatory

molecules within the brain. The alternative response is the release

of anti-inflammatory signaling factors associated with functional

repair mechanisms in brain tissue. How such strikingly different

responses could be activated in the human brain following ICH

remains unknown.

Lauren Sansing, associate professor in neurology at Yale University,

along with Roslyn Taylor, lead author and researcher in

the Sansing lab, sought to examine the microglial response following

ICH, and to determine the cause behind the activation of

the alternative recovery responses. By studying changes in gene

expression, Sansing and her team could pinpoint the mechanism

behind these responses. To do this, the researchers analyzed the

changes in activation of 780 genes in microglia. They noticed the

most rapid changes in 78 of these genes occurred between days

three and seven following ICH. This time period, called the acute

phase, is marked by edema, the swelling of the brain due to fluid.

With hemorrhage causing damage to the brain, its microglia repair

mechanisms are crucial. The researchers found that by day

seven, microglia activate genes that aid in recovery, releasing anti-inflammatory

molecules instead of pro-inflammatory ones. “It

would make sense that microglia would turn off the inflammatory

process pretty quickly,” Sansing said.

Once the researchers observed these changes in microglia phenotype,

the question became determining what was mediating

the alternative, reparative mechanism. Searching for possible

pathways, researchers found a signaling protein most responsible:

the TGF-β1 pathway. Earlier findings have shown the importance

of this signaling pathway in the development of microglia. “It

wasn’t surprising that TGF-β1 became important in this recovery

phase, but it had never really been identified before,” Sansing said.

Now, they wanted to test whether introducing TGF-β1 protein

would increase the repair functions of microglia. Taylor and her

team studied the inflammatory responses in microglia in cell culture

by treating them with thrombin, a protein-cutting enzyme

which stimulates microglia to react similar to the response following

ICH. They then treated the cells with TGF-β1 protein and

observed the response of microglia. Their results were promising—they

found that inflammation was reduced.

Following their findings of the role of the TGF-β1 pathway

in reducing the inflammation of the classic microglial response,

the researchers treated mice with TGF-β1 protein directly

into the brain and observed the response. They found

that TGF-β1-treatment given within four hours after the occurrence

of ICH resulted in recovered motor function within

a day. Researchers were then interested in how these results

were relevant in human patients.

Applying these findings to human patients, the researchers

found the earlier the TGF-β1 pathway was induced, the higher

the chance of recovery. The researchers measured patients with

the modified Rankin scale, which categorizes severity of stroke

on a seven-point scale. Those with an earlier increased activation

level of the TGF-β1 protein pathway, six to 72 hours after ICH,

had less severe outcomes—and thereby a lower modified Ranking

score—than those with later activation.

By studying the changes in response of microglia, Taylor and

her team have provided promising outlook on the mechanism

behind repair following brain hemorrhage. “I think that our findings

will help provide further insights as to what TGF-β1 may

be doing specifically in microglia in neuroinflammatory diseases,”

Taylor said. While the researchers are still unsure what causes

earlier activation of the TGF-β1 pathway in some patients, the

results support the role of this pathway in repairing brain damage.

Until then, Taylor and her team hope other researchers will

continue brainstorming ways in which the TGF-β1 pathway may

be involved in therapeutic treatment for stroke victims. “The big

question remains whether we can we actually intervene on this

pathway by giving patients TGF-β1 protein,” Sansing said.


March 2017

Yale Scientific Magazine



applied physics


The music of the spheres, resonating into infinity


The next time you pick up a wine glass or glass bottle,

try timing how long you can keep it ringing from a single

tap. A group of Yale researchers have recently discovered

that this “lifetime” of sound in glass can be extended

by building on top of pre-existing sound waves. Glass has

become the center of study for many modern scientists

due to some of its strange interactions with sound waves.

By investigating the interesting characteristics of sound

waves traveling in glass, the researchers were able to improve

our understanding of “acoustic atoms,” a mysterious

phenomenon of sound. They developed a model to explain

the life extension of sound waves in glass, demonstrating

an important intersection between theoretical and applied

research in the area of quantum physics.

Acoustic atoms, also termed “absorbers” by the Yale researchers,

are not completely understood in the field of

quantum physics. Generally speaking, they are similar

to atoms—they can absorb particles of light, or photons,

which cause their inner electron particles to vibrate and

absorb that light energy. Acoustic atoms are involved in

the lattice structure of a material such as glass. “Inside of

glass, absorbers behave like atoms,” says Ryan Behunin,

one of the lead researchers in this discovery. “Saturation

is the term that describes this phenomenon of waves in

glass tubes,” he said. Absorbers have limited conformations

and respond to energy in quantized amounts. This

leads to the formation of sound waves if the energy is

large enough to vibrate the absorbers between the conformations

very quickly.

Some older publications on the physical properties of

glass materials describe a wave-like potential for sound

release. Ryan described the shape of these potentials as

“bowl-like,” or containing stable local minima that rise

on either side. A trio of rolling hills most accurately illustrates

this phenomenon. A hill in the middle separates the

first low point from the second stable low point, creating

a two-point potential system, or “two-level system”. The

acoustic atoms can settle in either low point, but can move

around if they overcome the high energy of the hill.

If the acoustic atom finds itself in the middle of these two

points, at the top of the hill, it may fall into one of the low

stable points and release energy as a result. This released energy

can be observed as sound.

Behunin and fellow researchers discovered that by inducing

other sound waves first, like playing music in the

background as the wine glass is tapped, the waves from

these acoustic atoms continue to live for a longer period

of time, and louder background musics increase the period

of time that the glass resonates.

One application of this Yale study is the improvement

of optomechanical sensors from a better understanding

of quantum physical properties. This could aid in developing

remote sensors and physical link layers of information

technology, such as Ethernet cords used by computer

systems. The researchers also expanded the current base of

knowledge on the quantum mechanics of sound. Although

their discoveries elucidated the physics of producing sound

in glass, the concept of acoustic atoms remains largely a

mystery, and further research is needed to understand its

strange properties.

The purpose of this study was not just to observe a phenomenon,

but also to determine a model to explain this

phenomenon. Their model shows the importance of theoretical

research. “From this, we can see the applications

toward the performance of whole classes of systems,” Behunin

said. The idea behind their research was twofold:

focusing firstly on finding results and applying them

elsewhere in optomechanics, and secondly on strictly

discovering a theoretical principle. With this mindset,

the Yale team developed a model and demonstrated the

impact of their research on others in the quantum and

optomechanical fields.


►Finger movement along the edge of the wine glass generates

vibrational movement, producing audible sound waves.


Yale Scientific Magazine March 2017 www.yalescientific.org

molecular biology



Stress hormone’s potential role in captured birds’ behavior



►Professor Richard Carson and post-doctoral fellow Christine

Lattin use Positron Emission Tomography (PET) to analyze

stress hormones.

Beyond the dramatized experiences shown in movies like Finding

Nemo and Madagascar, most people have only vague notions

of what goes through the mind of a captured animal. Yet while captivity

is certainly not ideal, animal capture is critical to conservation

efforts focused on population growth or animal rehabilitation.

Moreover, research using captured animals often has implications

for humans. Captured and freely living wild animals exhibit many

differences in behavior and physiology, but up until recently there

has been little research on the root causes of these differences. Using

captured wild sparrows, researchers led by professor Richard Carson,

Director of the Yale Positron Emission Tomography (PET) Research

Center, have shed light on a stress hormone that may play a

key role in some of the negative behavioral responses that occur in

captivity. Their research suggests that the caged bird—or any caged

animal—truly becomes a different sort of beast through the experience

of captivity.

It has long been recognized that captured and wild animals exhibit

marked differences in body composition as well as in patterns

of behavior such as breeding, eating, and aggression. The standing

hypothesis has been that chronic stress and increased stress hormone

triggered by a new environment induce these changes in

captured animals. The most commonly implicated hormone is corticosterone,

the primary long-term stress hormone in birds, though

no study has previously tested this link. Corticosterone itself exists

in two forms: a baseline form that is necessary for normal bodily

function and a stress-induced form that arises from stressors such

as predators or human contact.

Left unchecked, stress and its associated hormonal changes can

have dramatic impacts on the physiology and behavior of animals.

“There’s some evidence that wild animals may never fully habituate

to the stress of a captive environment, and in some cases they may

actually shift into a new state,” says Christine Lattin, first author of

the study and post-doctoral fellow at the Yale PET Center. The animals

may never return to their original physiological state, even

after a long period of time in captivity.

In testing the relationship between stress activation and physical

changes, the Yale researchers manipulated corticosterone levels in

captured wild house sparrows. One group of birds was treated with

injections of the drug mitotane,s which inhibits the production of

stress-induced corticosterone. The other group received injections

of a placebo drug. Using CT imaging, various tissues were visualized

at initial capture and at the end of two weeks. Corticosterone

levels within the blood were also measured in response to stress.

Bird behavior was analyzed using video recordings.

At the end of two weeks, both groups had experienced significant

changes in organ size, and while mitotane did not mitigate

physiological changes, it did reduce stress-related behavior and

corticosterone release in response to stress. Birds are known for

undergoing rapid tissue remodeling in response to changing environments.

The sparrows showed decreased heart volume, increased

fat storage, and decreased density, but not thickness, of

their major flight muscle, indicating that the muscle was being replaced

by fat.

The most compelling reason for the observed tissue remodeling

comes from the behavior of the captured birds. During their two

weeks in captivity, the control sparrows increased their frequency of

beak-wiping, a well-known stress behavior in birds, as well as other

stress behaviors. The story was different for mitotane-treated birds,

which engaged in much less beak-wiping, and which showed reduced

plasma corticosterone in response to stressors such as human


These findings are important because they reveal a potentially

confounding influence of stress in behavioral studies using captured

animals. They also hint at evolutionary reshaping that occurs

in breeding captured animals for either domestication or research.

“Anytime you breed animals in a captive environment you are

actually altering the stress response [of the population as a whole]

because only the more stress-tolerant individuals will breed,” said

Lattin. This individual variation in resiliency during stress is a principle

that holds true for both animals and humans.

Lattin notes that the study can serve as a “paradigm” for chronic

stress that has been previously unexplored in biomedical research.

The next frontier for the lab is dopamine, which has also been

shown to play a role in the stress response in addition to its function

in reward signaling.

Future studies using PET to quantify and analyze dopamine receptors

and dopamine-corticosterone interactions will continue to

increase our understanding of the life of the caged bird.


March 2017

Yale Scientific Magazine




is on

by William Burns

art by Sida Tang



What goes on in a cheetah’s brain when it hunts a gazelle? When a python

strikes at a rabbit? When a bear snatches a fish from a river? When an orca

attacks a seal? Innumerable predatory-prey relationships exist across the

animal kingdom, yet little is known about how the brain controls predation.

Which parts of the brain are involved? How does the brain coordinate the many

muscles involved in hunting related tasks like pursuit and biting?

12 Yale Scientific Magazine March 2017 www.yalescientific.org



Researchers at the

Yale School of Medicine,

led by Ivan de

Araujo, associate professor

of Psychiatry, are looking

for answers. The team of

scientists identified a sub-region

of the amygdala, an olive-shaped

region of the brain, as the epicenter

for predatory hunting. The amygdala

has long been recognized as a contributor

to emotions like fear and aggression,

but these researchers dug deeper to understand

the molecular pathways which

drive predatory instincts. Shining flashes

of laser light into the mice’s brains, the researchers

could turn on or off the neurons

that fire when mice hunt. Accordingly,

the researchers could transform the mice

at will from passive creatures to gluttonous

predators. Through their findings, the

team of scientists uncovered clues relating

to the evolution of the brain.

Firing the Neurons

Previous studies showed that when rats

hunt insects, the central amygdala (CeA),

an almond-shaped sub-region of the amygdala,

surges in activity. This led the researchers

at Yale to question how the CeA of

predators’ brains coordinate the plethora of

muscles involved with hunting. “Predatory

behavior is a particularly complex task because

an animal needs a number of different

muscles to run, jump on things, and use its

head to kill,” De Araujo said.

First, the researchers injected the

central amygdala of the mice with a virus

that contained a gene encoding a

light-sensitive ion channel. Ion channels

allow positively charged sodium ions to

flow into the negatively charged axon of

the neuron. The change in charge distribution

along the length of the axon,

called depolarization, causes the neuron

to fire. Thus, the virus made neurons in

the CeA of the mice more prone to firing.

The signal traveled through the body until

it reached certain target muscles, such

as the jaw and neck muscles.

To control when the neurons fired, the

researchers inserted an optrode, an optic

fiber cable connected to an electrode.

Through this cable, the researchers could

send a specific wavelength of laser light

into the mice’s brains to turn on the neurons

involved when a mouse hunts. This

technique, called optogenetics, allowed

the researchers to use the energy from

the laser to manually stimulate the parts

of brains in mice which control hunting

and biting.

“Optogenetics has two great advantages.

First, you can target and study a specific

group of neurons. Second, the control

over when the neurons fire is specific. The

technique is very transient and very fast,”

said Wenfei Han, first author of the paper.

Optogenetic activation triggered only the

neurons injected with the virus to fire more

intensely according to electromyogram

(EMG) recordings, which measure electrical

activity in muscles.

Initiating the Hunt

When the CeA was stimulated using optogenetics,

the normally indifferent, docile mice

transformed into bestial predators. For example,

when a cricket was placed in the cage, the

mice captured and killed their prey in a much

shorter time than they did when the CeA was

not stimulated. The mice attacked even inanimate

objects; when a bottle cap was placed in

front of them, the mice grasped and bit the cap

as if it were prey. Such attacks were not observed

when the laser was off.

Upon laser stimulation, the mice attacked

the closest object they could find. When a food

pellet was placed in the opposite corner of the

cage and the laser was turned on, some mice

started to eat the cotton bed on which they were

resting before stimulation. In some cases, the

mice would grab onto the laser cable itself and

chew straight through it. Unsurprisingly, when

the cable split, the mice ceased hunting and returned

to their previous docility. Even when no

food was placed in the cage, the CeA-stimulated

mice positioned themselves in an eccentric

feeding position, tensing their hind legs and

holding their front legs to their mouths

as if they were eating. The researchers

called this phenomenon “fictive

feeding,” as it reflected the feeding




position predators make when

feasting on their prey.

These results showed that predatory

behavior is an opportunistic behavior,

meaning that animals hunt because

they see the prey, not because they have a

physiological need for food. Hunting opportunistically

has an evolutionary advantage

because if an animal waits until it is hungry,

it may be too weak and likely die from exhaustion.

“Opportunistic hunting may have

remained in other species, including humans,

because we also eat opportunistically. Our tendency

to acquire calories even in the absence

of hunger simply because we see food or see

others eating reflects our fundamental hunting

instincts,” De Araujo said.

The researchers also tested how mice interacted

with each other upon laser stimulation.

“When the mice were together, they became

more curious, but we didn’t observe any attacks,”

Han said. Interestingly, when a male and

a female were placed in the same cage, the male

started to groom the female. “Oral movements

were triggered but not biting.” Han added. The

researchers realized the amygdala was involved

in many more complex behaviors than aggression

and fear.

Digging Deeper

The researchers identified two distinct neural

pathways critical for hunting, both of which

originate in the CeA: one for pursuing prey, the

other for biting. The neurons related to biting

prey were located in the parvocellular reticular

formation (PCRt), a region of the brain located

just downstream from the CeA. When the

CeA to PCRt pathway was stimulated, the mice

stopped moving, sat down, and situated themselves

in “fictive-feeding” positions. When the

researchers disrupted the pathway with a pathway-specific

lesion, the mice had a much harder

time capturing their prey. The researchers

reasoned that the neurons in the CeA interact

with nearby neurons in the PCRt, enabling biting

activity by disinhibiting the circuitry in the

PCRt. Thus, they concluded that the PCRt was

dependent on the CeA and critical for delivering

bites to prey, but separate from the pathway

involved in pursuing prey.

For that task of pursuing prey, the researchers

identified another region: the periaqueductal

gray matter (PAG). PAG, located in the midbrain,

is typically associated with processing of

pain. Activation of the pathway connecting the

CeA and PAG decreased the speed at which

the mice pursued their prey, decreased the

time it took for the mice to initiate the chase,

and decreased total hunting time. Lesions to

this pathway caused a ten-fold increase in the

delays to initiate pursuit. This delay was not

observed when the CeA to PRCt pathway was

disrupted. Further, activation of this pathway

did not show fictive-feeding as did the CeA to

PCRt pathway.

From their analysis of these pathways, the

researchers concluded that the CeA acts as a

control center, coordinating various, independent

pathways in the brain related to effective

and efficient hunting. “One way the brain may

coordinate the different parts of the body involved

in hunting is by positioning these two

subpopulations of neurons close enough to

each other that they can communicate and

understand what the other is doing, yet project

these two groups into different promotor

areas of the brain so that messages to the legs

do not get mixed up with messages to the jaw,”

De Araujo said. Scientists have long sought

this model for how the CeA functions and integrates

processes related to pursuit with processes

related to prey capture.

Evolutionary Ties

The emergence of gnathostomes, or jawed

vertebrates, was revolutionary in the course

of evolution. The success of jawed predators

and the submission of jawless prey gave rise

to a food chain with the predators on top. The

appearance of jaws in vertebrates was met

with additional physiological changes, such

as the appearance of additional support bones

in the shoulder to support more robust neck

muscles. “A new head appeared at some point

containing a jaw, mandibles, and neck muscles

— structures which allowed animals to catch

prey with improved efficiency” De Araujo said.

Some hypothesized that jaws first evolved in

fish for respiratory capabilities, contributing to

gill bars, support structures that allow fish to

breath. Opponents to this theory point to the

morphological differences between jawed fish

and gill bars. Regardless, the appearance of

jaws ushered in new ways to obtain and process

food, leading to a major diversification of


Furthermore, the rise of jawed vertebrates

coincided with a major rewiring of the brain.

One possibility is that the amygdala emerged

as a command center for hunting activity. De

Araujo speculates that the CeA appeared in

vertebrates when the jaw and neck muscles

appeared. Evidence for this hypothesis lies in

one of few jawless animals left — lampreys.

Genetic markers for neurons in the CeA are

absent in lampreys. “That’s an indication that

the major changes in the brain of vertebrates

when their heads changed was the appearance

of the central amygdala, because anatomical

work on lampreys show that their brains look

very similar to that of a reptile or a rodent,” De

Araujo said.

Now with a new model for the role of the

central amygdala and how sensory-motor

tasks are achieved, these Yale researchers hope

to use developmental genetic studies to determine

the exact role the amygdala played in

the evolutionary appearance of jaw and neck

muscles. “Evolutionarily speaking, this work

may help us understand what happened to the

brain when the head sustained these major reconfigurations,”

De Araujo said. The hunt is on

for answers.



WILLIAM BURNS is a freshman Biophysics & Biochemistry major in Morse

College. He is the copy editor for the Yale Scientific Magazine and works in

Professor Forscher’s lab studying cytoskeletal dynamics underlying growth

cone motility in neurons.

THE AUTHOR WOULD LIKE TO THANK Professor de Araujo and Wenfei

Han for their passion and dedication to their research.


Han, W., Tellez, . . . Araujo, I. E. (2017). Integrated Control of Predatory Hunting by

the Central Nucleus of the Amygdala. Cell, 168(1-2). doi:10.1016/j.cell.2016.12.027

14 Yale Scientific Magazine March 2017 www.yalescientific.org



Your cell’s secret


Exploring a recently discovered

microprotein’s role in your cells’

gene cleaning mechanism

by Stephanie Smelyansky

art by Yanna Lee


molecular biology

Imagine trying to find a needle in a haystack, or a dime in a sea of

quarters — the sheer magnitude of the search renders it nearly impossible.

That’s what researchers at Yale University and the Salk Institute

sought to do when they started their search for tiny cellular

proteins against the background of the whole proteome, which consists

of all of the proteins in the cell.

Researchers at Yale University and the

Salk Institute recently developed new

techniques for detecting previously invisible

microproteins. Their research allowed

them to identify 400 new microproteins,

amongst which a novel microprotein they

called NoBody—short for non-annotated

P-body dissociating peptide—proved remarkable

due to its role in an important intracellular

mechanisms. NoBody interacts with other

proteins in the cell to help clean out excess genetic

material in cells.

The journey from gene to protein

Proteins such as NoBody do not randomly

appear in individual cells; rather, they are coded

for in each cell’s DNA. In DNA-based organisms,

DNA can be thought of as the master

computer program that encodes all different

genes, from genes determining eye color to

genes determining kidney function. DNA, deoxyribonucleic

acid, is a double stranded helical

molecule composed of various nucleic acids

bound to a ribose sugar backbone. There

are four possible nucleic acids that make up

the different bases of DNA: cytosine, guanine,

adenine, and thiamine. The four bases can

bind to one another to form base pairs, but

they always bond in the same pairs, with cytosine

binding to guanine and adenine bonding

to thiamine. In any given DNA molecule in a

cell, the bases on one strand of the molecule

are complementary to the bases on the other

strand, meaning that they follow the described

binding pattern. These chemical interactions

allow the DNA to take on the aforementioned

double stranded helical shape. These bases are

also responsible for encoding all of a cell’s genetic


Even though it may seem limiting that cytosine

always binds to guanine and adenine to

thiamine, it’s the order in which these bases appear

in the genome that matter rather than the

variety of bonds they can make. The order of

the bases on each strand of DNA code for different

genes. Once read and processed, each of

these genes codes for a functional protein. The

first step in converting the genetic code into a

living protein is transcription, the process of

converting the gene of interest into a complementary

sequence in DNA’s sister molecule,

RNA. This RNA resulting from transcription,

called messenger RNA or mRNA, codes directly

for a protein. The mRNA molecule then

undergoes translation, the process that converts

the mRNA into a protein. In translation,

a cellular organelle called a ribosome reads the

bases on the mRNA molecule in three base

reading frames called codons. Each of these

codons codes for a specific amino acid, used

as a building block for generating proteins. As

the ribosome translates the mRNA, more and

more amino acids are brought over and added

to the amino acid chain until the final product,

a protein, is formed.

Each protein consists of long chains of amino

acids linked together by peptide bonds.

The different chemical functional groups on

each of these amino acids interact with one


►Nadia D’Lima, one of the authors on the paper, conducting lab work on the NoBody protein.

another to dictate protein structure and function.

The variation in amino acid functional

groups allows proteins to take on a wide variety

of functions, from catalyzing biological reactions

to providing structural support within

the cellular cytoskeleton.

NoBody: the gene sweeping protein

NoBody isn’t like most other proteins. For

starters, typical proteins can contain hundreds

of amino acids and are incredibly large and

bulky. As a result, most protein identifying algorithms

are geared towards identifying genes

that would code for these long polypeptide

sequences. These algorithms are incapable of

recognizing shorter amino acid chains and

they thus completely overlook the existence of

microproteins such as NoBody.

Sarah Slavoff, an associate professor of

Chemistry and Molecular Biophysics and

Biochemistry at Yale and one of the two senior

authors on the paper, first came up with

the idea to search for microproteins while still

16 Yale Scientific Magazine March 2017 www.yalescientific.org

molecular biology


a post-doctoral fellow at Harvard University.

“Maybe there are whole classes of human

genes that remain invisible to geneticists because

they circumvent our expectations of

what they look like,” said Slavoff. Current genome

sampling algorithms have a strict cutoff

as to the length of genes that they can sample,

so she had a hunch that most researchers

might be under-sampling shorter genes that

could yield microproteins such as NoBody.

Her collaborator and the other senior author

on the paper, Alan Saghatelian of the Salk

Institute, also believed these microproteins

might exist, citing previous evidence in flies.

As a result, Slavoff and her colleagues set out

to develop their own methods to find and catalog

these small genes.

According to Slavoff, the new methods they

developed were “conceptually simple,” combining

existing methods in large-scale protein

analysis and mass spectrometry, an analytical

technique that sorts molecules based on their

masses. They started their research by breaking

apart human myeloid leukemia cells, from

which they separated all of the small proteins

and peptides. Next, they performed a proteomics

work-up of the proteins by enzymatically

digesting the proteins and then subjecting

them to mass spectrometry to determine

the amino acid sequences of the small proteins

and peptides. They then compared the amino

acid sequences to RNA sequence databases.

Any known peptide sequences that matched

up with the RNA database were scrapped,

leaving the research team with a new database

of about 400 novel microprotein sequences.

Out of the 400 newly discovered sequences,

researchers decided to focus on NoBody

because the protein seems to be highly conserved

amongst mammals, despite the fact

that it is probably a relatively recent evolutionary

development. This high degree of evolutionary

conservation suggested that it might

play an important role in cellular mechanisms.

NoBody, it turned out, was an essential regulator

of the mechanism responsible for mRNA

degradation, as it interacted with special clusters

of proteins called P-body granules. These

P-body granules interact with mRNA to remove

the RNA’s protective 5’ cap, initiating the

degradation of the mRNA from the 5’ end to

the 3’ end. When large amounts of NoBody

are present in cells, NoBody interacts with the

P-body granules to actually inhibit this, slowing

down the general rate of mRNA degradation.

In the absence of NoBody, mRNA degrades

much more quickly. The degradation

of mRNA is important in controlling protein

levels in the cell and in making sure the right

proteins are created at the right time. Without

such a mechanism, each mRNA would constantly

be translated even if the function of

the resulting protein was no longer necessary,

leading to an overflow of proteins that could

kill the cell.

Yet it seems dubious that a protein as small

as NoBody is powerful enough to cause such

a large change in a cellular pathway. Additionally,

NoBody doesn’t even have a three

dimensional structure; it is unfolded, taking

on a denatured form. However, that doesn’t

mean that NoBody is absolutely helpless.

According to Slavoff, while NoBody might

be too small to perform functions such as

catalysis, it can bind to various proteins inside

the P-body granules and cause allosteric

changes that prevent those proteins from executing

their function.

The future of NoBody

The implications of finding a protein such

as NoBody expand the horizons of cell biology,

biochemistry, and medicine. For starters, it

demonstrates that there is a whole class of previously

undetected proteins operating in cellular

mechanisms that scientists thought that

they knew very well. “[Microproteins] represent

a new class of molecule that biologists can

explore in health and disease,” said Saghatelian.

Like other microproteins, NoBody itself

can also have a tangible role in human disease.

“You can think about [mRNA degradation]

as the back end of gene expression regulation,”

Slavoff said. This implies that mRNA

degradation is another way to regulate the creation

of proteins. This is especially important

in diseases like cancer, which typically have

a heavy mutation load. Proteins such as No-

Body could be used to affect the rate at which

mutated mRNAs coding for defective proteins

are degraded, and increasing the speed of degradation

for these mRNAs could stop a cancerous

cell in its tracks.

Additionally, NoBody might play a large

role in neurological disease. In diseases of aging

such as Alzheimer’s disease and Parkinson’s

disease, newly translated proteins have

a tendency to misfold and create damaging

protein aggregates. The proteins in P-bodies

can also misfold and create protein conglomerates

that may play a role in these diseases.

Since NoBody is able to exert a large effect on

the structure and function of these P-body

proteins, it might also play a role in neurological


There’s still a lot of research to be done on

NoBody and microproteins in general. One

goal is to gain a better understanding of what

are NoBody’s targets in the cell as well as to

gain a better understanding of the biochemical

interactions that allow NoBody to control

the formation of P-bodies. Additionally,

Slavoff is working on developing new technologies

for identifying microproteins, specifically

technology that could potentially

combine typical mass spectrometry experiments

with experiments determining the

function of newly discovered microproteins.

Saghatelian’s lab is continuing to characterize

the other microproteins. “So far, we have

about 400 to study,” Saghatelian said. Who

knew there was so much work to be done on

proteins so small in size!



STEPHANIE SMELYANSKY is a sophomore in Timothy Dwight College

studying molecular biophysics and biochemistry. She is the president of

Synapse and a member of the Yale Glee Club.

THE AUTHOR WOULD LIKE TO THANK Professor Slavoff and Professor

Saghatelian for their time and enthusiasm about their research


J. Ma, C. C. Ward, I. Jungreis, S. A. Slavoff, A. G. Schwaid, J. Neveu, B. A.

Budnik, M. Kellis, A. Saghatelian. “The discovery of human sORF-encoded

polypeptides (SEPs) in cell lines and tissue.” Journal of Proteome Research,

2014, 13, 1757–1765.


March 2017

Yale Scientific Magazine




It’s been 67 years since physicist Enrico Fermi’s

seemingly innocuous remark “Where

is everyone?” sparked the investigative

drive of scientists all over the world. Fermi

once contemplated the possibility of life in the

universe as a numbers game. With hundreds

of billions of sun-like stars in our milky way

alone, it seems that if planets like ours are at

all commonly found, life would have arisen a

number of times, and, like us, sent its signal out

to the universe.

We have seen no such signal, and this Great

Silence has fascinated researchers ever since,

especially as the search for planets like Earth

proves particularly elusive.

It wasn’t until decades after Fermi’s death

that our cosmic loneliness began to lift with

the discovery of the first extra-solar planet.

The last decades of planet hunting have

since unearthed thousands of extra-solar

planets with diversity in masses, orbits, and

host stars beyond what was ever expected.

From the first planet unexpectedly found

orbiting a dead, violent stellar remnant

known as a pulsar, to planet 51 Pegasi b—a

planet the size of Jupiter—the early years of

exoplanets showed that our galactic neighborhood

was full of unexpected worlds.

These new solar systems shattered our fragile

theories of planetary formation, previously

built on a sample size of one.

Looking out into the night sky peppered

with stars, astrophysicists see millions of suns,

many with planets potentially similar to our

own. In a recent article, Yale researchers used

noise as information, championing unique

mathematical approach based on multi-fractal

analysis to sift through spectral data, pinpointing

potential exoplanets—even in astonishingly

noisy data sets. Their work will further the

region in which we can search for exoplanets.

Planets, stars, and life in the universe

Planets are hard to see. They are small, dim,

faraway, and easily lost in the glare of light from

their star. This makes direct detection difficult,

especially for the tiny earth-like planets, which

no longer glow with heat from their formation.

For these reasons, planets were first discovered

by their influence on the light of their host star.

Planets and suns orbit around a mutual center

of mass. Since the star is far more massive,

that point lies inside the star, making it appear

to wobble—its light shifts blue as it moves toward

us, and red as it moves away via the Doppler

effect. With knowledge emboldened by

our physical model of gravity and the laws of

Kepler, researchers can fit the signal of a planet

to this periodic oscillation using a method

we call Radial Velocity. But for the Earth-like

planets, it’s not that simple. Their low mass creates

only a small signal; a miniscule ten-centimeter

per second shift for the star, near the

lowest detection capabilities of our best instruments.

In addition to the challenge of instrumental

noise, the spectra of stars are marred by

noise from our own atmosphere. Finally, and

perhaps most challengingly, planet-hunters

must reckon with astrophysical effects, since

stars can naturally have periodic variations in

starlight. For all their twinkling, we tend to

think of stars as relatively constant points of

light, but in actuality, they are broiling cauldrons

of plasma prone to spectral variations.

These signals can mask and mimic the presence

of an exoplanet.

But despite all of the exoplanets discovered

thus far, earths have remained elusive, and

we’ve never been able to discover such a planet,

or detect any world with that elusive ten-centimeter

per second signal generated by a planet

with Earth’s mass and distance from the sun.

Worlds unknown – in ordered chaos

With so many timescales of noise of so many

different types, it’s difficult to find tiny planetary

signals. Some scientists try to fit models

of stellar activity, atmospheric signatures, and

planetary motion to the data. Combined, these

result in tens of degenerate free parameters,

which produces high uncertainty. In addition

18 Yale Scientific Magazine March 2017 www.yalescientific.org



to this high uncertainty, the mechanisms of

stellar activity aren’t precisely well characterized

or well suited to observation. There’s no

way to resolve the surface of the star as we take

spectra, and thus no way to absolutely take out

the activity signatures with certainty. Still, other

scientists do their best with the data, trying

to only search for planets around “quiet” stars,

and only then checking to determine whether

the “planet” might be the remnant of noise.

But there is one branch of mathematics

suited to chaos and noise. Benoit Mandelbrot,

known as the father of fractal geometry, developing

this field at Yale as the Sterling Professor

of Mathematics until his retirement in 2004.

His innovations portray nature in the way

it exists, distilling the jagged complexities of

coastlines, galaxies, and the human cardiovascular

system into a beautifully defined mathematical



►Parameter space of discovered exoplanets,

colored by method of discovery, where radial

velocity is the method explored by multifractal

analysis. 0.1 meter per second signals are

outside of what has been detected. Earths as

we know them are as yet unseen.

A decade after Mandelbrot’s death, John

Wettlaufer, A.M. Bateman Professor of Geophysics,

Mathematics and Physics at Yale

continues to apply this chaotic mathematics,

but with an added layer of complexity. Multifractals

are fractals that themselves exhibit

fractal behavior. Not as easily recognizable as

their simple repeating counterparts, these objects

exhibit self-similarity on many scales of

time and space, with rules that apply differently

at different levels. Each of those rules is

in itself fractal. The complexity of multifractals

is well suited for exoplanet data, leading

to new modes of searching for exoplanets.

A methodological agnostic

“I don’t know what the signal is… but I know

what I observe,” said Wettlaufer. With a background

in arctic sea ice geophysics, he realized

that scientists easily get carried away with

models replete with unspecified parameters.

Scientists will often take data on something

like arctic ice melting, see the downward trend,

fit a line and extrapolate that in 2040, there will

be no ice left. That thinking is problematic.

Noise is a part of life, a part that can help scientists

predict the signals, and their future. In

the labs of other fields, noise can be suppressed,

but in the context of systems as large as the

earth or the universe itself, such control is impossible.

Noise is something that must be embraced

to recover the underlying process. In

the noisy data, he believes there are underlying

principles to be understood, but Wettlaufer refuses

to assume that he knows what they are by

imposing his own assumptions onto the data.

“It’s an ill-posed inverse problem,” Wettlaufer

explained. “Nature has produced the solution

for you. And now what?” When researchers

take measurements of a star, they don’t see the

surface features that create noise, measure tiny

blemishes on the star, or plot the motion and

characterization of every single atmospheric

particle that contaminates the data, and they

can’t directly observe the planets as they move

around. It’s the sum of all these effects that generate

the data received. Researchers are blind

to everything but the data that results from everything

combined, so the objective is to work

backward to reconstruct the planets.

Using the mathematics of multifractals,

Wettlaufer and his team, mathematics graduate

student Sahil Agarwal GRD ’19 and Fabio

Del Sordo, a postdoctoral fellow in Geology &

Geophysics, took a step back and let the data

do the talking in a recent paper.

Applying a method called Multi-fractal Temporally

Weighted Detrended Fuctuation Analysis

(MF-TWDFA, for short), the team was

able to probe the data for multi-fractal behavior,

looking for self-similarity, or resemblances

within sets of data, to determine which are

the most important. Instead of fitting the data

to just any polynomial, the team posited that

signals closer together in time were more likely

to be correlated. The rule is more certain to

consistently apply at short time scales, allowing

for the characterization of noise. For instance,

El Niño Southern Oscillation has a white noise

structure, whereas this method reveals that the

change in arctic sea ice has white noise, but on

a yearly timescale. The team’s recently accepted

paper in Scientific Reports looks at the stability

of these processes for exoplanets and sea ice

data. Stability is of paramount importance in

both climate systems and exoplanets, where

unstable orbits are known to occur.

Together, the team recovered the same

planetary signals the astronomical community

had come to a consensus upon for

known planetary systems—and they then

proceeded to push their method to the

limits. Even when their method used simulated

stellardata, intentionally marred

with terrible signal to noise, they recovered

accurate planetary signals.

This experimental method will be further

tested by Wettlaufer and his team and applied

to an immense set of exoplanet data through

a new partnership with Michel Mayor and

Didier Queloz, co-discoverers of the first exoplanet.

Using noise to differentiate signals,

they will refine and compare their method

with typical approaches used by others in

the data consortium on a large scale. For exoplanets,

they’d like to eventually deliver an

algorithm to implement during observations,

which could help decipher signals in time for

meaning. They also speculated on the many

possibilities promised by their time-conscious

multi-fractal method—including better

market predictions and further application

to environmental problems.

Making no assumptions. Removing no information.

With techniques like MF-TWDFA,

it seems that Fermi’s Great Silence is giving

way to beautiful, meaningful noise.



SOPHIA SANCHEZ-MAES is a sophomore Intensive Physics and

Astrophysics major in Timothy Dwight College. She is co-president of Yale’s

Society of Physics Students, and has worked on / is working on research with

Professors Korenaga, Laughlin, and Fischer, as well as Dr. Fabio Del Sorto.

THE AUTHOR WOULD LIKE TO THANK Professor John S. Wettlaufer, Sahil

Agarwal, and Fabio Del Sordo for their research, and assistance in this article


Agarwal, S, Del Sordo, F, & Wettlaufer, J. “Exoplanetary Detection By Multifractal

Spectral Analysis.” The Astronomical Journal 153, no. 12 (2017): 12pp.


March 2017

Yale Scientific Magazine






by Jessica Schmerler

art by Yanna Lee

Ever wonder why skin tends to thin and break more easily as

people age? How about whether hair grows back differently

depending on if you shaved or removed it? If you never thought


esearchers at Yale were investigating

the effects of PDGFA—a protein involved

in cellular signaling, growth and

division—on the growth cycles of hair follicles,

when they discovered that a subpopulation of,

adipocyte stem cells, stem cells derived from

fat cells,, were important for both hair cycling

and aging. The study, published in December,

explored the molecular mechanism behind the

maintenance and expansion of dermal white

adipose tissue, which stores fat cells in the

skin’s dermis, and how this process is affected

by serial hair removal and aging. Their findings

expand the scientific community’s understanding

of adipose tissue and point to several

clinical and cosmetic applications.

Getting the Fa(c)ts Straight

In order to grow, tissues need to maintain

small groups of stem cells, and fat cells are

no exception. The stem cells for fat tissues

exist in storage sites called depots and can

be regulated through a variety of mechanisms,

but very little is known about how

these cells are maintained or what signals

these two phenomena are connected, you are in good company.

activate them to grow and become mature,

fully functioning fat cells in a process

known as differentiation.

In 2012, a paper by Matthew Rodeheffer,

one of the Yale researchers on the team, illustrated

that fat stem cells expressing a cell-surface

protein called CD24 commit to becoming

fat cells when they stop expressing that

protein. The Yale team decided to build on

Rodeheffer’s finding, focusing on how another

protein regulates the differentiation of

these CD24-expressing fat stem cells. They

choose to study PDFGA because it was expressed

in fat cell precursor cells and was

known to be important for stem cells in other

systems. They specifically investigated how

PDFGA regulates cell differentiation in the

white adipose tissue located in the dermis

of the skin because these cells showed rapid

turnover, and the research team could observe

cell growth and regression in mere days.

In their study, the team investigated expansion,

a process that increases the area occupied

by fat cells. Their previous work had

shown that expansion occurs during hair

growth and is preceded by the proliferation

of fat stem cells expressing CD24. Thus, they

predicted that there was a potential link between

the processes of fat stem cell proliferation

and hair growth. Supporting this prediction,

they found that hair removal affected

CD24-expressing fat stem cells. Waxing the

mice in consecutive rounds led to a loss of

fat area and fat cell numbers. The researchers

also wanted to investigate how aging affected

these processes: they found that 50%

of CD24-expressing fat stem cells were lost

during the aging process.

Working with these mice, the group established

that PDGFA was responsible for

maintaining dermal white adipose tissue

mass and fat stem cells. Fat stem cells expressed

higher levels of PDGFA as they

proliferated and lower levels as they aged.

Furthermore, when they deleted the gene

coding for PDGFA in the dermis of the

skin, the expansion area of the depot decreased

during hair growth. The rate of expansion

was not slowed, however, since a

related gene, PDGFB, was over-expressed

in other cells to compensate for the lack of

the protein in the fat stem cells.

Interestingly, only the fat stem cells in

the dermis that expressed CD24 seemed

20 Yale Scientific Magazine March 2017 www.yalescientific.org

cell biology


to be affected by changes in PDFGA levels.

Fat stem cells that did not express CD24 were

unaffected by the deletion of the PDGFA-encoding

gene, and no changes were observed

in adipose depots that were not in the dermis.

Understanding the Mechanism

Once the researchers identified PDGFA as

a key player in the maintenance and growth

of CD24-expressing fat stem cells, the next

step was to understand exactly what role it

played in these processes. Using a program

called Ingenuity Pathway Analysis (IPA),

which analyzes gene expression data to

highlight key interaction networks, the researchers

sequenced the RNA of fat cell precursors

that had been treated with PDGFA

to identify pathways correlated with the protein.

The data highlighted significant changes

in pathways involved in proliferation, differentiation,

and survival—indicating that

PDGFA is significant in these processes; in

particular, their results implicated two pathways

called PI3K/AKT and MAPK.

The PI3K/AKT pathway is a signaling pathway

involved in cell proliferation, growth,

and metabolism. The research team’s data indicated

that the pathway could be activated

by PDGFA in mesenchymal cells, stem cells

that eventually differentiate into connective

tissue cells., They found that an increase of

PDGFA in treated cells correlated with an

increase in phosphorylated AKT—the major

signaling molecule involved in this pathway.

Further indicating a connection, the researchers

found that inhibition of the PI3K/

AKT pathway negated the effects of PDGFA

treatment, and deleting genes that encoded

AKT2, a protein in the pathway, reduced the

area of the dermal white adipose tissue in later

stages of hair growth. As with the previous

experiments, these effects were restricted to

CD24-expressing fat stem cells.

Although PDGFA seemed to only affect the

activity of this pathway in dermal white adipose

tissue, the PI3K/AKT pathway has been

shown to aid growth and maintenance in other

adipose tissue depots. The team speculated

that in dermal white adipose tissue, signals

from atrophied fat cells in the dermis may

have stimulated the activation of CD24-expressing

fat stem cells during the hair cycle.

They also predicted that aging reduces the

possibility of this activation. Similar mechanisms

are thought to activate other depots

for adipose tissue during obesity. For example,

one recent study showed that during a

high-fat diet, CD24 adipocyte stem cells are

activated to induce the expansion of abdominal

fat depots while subcutaneous fat depots

remain unchanged. This activation was

shown to occur when the bodily signals present

during obesity activate PI3K/AKT signaling,

similar to way PDGFA activated this

pathway and caused the expansion of dermal

white adipose tissue. In essence, the researchers

hypothesized that white adipose tissue depot-specific

mechanisms that activate PI3K/

AKT signaling could actually be used to regulate

many other types of adipose tissue. In

future, the team plans to identify the targets of

AKT2 to further elucidate the pathway connecting

PDGFA with dermal white adipose

tissue expansion and fat cell maturation.

Fun Fa(c)ts

So why is this one little molecular mechanism

important beyond its role in hair

growth? First of all, dermal white adipose tissue

has been shown to play a role in several

important bodily functions, including wound

healing, responses to infection, and thermal

regulation. As such, understanding the mechanisms

by which adipogenesis occurs may

help us identify how defects in the molecular

pathways contribute to diseases such as skin

disorders or immune response malfunctions.

According to Guillermo Rivera Gonzalez,

lead author on the paper, one future direction

for the team is to investigate how mature fat

cells communicate with the immune system

to affect the immune response. In particular,

he would like to examine the interaction between

the immune system and adipose tissue

in wound healing. Research on this interaction

could have important implications for

improving the body’s capacity to heal.

Another of the important functions of dermal

white adipose tissue is to maintain skin

integrity over time. As PDGFA levels decrease

with age, the pool of CD24-expressing

fat stem cells is also depleted, slowing the

rate at which new fat cells are generated. As a

result, aged skin is extremely thin and fragile

and loses elasticity, one of the reasons why

human skin wrinkles and becomes easily broken

with age. Thus, a better understanding of

the mechanisms involved in maintaining skin

integrity could potentially improve skincare

later in life. “If we can improve maintenance

of adipose tissue in aging, we could increase

the strength of the skin and it would be more

resistant to mechanical stretch that could

break the skin,” says Rivera Gonzalez.

Furthermore, as PDGFA has been shown to

be involved in regulating stem cells of other

tissues, its role in other types of adipose stem

cells outside of dermal white adipose tissue

can be further explored. “We may be able to

maintain fat in aged skin using PDGFA, or

PDGFA may regulate adipose stem cells in

other tissues,” said Horsley, the principal investigator

on the paper. As the full processes

of fat cell maturation have only recently begun

to be understood, there is a lot of potential

for future exploration into the many

applications of adipose tissue maintenance,

from cosmetics to old age.

Given the role of adipose tissue in countless

bodily processes, understanding the signaling

pathways involved in its functioning is critically

important. This study has provided one

of the first insights into how adipocyte stem

cells are maintained in the skin, or in any other

depot of adipose tissue. The future seems

bright in this area of study, and hopefully future

studies will further clarify this relatively

unknown but promising biological pathway.



JESSICA SCHMERLER is a senior in Jonathan Edwards College majoring

in molecular, cellular & developmental biology, neuroscience track. She is

a member of the Yale Journalism Initiative, a freelance writer for Scientific

American MIND magazine, and Editor-in-Chief of the Yale Global Health

Review. She also works in William Cafferty’s lab studying spinal cord injury.

THE AUTHOR WOULD LIKE TO THANK Drs. Rivera Gonzalez and Horsley

for their time and enthusiasm about their research.


Rivera Gonzalez, G.C. et al. (2016). Skin Adipocyte Stem Cell Self-Renewal

Is Regulated by a PDGFA/AKT-Signaling Axis. Cell Stem Cell, 19, 738-751.



March 2017

Yale Scientific Magazine



at the checkpoint by Diyu Pearce-Fisher

art by Julia Shi

cell biology


Think that cancer can only be treated by means of

dangerous chemotherapy, radiation, or a foreign

substance created in test tubes? Think again.

Researchers at the Yale Cancer Center and the

Yale School of Medicine believe that a certain

type of cell in your body could provide remarkable

new insights on the treatment of cancer.


from Yale

School of Medicine


Madhav Dhodapkar’s

lab at the

Yale Cancer Center

investigated memory

T cells in patients with

melanoma — a type of

skin cancer. This research,

which was led by first authors

Chandra Sekhar Boddupalli,

Noffar Bar, and Krishna Kadaveru,

was published in the Journal of Clinical

Investigation in December 2016.

The team embarked on an investigation

of drugs that target the special checkpoints

in the immune system. Previous

studies had suggested that only a small

subset of T cells — special cells that attack

foreign invaders in the body — express

these inhibitory checkpoints within

tumors. To improve the success rates of

these treatments in patients with melanoma,

the researchers started studying the T

cells in the tumors of their patients, aiming

to characterize function and properties

of these cells to improve immunotherapy


Our Bodies’ Defense Against the World

The researchers studied T cells, which allow

a host organism to have a quicker immune

response against a pathogen to which

the host’s immune system has already been

exposed. T cells are not extremely rare or

aberrant, nor are they specific to cancer patients.

Rather, they are a part of a normal

human immune system. In fact, if you have

ever had an infection or disease — even

a simple rash on your skin — then these

cells are probably working as part of your

immune system today. The immune system’s

job is to help preserve the internal

conditions necessary for life processes by

combating potential threats from foreign

agents. On any given day, our bodies are

exposed to a myriad of these threats —

malicious bacteria on the door handle we

touch, viruses we are exposed to by our

neighbors, deadly tumors we develop, or

even toxic chemicals in the air that we inhale.

Such substances or organisms that can

cause diseases are called pathogens, which

are specifically targeted, often destroyed,

and remembered by a variety of specialized

cells utilized by the immune system.

Each T cell has a specific receptor that

can only bind to a specific antigen, the part

of a substance or organism that a T cell

can identify. Upon binding to the antigen,

T cells can recruit other immune cells to

help eliminate the foreign agent. The Yale

researchers studied a special class of T cells

called memory T cells. Memory T cells are

unique because they persist in the body after

the threat has been removed. Moreover,

if the host’s memory T cells are re-exposed

to that specific pathogen, the cells quickly

replicate to magnify and facilitate the immune

response to the threat. Vaccines, for example,

take advantage of this mechanism to

create memory T cells for pathogens, so that a

faster immune response occurs when people

are exposed to these pathogens a second time,

helping the person recover more quickly.

Although most T cells recognize foreign

agents as pathogens, every person has a certain

number of autoreactive T cells, which trigger

an immune response to the person’s own cells.

When T cells are too active, the rate of autoimmune

response increases. To prevent over-reactive

T cells and their autoimmune consequences,

the immune system has inhibitory

immune checkpoints — built-in mechanisms

that keep T cells from becoming too active.

These inhibitory checkpoint molecules can

also be expressed by cancer cells, which helps

to explain why cancer is so deadly — it represses

immune response that normally could

remove the diseased cells. Recently, immunotherapy

treatments for cancer have been developed

in which certain drugs remove the inhibitory

effect from T cells, allowing them to fight

against the tumor. However, these anti-inhibitory

drugs only work for a small percentage

of melanoma cases, leading the researchers to

further investigate ways to improve treatments,

especially through the use of memory T cells.

Using Memory to Overcome Disease

It was once believed that memory T cells

were in constant circulation in the blood

and that as they circulated throughout the

body, they would arrive at the tissues requiring

an immune response. However, in

the past few years, scientists have found

that while some memory T cells that travel

in the blood, certain types of memory T

cells travel to an infected site within a tissue


March 2017

Yale Scientific Magazine



cell biology

and then stay at that site for an extended

period of time. Because these special memory

T cells don’t circulate throughout the

body, they are ready to rapidly generate an

immune response when the same pathogen

enters the tissue again. Such memory T cells

are called tissue resident memory T cells

(TRM cells), since they reside in the tissues.

While studying the T cells within melanoma

tumors, the Yale researchers realized

that the T cells that express the inhibitory

checkpoints have the markers of tissue

resident memory T cells. They also found

that these T cells express genes previously

known to be expressed by tissue resident

memory T cells and that that there were

differences in the T cells that were present

in different tumors within the same patient.

Recent clinical studies with immune

checkpoint blocking agents have shown

that occasionally, some of the tumors in a

patient responded to treatment, while other

tumors in the same patient did not respond.

The researchers hypothesized that the discrepancy

in the responses in such cases

may be due to differences among T cells in

different tumors, and these differences persist

because these T cells were not in circulation

and could not travel to other tumors,

a characteristic of TRM cells. To ensure that

the cause of the differences in the tumors’

responses was the TRM cells and not the

nature of the tumors themselves, the team

ran tests to compare the expression of the

tumors’ protein-coding genes. They found

fewer differences in protein expression existed

between the different tumors than between

the different T cells found in the tumors.


►A microplate is being analyzed under the microscope in Associate Professor of Pediatrics

(Hematology/Oncology) Dr. Kavita Dhodapkar’s lab.

From further research conducted after the

paper was published, the group hypothesized

that the differences among T cells and not the

tumors were the factors causing the different

responses. Further supporting their claim that

the tumors’ T cells were TRM cells, the researchers

found a specific type of transporter

and markers of TRM cells in the tumor cells.

A New Hope with Adaptive Therapies

The ability of TRM cells to protect against

pathogens and potentially protect against

tumors makes them especially enticing for

more scientists to research. Still, even though

there are proposed transporters and markers

for TRM cells, much remains unknown about

these cells. “We need to pay attention to understanding

their function, what they are,

what they are recognizing, because that will

help us treat these patients,” said Dhodapkar.

“There is a very urgent need to understand

the functional biology of these tissue resident

memory T cells,” Boddupalli said. “It is very

important to understand these tissue resident

memory T cells because it can give us better

perspective in designing targeted therapies

for autoimmune diseases, and also for cancer.”

Cancer has long seemed like an incurable

disease. Each tumor is so different that

it is hard to imagine a single unified cure.

For example, existing cancer vaccines — in

which patients are exposed to many cancer

antigens with the aim of triggering a strong

immune response — are not very effective.

Thus, it is no surprise that T cell therapies

for most diseases generally only work on

a small percentage of people However, the

reason that only some people respond to

therapy is not well elucidated, partially because

the functions and properties of the T

cells used are poorly understood.

“We give millions of cells for the adoptive

T cell therapy, but very few of [the T

cells] actually get into the tumor and stay

there. So we need to learn how to make that

happen,” said Dhodapkar. To fully achieve

an understanding of the functions, mechanisms,

and needs of these cells, scientists

can utilize TRM cells as a tool that can arrive

at the site of a tumor, stay there for a

long time, and eliminate the cancer. The researchers’

work has been a big step in fully

understanding these TRM cells and, by extension,

creating a more successful cancer


Today, a myriad of new discoveries, techniques,

and possible cures to disease is

emerging, making it seem feasible to solve

problems once deemed unsolvable. Perhaps a

more universal cure for cancer is on its way!



DIYU PEARCE-FISHER is a sophomore Biomedical Engineering major in

Berkeley College. She works in Dr. Stuart Campbell’s lab.

THE AUTHOR WOULD LIKE TO THANK Dr. Kavita Dhodakpar and Dr. Sekhar

Boddupalli for the time and efforts towards facilitating the process of writing this



Dhodapkar, and Kavita M. Dhodapkar, 2016. “Interlesional diversity of T cell

receptors in melanoma with immune checkpoints enriched in tissue-resident

memory T cells.” JCI Insight.

24 Yale Scientific Magazine March 2017 www.yalescientific.org




A new understanding of navigation mapping in the brain



►Egyptian fruit bats were ideal test subjects because of their

incredible navigation skills.

Finding your favorite bakery in your hometown is incredibly

simple: you know every landmark, crossroad, and turn

on your way to an aromatic, flaky croissant with a mug of

your favorite coffee. However, if you’re travelling in Paris or

San Francisco, it can be harder to track down the highly regarded

café you heard about on social media. This is often

when a map app comes in handy. By following the app’s instructions,

you can easily find your destination.

Although it may not seem obvious when you are lost in a

foreign city, your brain has a “map app” of its own. Within

the brain, the region called the hippocampus is responsible

for memory—including memory related to navigation—

so it can be likened to the mobile application that aids you

while travelling. Location services that track your current

location are the “place cells” of the hippocampus, responsible

for identifying where you are in relation to your surroundings.

The total distance calculated by your app is mirrored

by the “grid cells,” which similarly monitor distances

to distinct locations around you. Your app’s compass icon

finds a parallel in the “head-direction cells” that activate

when you are looking in a certain direction. The finishing

touches to the map of your current surroundings are provided

by the edges of your mobile device’s screen and the

“border cells” of the hippocampus, respectively.

When using a map application, your focus is almost always

the destination. This isn’t surprising; it’s why we say

“‘X’ marks the spot” in classic vernacular. Consequently, it

is interesting that research on the hippocampus and navigation

has not been more focused on the goal: reaching the

destination. A turning point toward more destination-based

studies was recently fueled by Ayelet Sarel, Arseny Finkelstein,

Liora Las, and Nachum Ulanovsky of the Weizmann

Institute of Science. The team of researchers wanted to gain

a deeper understanding of how navigation-related goals are

mapped in the brain. “I was fascinated by the possibility

that we may find neurons that could support this natural

strategy of goal-directed navigation,” Sarel said.

For their experiment, the researchers turned to bats for

a number of reasons. The bats’ ability to fly allowed for

three-dimensional observations of movement, as opposed

to the two that would be possible with non-flying animals.

The bats also provided some diversity to this field of research,

as rodents are the most-used subjects for studies

of this nature.

In the first stage of the experiment, Ulanovsky’s Egyptian

fruit bats flew to their goal: their favorite fruit. Tracking

devices, which the bats wore during the experiment,

allowed for the team to monitor activity in the hippocampal

cells, leading to the discovery that around twenty percent

of the brain cells were encoding information related

to the destination. Curious about how blocking the fruit

would affect brain activity, the researchers placed a cover

in front of the bats’ target. When they found that occluding

the goal did not change the bats’ neural representation

of the trajectory to the delicious treat, they were pleasantly

surprised. The consistency in the hippocampal representation

suggests that navigation is based on memory—not

solely on an organism’s current ability to sense the destination

by sight or smell.

“The main surprise was to find beautiful representations

of direction and distance to the goals, which fit behavioral

predictions very nicely,” Sarel said. Looking ahead, the scientists

at the Weizmann Institute hope to conduct similar

studies in more natural conditions, as opposed to a controlled

lab environment. Further, they would like to study

how the neurons behave when there is more than one goal.

In the meantime, the results of this study have exciting

implications for Alzheimer’s disease research. There is not

yet a cure for Alzheimer’s, which is characterized by memory

loss and afflicts over five million Americans, but this

research could provide a map for how to fight back against

the disease. By better understanding the way memory is

handled by the brain, scientists have a baseline that makes

it easier to understand what has gone wrong in cases of dementia

and serious memory loss. We’re not there yet, but

with studies like this one, we’re one step closer on a journey

to an important destination: a comprehensive understanding

of how the brain works.


March 2017

Yale Scientific Magazine



public health




Diagnosing illnesses in their beginning stages is difficult — warning

signs are usually shrugged off and attributed to simple reasons

like working late or sleeping poorly. Consequently, diseases may

worsen until their symptoms can no longer be ignored or until it is

too late. By then, nothing can be done about the disease’s onset, and

the risk of spreading a contagious disease often increases.

As recently reported in PLOS Biology, a team of Stanford researchers

led by Professor and Chair of Genetics Michael Snyder is

working to take the guesswork out of disease diagnosis. Using data

from wearable biosensors like smartwatches or other health trackers,

they could accurately determine when users were getting sick—

even before symptoms developed—by detecting subtle changes in

a few key physiological measurements. Remarkably, they were also

able to flag the early warning signs of complex diseases such as

Lyme disease and type 2 diabetes.

In the last few years, wearable biosensors have become more

popular and reliable at recording physiological measurements.

The popularization of wearables inspired the Stanford team to take

advantage of this source of medical data and test its diagnostic capabilities.

Although physicians use many such devices already for

health-monitoring purposes, such as tracking physical activity or

sleeping patterns, few have considered using them for preventative


The Stanford team monitored changes in heart rate, blood oxygen

level, and skin temperature. When people are healthy, these

measurements are stable, allowing the team’s algorithm to establish

a baseline for comparison. When people get sick, the algorithm can

then correlate deviations from the baseline with the onsets of diseases.

For example, for many illnesses associated with inflammation—such

as common colds or even Lyme disease, heart rate and

skin temperature tend to increase while blood oxygen tends to decrease.

Alternatively, patterned variations in heart rate can also indicate

signs of insulin resistance, which is a key risk factor for type

2 diabetes.

The main advantage of their algorithm lies in its extensive customization

tailored to each user. “The key is that it’s all personalized.

Everybody has a different baseline skin temperature or heart

rate, and so we’re trying to find deviations from those personalized

baselines,” Snyder said. Even though everyone’s bodies respond to

illnesses differently, the algorithm can set thresholds for detecting

diseases on a user-by-user basis depending on each individual’s

unique physiology.

While promising, the project is still in its preliminary stages. One

main limitation of the study is its relatively small scale; the Stanford

team used only one type of wearable biosensor, so future research

will need to include a variety of the wearables now available on the

market. In addition, since their initial study only tracked forty-three

participants, the researchers plan to increase the number of test subjects

to ensure that their algorithm works on a large population. On

the logistical side, the team also needs to meet important regulations

set by the FDA, which ensure that the tool operates properly,

before the algorithm can be released for public use.

Perhaps the biggest obstacle, however, will be convincing the

public to adopt and use the new technology. Bobak Mortazavi, an

Instructor in Cardiology and researcher at the Yale School of Medicine,

also studies wearable biosensors. “A real issue going forward

is going to be alarm fatigue. After too many false positives, people

are going to get annoyed, start tuning out the alarms, and stop

wearing the devices,” Mortazavi said. He also highlighted concerns

about data ownership and the legalities of how the data will be used.

“There are a lot of issues that still need to be fleshed out. The realistic

usability side of this technology hasn’t really happened yet,”

Mortazavi added.

Once perfected, this system could significantly shift our current

approach to disease prevention and treatment. Early diagnosis can

streamline medical procedures, while an increase in medical data

can help physicians make decisions that are more accurate. Physicians

are currently limited to the use of data collected during patients’

periodic visits to the doctor’s office, so having months of

long-term, uninterrupted data may help them recognize trends that

would be otherwise be impossible to track.

Snyder likens wearable biosensors to sensors on cars. “You have a

car with hundreds of sensors monitoring its health, so you wouldn’t

even think about driving around without those sensors,” Synder

said. “Yet, the average person has zero sensors and goes around

without anything monitoring their health.” One day, with the help

of wearables, figuring out if we are sick might be as simple as checking

the engine light on our car dashboards.


► Wearable biosensors like smartwatches could one day

detect when we get sick.

26 Yale Scientific Magazine March 2017 www.yalescientific.org







►The Longwave Infrared Camera (LIR) used infrared light to

analyze temperature variation in Venus’ atmosphere. The white

regions are the hottest areas.

Although our immediate neighbor is visible twice a day from

Earth, we know little about the planet Venus. It is very difficult

to keep a spacecraft on its surface—where the temperature is

hot enough to melt lead, and only radar imaging can pierce the

fast-swirling clouds that cover the upper atmosphere. However,

recent data from the Japanese Aerospace Exploration Agency’s

Akatsuki spacecraft has signaled a long-awaited breakthrough in

Venus studies.

The Japanese research team was using Akatsuki’s Longwave

Infrared Camera (LIR) to record heat patterns in Venus’ atmosphere

when the scientists noticed irregularities over some of the

largest Venusian mountain ranges. They attributed these results

to gravity waves, vertical air disturbances that are common on

many planets, including Earth. This finding—which may explain

the existence of the clouds that conceal Venus’ surface from our

view—also has applications to Earth.

“It is hard to imagine anything more different from our planet,”

said Ronald Smith, a professor of Geology & Geophysics at

Yale, regarding the Venusian atmosphere. Venus’ three-layer atmosphere,

composed mostly of heat-trapping carbon dioxide, is

about 100 times as dense as Earth’s—so dense, in fact, that it often

acts as a gas and a liquid at the same time. In the highest layer,

enigmatic super-rotating sulfurous clouds blow constantly westward

faster than Venus spins on its axis.

Gravity waves, not to be confused with gravitational waves, are

common phenomena on Earth. Disturbances caused by triggers

in the lower atmosphere—such as thunderstorms, volcanic eruptions,

wind passing over mountains, and airplanes — travel upwards

into the atmosphere. When a small parcel of air is displaced

upwards, it pushes the next parcel up before it is pulled down by

gravity, and the ensuing chain reaction can propagate for miles.

“These waves oscillate through a balance of buoyancy and gravity,”

said Makoto Taguchi, the principal investigator for LIR.

When Akatsuki passed Venus in December 2015, LIR spotted

a conspicuous bow-shaped hot patch that remained directly

above the prominent Venusian mountain range Aphrodite Terra.

This warm region, as well as the fifteen others that the researchers

found during the subsequent eight months, indicated a slower-moving

air pocket among the otherwise super-rotating clouds.

“The stationary thermal structure reminded me of waves on the

surface of a shallow river in which a big invisible stone on the

bottom prevents the smooth flow of water,” Taguchi said. Since

gravity waves travel vertically, they interrupt horizontal airflow—

exactly as was observed on Venus. “After thorough theoretical

consideration and numerical simulations, we concluded that only

a gravity wave could have created the characteristic bow shape,”

Taguchi confirmed.

This discovery alters the conversation about the role of gravity

waves in maintaining Venus’ unusual atmosphere. “The most

tantalizing idea is that these gravity waves carry momentum, and

when they break down, they release strong winds, which could

explain the mechanism of super-rotation,” said Smith, who investigated

similar phenomena above the New Zealand Alps in 2014.

Because Venus’ atmosphere thins with altitude, gravity waves that

are small at the surface amplify until they finally shatter—like the

crack at the end of a whip—and deliver their stored energy to the

upper atmosphere. The behavior of these gravity waves as they

cross layers of the Venusian atmosphere also provides indirect information

about characteristics such as temperature profile.

Surprisingly, one of the most far-reaching consequences

of the Akatsuki mission may have nothing to do with Venus

specifically. LIR’s camera, an uncooled microbolometer array

(UMBA), represents a breakthrough in space imaging. Standard

cooled semiconductor bolometers, which are common

in meteorology and astronomy for measuring slight changes

in temperature using infrared radiation, are bulky, heavy, and

energy-intensive. UMBA is not dependent upon a cooling apparatus

and is thus better suited for spacecraft where compactness

is a guiding consideration. “This was the first mission to

use UMBA to take a snapshot of a planet,” said Taguchi, who

hopes that UMBA will make infrared imaging accessible to a

wider variety of space missions.

Understanding Venusian gravity waves is important for many

branches of Earth science: the same gravity waves that make for

bumpy airplane landings in Denver also factor into cloud movement

and carry chemicals from Earth’s surface into the upper atmosphere.

Accounting for this variable, however, is still one of the

biggest weaknesses of existing climate change and weather models,

and any step towards filling this gap is substantial.


March 2017

Yale Scientific Magazine




The Powerpuff Sponges

Sea sponges solve problems in structural engineering

By Charlie Musoff | art by Isa del toro MIJARES

Spongebob is weak; therefore, he cannot lift a marshmallow

dumbbell. This logic seems sound because it is grounded

in the public’s perception of sea sponges as little more than

mush. While it is fine for Nickolodeon writers to exploit this

view, it would be unwise for engineers to hop on the bandwagon.

Bioinspired science teaches us that nature’s ingenuity

manifests itself in unusual ways. Madhusudhan Venkadesan,

an assistant professor of engineering at Yale, believes that the

natural world and its vast applications should be a primary

inspiration for engineers. “All of [these applications] inspire

us to learn a little more about other organisms on this planet,”

Venkadesan said. If the beetle you just squashed underfoot

can inspire titanium suspensions for military vehicles,

why write off squishy sponges?

As it turns out, sponges aren’t so soft after all. Bundles of

silica rods called strongyloxea spicules are located within the

body of the orange puffball sea sponge, Tethya aurantia, to

help it maintain its form. In the ocean, where sponges are not

only subject to currents and tides, but also must pump moving

water through their bodies, structural integrity is of paramount

importance. Brown engineers Haneesh Kesari and Michael

Monn started to uncover these sponges’ strength when

they noticed the consistent shape of the spicules: always about

two millimeters in length and tapered evenly at both ends.

By measuring spicules and comparing them to a mathematical

model, Kesari and Monn found evidence to suggest that

the spicules were ideally suited to resist buckling, which gives

them major potential for applications in architecture, transportation,

biomedical engineering, and other fields.

It is unsurprising that sponges have developed the perfect

support system. After more than seven hundred million years

of evolution—trial and error, if you will—sponges were bound

to stumble upon the optimal spicule by random chance and

variation alone. Spicules serve a single function, whereas human

bones, for example, have many functions — anchoring

muscle, making bone marrow, and maintaining our shape—so

spicules have had a better chance of taking a form that suits exactly

what they do. As Kesari explained, it is as though sponges

have had to pick only a handful of winning lottery numbers

throughout their long evolution, whereas humans have had to

pick hundreds in a fraction of the time. As humans and as engineers,

it is easy to assume that we are the smartest and make

the best structures. However, Monn noted, “We don’t appreciate

the simplicity through which nature can arrive at the same



►Orange puffball sponges rely on their internal network of spicules

to maintain their shape.

28 Yale Scientific Magazine March 2017 www.yalescientific.org

Once Monn and Kesari noted the consistency of the spicules,

the researchers investigated their purpose through the lens of

an engineer. Venkadesan remarked that lots of successful bioinspiration

stems from salient observation of an organism’s

form or motion that is then applied to engineering. By developing

a structural mechanics model, or a model of the forces

acting on an individual spicule, the Brown team determined

that a load applied to a sponge would compress its spicules

from both ends, instead of causing them to buckle and break

at the center, which happens in similarly shaped, slender columns.

Bioinspired designs often overlook this structural property

in favor of toughness, the ability of a material to break

gradually rather than all at once. Spicules stand out because

in the context of the natural world, toughness is not their

most important quality. Kesari reflected that if engineers have

preconceived notions of what specific properties a material

should have, they risk overlooking its intended function and

stagnating the field.


►Kesari and Monn looked at dozens of spicules under a microscope

to measure their dimensions.

With buckling resistance in mind, the team took measurements

of dozens of spicules to determine their shape and compare

it to the “optimal column.” The Clausen Profile—a model

of the perfect dimensions for a column—predicts that columns

with tapered ends can better avoid buckling. The model

dates back to the nineteenth century and has never been used

in a practical application, so it took effort to dig up. Conforming

to this model and unlike other aesthetic columns in the

engineering world, spicules are tapered in precisely the right

way to maximize their buckling resistance. Compared to an

untapered column of the same length and volume, spicules can

withstand 33 percent more compressive force—a huge difference.

“[We’re] linking this previously known shape to designs

that are practical,” Monn said. Although Venkadesan warns

against replicating an observed form in exact detail without

consideration for what sort of function it achieves, spicules’

relevance is broader. Even without adopting the exact shape,

the engineering foundation behind spicules can be used to improve

material design across a variety of fields.



Now understanding how to approach the design of slender

columns, the team can combine its findings with the best materials

to supersede the engineering of the natural world. The

researchers break down potential applications of their work

into three categories. The first, on a micro-scale, would be

used mostly in the context of medicine. Integrating a tapered

structure into different products—such as needles, catheter

guide wires, and arterial stents—would help them be be as unobtrusive

as possible, minimizing surgical incisions but maximizing


The second use is larger-scale stationary applications, such

as trusses or the frameworks that support structures like a skyscraper

or bridge. An optimally slender truss will save weight

and material. Kesari relates this idea to packing boxes: of

course, cement works best if the only condition is that the box

cannot break, but cardboard strikes a much more attractive

balance between retaining its shape and being light enough to

carry. Beyond building a more economical truss, this innovation

will introduce a new failure mechanism against buckling,

which, if unaccounted for, could pose a major problem on this


However, the area where the team sees the most potential is

in transportation. Implementing better materials is critical in

this field because performance remains important with every

trip. Beyond more efficient construction—from which a static

structure would also benefit, a tapered column could cut fuel

costs and has incredibly attractive economic and environmental

implications. This application is arguably the most ingenious

and the most important in today’s world.



don’t appreciate the

simplicity through which

nature can arrive at the

same conclusions.


Although it is hard for revolutionary designs to overtake the

default, Kesari and Monn believe that there is reason enough

to make the principles behind the spicules’ structure more

widespread. They hope to drive radical changes in materials

science. In the end, it would be a shame if squishy sponges

showed potential to be stronger than Larry the Lobster and the

engineering world failed to capitalize on it. Spongebob simply

would not forgive us.


March 2017

Yale Scientific Magazine



materials science


the Chemistry of


Jean-Pierre Sauvage, who recently shared the 2016 Nobel Prize in

Chemistry for his work on interlocked molecules—have managed

to create chemical knots with three and five crossings (trefoil and

pentafoil, respectively), the Manchester team managed to create

a structure with an unprecedented eight crossings (octafoil). This

morphology lent their knot considerably more strength than its

precursors, giving it the potential to inspire applications in a range

of fields, spanning from materials science to biochemistry and

pharmacological chemistry.

The key to accomplishing this chemical feat lies in a concept

famous to physical organic chemists called “chemical preorganiby


Most of us remember being four or five years old and feeling the

excitement of learning to tie our shoes for the very first time. A

feeling similar to that elation surged through a group of researchers

at the University of Manchester’s School of Chemistry earlier this

year—the only difference being that their laces were half a nanometer

in diameter, about ten-thousand times thinner than a human


Led by professor David Leigh, the team of scientists synthesized

the most intricate and tightest chemical knot ever made by stringing

together 192 carbon, oxygen, nitrogen, and iron atoms into a

continuous looped structure. While past researchers—including

30 Yale Scientific Magazine March 2017 www.yalescientific.org

zation” and dates back to Donald J. Cram, who many years ago

shared the 1987 Nobel Prize in Chemistry. Within the Manchester

team’s work, preorganization refers to the fact that, before attempting

to actually form the new bonds that closed and tightened the

knot, the researchers had to perform a preliminary step that first

weaved together the structure’s disparate strands, bringing them

closer together before tying.

Though Sauvage and the other scientists who synthesized the

earlier trefoil and pentafoil knots also relied on this fundamental

chemical concept, they only successfully managed to weave together

two macromolecular strands. “If you only tie two bits of

string together, you can only make a very limited number of knots,

whereas if you can braid three or maybe more strands, then you

can, in principle, make billions of knots,” Leigh said. For Leigh

and his coworkers, the key to successfully weaving together an unprecedented

four macromolecular strands was to use four iron atom-supports,

whose individual valence orbitals—which orient the

atoms’ reactive electrons in three-dimensional space—were each

perfectly shaped to coordinate two of the eight crossings. And the

iron atoms did enough to lock all of the strands in place.

Next came the crux of the synthesis procedure: actually tying together

the adjacent strands. To do this, the researchers relied on

the fact that they had specifically imbued the individual strands

with special reactivity in the form of double bonds—chemical

entities inherently equipped with loosely held electrons, ready to

react with one another and connect. Finally, after removing the

iron atom-supports in the final step, the chemists isolated the final

eight-fold knot, with a total unwound length of a miniscule twenty

nanometers—500 times smaller than a red blood cell’s diameter.

Reflecting on his team’s achievement, Leigh jokingly remarked

on the perspective of an outsider looking in. “It looks like it was

just a stroke of magic or luck that after mixing together all the ingredients,

it quickly assembled. But, in reality, synthesizing our

knot was a bit like assembling a Boeing 747: the pieces won’t actually

fit together unless you meticulously plan ahead of time,” he said.

By far, though, the most exciting thing about the team’s invention

is its endless applications, according to Leigh. “Knotting and weaving

have always led to breakthroughs in technology,” he said. “In

prehistoric times, humans wove knots to tie axe blades onto their

handles. Technological improvements to weaving machines even

helped spark the Industrial Revolution.”

Many foreseeable applications of Leigh’s knot also lie in the realm

of materials and fabrics—within the field called materials science.

Chemists and physicists might, for example, be able to knit together

billions of these knots to engineer light, flexible, and durable

materials. The fact that the team’s knot is so tight and strong might

help it to eventually replace bulkier plastics and polymers like

Kevlar—a material built from millions of tiny rod-like structures,

densely aligned like boxed pencils, which is currently used to manufacture

everything from bullet-proof vests to car brakes. Leigh explains

this potential application by comparing sets of plate armor

made from solid metal to sets made from interlocked metal chains.

“Both can stop an arrow,” Leigh explained. “The only difference is

that one is much lighter and more flexible than the other. But does

that really translate to the molecular level? We just don’t know.”

In addition to synthesizing their eight-fold knot, the Manchester

team also demonstrated that the knot quickly forms a chemical

complex—an association with nearby molecules—in solution with

materials science


a negatively-charged chloride ion, which fits perfectly within the

knot’s open core. Such a discovery might allude to the knot motif ’s

potential applications in host-guest chemistry—an area in which

organic chemists study the binding of different structures, usually

of one or more small “guest” molecules and a macromolecular

“host.” Scientists who study host-guest chemistry often work within

biological and pharmacological contexts, trying to figure out ways

to solubilize drugs and deliver them to targeted spots within our

bodies, allowing for lowered dosages. With the team’s newfound

method for synthesizing more intricate knots, those specializing

in pharmacology may be able to incorporate knot motifs into hosts

to lend them better structural complementarity to potential guests,

improving current drug-delivery systems.

The team’s work may even help other groups of chemists synthesize

molecules structurally unrelated to knots. Leigh and his team

showed that the simpler pentafoil knot can actually act as a catalyst—an

agent that speeds up chemical reactions. But when they

unwound that very same molecule, it ceased to be catalytically active.

It’s astonishing to find that two molecules, each with the same

connectivity, can behave so differently, according to the researchers.

Still, whether the team’s eight-fold knot also possesses this sort

of marked catalytic activity hasn not yet been verified.

With an eye towards the future, Leigh knows that many questions

must still be answered before trying to apply the knot to real-world

situations. How exactly does the knotted structure affect

the strength of chemical bonds within? Does it make bonds weaker—a

phenomenon we observe within the physical world with fishing

nets? If so, how much weaker? This amount of weakness might,

for example, determine whether their structure stores enough energy

in the form of strain to perform new chemical reactions, and

whether this strain, on the flip side, would lessen their knot’s ability

to replace strong materials like Kevlar.

At the current moment, the team members find themselves

steeped in questions—many more than can currently be answered.

Although the many potential applications tied up within their

chemical knot currently hang in the realm of imagination, Leigh

and his colleagues look forward to unraveling these possibilities in

the near future.


► Chemists at DuPont first synthesized Kevlar, a material five times

stronger than steel, in 1965.


March 2017

Yale Scientific Magazine




Modern Animals


by Dawn Chen | art by Julia Shi

If you’re hoping to run a fruit fly drinking contest, you should

definitely invite the species Drosophila melanogaster—though you

might need some really tiny cups. This species of fruit fly, which

lives in alcohol-rich rotting fruits in the wild, is able to tolerate a

far higher environmental alcohol concentration than its close relatives.

Previous gene sequencing analysis suggested that one reason

for the difference is that Drosophila melanogaster has a slightly different

alcohol dehydrogenase (ADH) protein—an enzyme responsible

for breaking down alcohol—than its close relatives. However,

researchers at the University of Chicago recently have found evidence

against this explanation.

Within the evolutionary biology community, there is a longstanding

hypothesis explaining the high alcohol tolerance of Drosophila

melanogaster: in order to adapt to its ethanol-rich environment,

this species’ ADH protein has evolved to become more efficient at

breaking down alcohol inside cells. Although this sounds fairly intuitive,

the researchers genomically engineered Drosophila to produce

the ADH gene of its two million-year-old ancestors—which

were almost certainly less tolerant of alcohol—and discovered that

the ADH gene did not evolve to become more efficient at breaking

down alcohol.

“This research addresses a major challenge in evolutionary biology,”

said Mo Siddiq, a graduate student in Ecology & Evolution

and lead scientist on the project. “Not only can we build

hypotheses based on correlated observations, we can actually

go back in and test them biologically. That has historically been

the hardest part.”

Siddiq’s research has its roots in the history of how the field of

evolutionary biology was born; theories about evolution have been

in existence since ancient times. To the Ancient Greeks, Romans,

and Chinese, the study of the relationships between and development

of species was considered a branch of philosophy. Modern

evolutionary biology began to develop in the late 19th and early

20th centuries, when Charles Darwin’s theory of natural selection

and Gregor Mendel’s laws of biological inheritance were resolved

in a joint mathematical framework.

32 Yale Scientific Magazine March 2017 www.yalescientific.org

In the mid-20th century, there was a huge breakthrough in molecular

biology, when DNA was discovered to be nature’s hereditary

material and researchers developed the ability to detect differences

in protein and ultimately DNA sequences. These new

molecular approaches provided important tools for studying evolution,

but they led to a splintering in many biology departments—

with molecular biologists and biochemists falling on one side and

evolutionary biologists and ecologists falling on another. Dubbed

the “molecular wars,” this conflict has had effects that are still present


Collaboration between evolutionary biologists and biochemists

is not very common, perhaps because of these historical differences.

However, many scientists in both fields are working to bridge

the gap. “People are starting to realize that by taking a multidisciplinary

approach, we can get a deeper overall understanding,” Siddiq


A key, overlapping topic for these two fields is the search for genetic

changes in a species that help it adapt to its particular environment.

Genes dictate how the organism functions, just like a recipe

tells chefs how to make food. If the customer isn’t happy with a dish,

the chef might swap the recipe, forever changing how that dish is

made in the future. The same is true of natural selection on genes,

except nature selects for genetic changes that make organisms better

capable of surviving and reproducing in their environments (and

natural selection takes a lot longer). Often, distinct patterns of DNA

sequence—called signatures of selection—are produced when natural

selection is acting or has acted on a gene, and this can point the

way towards genetic changes that might have been important in the

evolutionary history of a species. However, many other factors such

as random mutations can also lead to rapid gene changes during evolution,

and some scientists remain cautious about interpreting what

signatures of selection mean for biological functions.

Siddiq and his advisor Joe Thornton, a professor of Ecology &

Evolution, set out to test the direct link between genetic changes

in ADH and whether those changes actually played a role in the

adaptation of Drosophila melanogaster to alcohol-rich environments.

They chose this system because there was a clear hypothesis

of cause and effect, and the genetic tools available in the fruit fly—a

widely-studied model in evolutionary biology—made it easily testable,

according to the researchers.

D. melanogaster evolved to survive in ethanol-rich environments

after it split from its sister fly species, Drosophila simulans, between

two and four million years ago. So, the scientists set out to determine

the ADH gene sequence from the last common ancestor between

Drosophila melanogaster and Drosophila simulans. Using

statistical methods, they traced back the gene sequence of ancient

ADH by comparing the genetic sequence of modern Drosophila

melanogaster to that of its modern relatives.

With the ancient ADH sequence in hand, Siddiq then biochemically

synthesized, expressed, purified, and characterized the ancient

ADH protein. To do this, the gene sequence for ancient ADH

was cloned into a plasmid—a small circular piece of DNA that is

easily inserted into E. coli bacterial cells. The bacteria then multiplied,

replicating their plasmids with each cell division and producing

large amounts of the protein. The expressed ADH protein

was isolated and tested for its ability to process ethanol. The result

was stunning: modern ADH and ancient ADH have the same ethanol-processing





►High ethanol tolerance allows D. Melanogaster to featon rotting

fruit, which produces alcolhol as it ferments.

To further verify this result and to test how the ancient protein

functions in the context of the modern organism, Siddiq partnered

with David Loehlin from the University of Wisconsin and Kristi

Montooth from the University of Nebraska to recreate living Drosophila

melanogaster fruit flies that express the ancient ADH gene.

The team produced DNA coding for the ancient ADH sequence

and injected this DNA into fruitfly eggs. They bred thousands of

these “ancestralized” flies and tested their ability to process ethanol

by putting them in chambers filled with different ethanol concentrations.

This result mirrored the previous one: the ancestralized

flies were just as good at metabolizing ethanol as their modern

counterparts. The scientists concluded that the species’ enhanced

ethanol-processing ability is not a result of adaptation in the ADH

protein, despite the signature of selection on ADH gene sequence

during evolution. This suggests that the previous hypothesis—

which assumed that changes in the Drosophila gene sequence were

an environmental adaptation—may be wrong, and other genes

need to be studied to understand how alcohol tolerance evolved.

But why might a generation of evolutionary biologists have been

wrong all this time about the role of ADH? The main reason could

be that alcohol tolerance is complex, and dozens of different genes

not directly involved in alcohol metabolism might have played an

important role.

Unlike college students, most biologists don’t care much about

how “buzzed” fruit flies can get. However, fruit flies are a central

model species that molecular biologists and geneticists use to

test their theories. This research could overturn a long-standing

hypothesis in evolutionary biology and show us a new way with

which hypotheses about the past can be tested. Moreover, the study

helps to verify the utility of newly-developed tools in molecular biology

that have a wide-ranging impact for future research.

Ultimately, this research only came through an incredible collaboration

between a biochemist in Chicago, a geneticist in Wisconsin,

and a physiologist in Nebraska. These three individuals had

met throughout their academic careers, at conferences and nextdoor

labs, and developed a connection that led them to an interdisciplinary

approach for testing their scientific hypotheses—an

approach that would have never come from a single department.

Perhaps this bodes well for young biologists: like the humble fruit

fly, they can go out with their colleagues and get some drinks—all

the while developing novel hypotheses in evolutionary biology.


March 2017

Yale Scientific Magazine





Theoretical model developed to explain human behavior


Four people work in a group, each given a sum of money. They

are asked if they wish to contribute some amount of money to the

public pot. The choices are thus made clear: either selflessly contribute

and allow the money to be evenly divided or selfishly keep

the money and share in the amount contributed by the others.

Such is the setup of a public goods game, which, like other game

theory-related concepts like a prisoner’s dilemma, provides insight

into inherent human behavior regarding cooperation and

selfishness. These games have inspired the research conducted at

Yale by Adam Bear, a fourth year Ph.D. candidate in Psychology,

and David Rand, an Associate Professor of Psychology, Economics,

and Management.

Basing their work on empirical data related to these games,

Bear and Rand have developed a theoretical game theory model

that explains that people who intuitively cooperate but can also

act selfishly succeed from an evolutionary perspective.

To create the model, Bear and Rand used MATLAB to construct

agent-based simulations consisting of virtual agents with

all permutations of behaviors, which interact with one another

in various environments through a computer system for several

generations. Afterward, they made mathematical calculations to

confirm the accuracy of their simulations.

“The idea of these simulations is they’re meant to model some

kind of evolution either over biological time or over cultural

time,” said Bear. “People who tend to do well when they play their

strategies are more likely to survive in the next generation than

people who do poorly, so these agents interact on a set of generations,

and once you do well, [you] tend to stay in the game; once

you do poorly, you tend to die out.”

The model itself takes several factors —such as type of thinking

and environment—into consideration.

With thinking, agents can either follow their intuition or use

deliberation. Bear describes intuition as a form of cognition that

uses heuristics—mental shortcuts—to get to answers quickly.

This way of thinking is efficient but may lead to errors in reasoning

due to its inability to reason through the details of the context

one is facing. On the other hand, deliberation allows agents

to take time to reason about the contexts and make more accurate

decisions. In the model, agents can strategize, choosing how

much intuition and deliberation to use.

The environment refers to the proportion of repeated to oneshot

interactions. Agents vary in how much they engage in

one-shot interactions and repeated interactions, in which they

may possibly establish a relationship.

From an evolutionary standpoint for which success seems built

on self-interest, Bear explains, “Say we’re in a repeated interaction:

it’s better if I’m nice to you if I’m going to see you again,” said Bear.

“But if I’m never going to see you again, say it’s a one-shot interaction

and no one else is seeing us…I’m better off being selfish if it

would cost me a lot to be nice to you.”

The conclusions of Bear and Rand’s model focused on environments

with more repeated interactions—as they more realistically

reflect the environment of the real world, according to Bear. He

described the best agent in their model: an agent that has a fast

cooperative response, but selfish response upon deliberation in

one-shot interactions.

Their research, however, received critiques from others working

in the field, particularly Kristian Myrseth, an Associate Professor

in Behavioral Science and Marketing at Trinity College Dublin,

and Conny Wollbrant, an Assistant Professor in Economics at the

University of Gothenburg. “The model makes this crucial claim

that evolution never favors strategies...where deliberation increases

your prosocial behavior,” Myrseth said.

Wollbrant added, “The problem is that we know today, we’re

fairly sure, that…people are often behaving prosocially, not for

strategic reasons, but because they feel that’s the right thing that

they should do.” These two researchers claim that the model does

not allow cases of inherent prosocial behavior to survive despite

the apparent evolution of people with such behavior existing in

the world today.

Nevertheless, according to Bear, he and Rand have continued

to work on additional versions of the model to make it more realistic

by incorporating how intuition and deliberation may not be

so black and white in terms of distinguishing the environment.

“There was this fun process of discovery in the model and

learning what the model was actually showing,” said Bear. “It’s

cool because you know you think when you model something,

maybe it’ll be obvious what you’re going to find, but actually, you

discover these interesting things that you didn’t necessarily anticipate

before modeling.”


►Agents who intuitively cooperate, but deliberate and defect to

selfish behavior in one-shot interactions, succeed evolutionarily.

34 Yale Scientific Magazine March 2017 www.yalescientific.org



Fighting Battery Fires with Microfibers


From the phone you’re holding to high-powered electric

cars, lithium-ion batteries are found in nearly every

rechargeable electric device. Since their invention in the

1970s, they have been widely used in household gadgets. In

contrast to typical single-use alkaline batteries, lithium-ion

batteries contain a much denser concentration of energy

stored in rechargeable cells. However, because of their highenergy

concentration, these batteries tend to heat up quickly

as they discharge, becoming dangerous fire hazards. In the

past couple of months, these risks have been highlighted by

the Samsung Note 7 explosions, when those phones ignited

right in their users’ palms, and by the hoverboard fires, which

led to bans of hoverboards in many public places—including

Yale’s campus. New research at Stanford may provide the ideal

solution to these unintentional dangers.

While scientists have already found some ways to lower

heat generation of charging and discharging batteries,

these methods often don’t protect against other issues like

manufacturing inconsistencies. For example, in the Samsung

Note 7 explosions, already-existing heat reduction systems

were unable to get around a structural issue: there was a weak

spot in the separator between the positive and negative ends

of the battery. This separator was designed to keep the two

ends, storing positive and negative ions, from touching each

other, so that the battery wouldn’t instantly discharge all of its

stored energy. This situation is akin to a pile of baking soda

wrapped in tissue paper, hanging above a jar of vinegar. A hole

or a weak spot in the paper would cause all of the baking soda

to fall out and fall into the vinegar, creating an ever-expanding

pile of foam. The tissue paper acted as a separator that kept the

baking soda apart from the vinegar. Similarly, in the battery,

if the separator had a weak spot, the ions would spill over and

mix, creating a short circuit that would heat up the flammable

liquid inside the lithium-ion battery. The entire battery would

then ignite in an explosive reaction.

Another option to reduce the risk of fire is to dilute the

flammable liquids inside the battery with anti-flammable

ones like triphenyl phosphate (TPP). However, this severely

deteriorates the conductivity of the liquid inside the battery,

reducing overall efficiency. Although a shorter battery life

is much better than third-degree burns, in the increasingly

competitive market for smartphones and consumer electronics,

every advantage is a valuable one. Recent advances in battery

innovation may provide a way to salvage this advantage.

In January 2017, researchers in the Yicui lab at Stanford

made lithium-ion batteries less flammable without hurting

their performance by developing their own custom separators.

The separators were woven from sophisticated microfibers

with nanometer-scale diameters. In contrast to classical

separators, these new ones contain the anti-flammable TPP

as a built-in safety mechanism. To create this fine thread,

the researchers used electric force to solidify a mixture of

chemicals containing TPP in midair as it fell from the tip of a

syringe. They then tested this thread to ensure the presence of

two distinct layers: the inner layer contains TPP, and the outer

layer is thick enough to almost completely stop TPP from

leaking into the electrolytes. In addition, the thin outer shell

is designed to melt away if the battery becomes excessively

hot. In that case, TPP flows out of the thread and completely

dissolves in the liquid to reduce the heat, similarly to how

an automatic sprinkler system activates to put out fires. This

solution addresses the need for a reliable thermal failsafe

that doesn’t affect battery performance, making it ideal for

consumer electronics like phones or hoverboards.

Here at Yale, Jaehong Kim, a professor in the Department

of Chemical and Environmental Engineering, is performing

similar research, working on a separator that is similar, but

is used for water filtration and treatment instead of battery

safety. Kim’s work focuses on helping the membrane maintain

functionality and increasing its durability through a selfhealing

feature. If a membrane used for treating drinking

water is damaged, it creates risks such as the outbreak of

waterborne pathogens. Repairing these filters often requires a

system shutdown to replace the membrane, which is especially

a concern in places without the infrastructure to support such

delays. Although the aftereffects aren’t as explosive as battery

malfunctions, an outbreak of disease could be even more

disastrous for affected communities.

For both membranes and battery separators, one thing is

clear: we should not need to sacrifice safety to achieve efficiency.


March 2017

Yale Scientific Magazine







►Dan McQuaid is a current junior in Ezra Stiles College. He

researches in the Crews Lab.

Growing up in the suburbs of NYC in Ossining, New York, current

Yale junior Dan McQuaid always had a personal relationship with

cancer, the focus of his interests and research. A few members of his

close family were diagnosed with it, and during McQuaid’s freshman

year of high school, one of them passed away. “I read a lot—read everything

I could about cancer,” McQuaid said. In particular, McQuaid

wanted to study cancer metastasis, the spread of cancer from a primary

tumor to other parts of the body, which accounts for the vast majority

of cancer-related deaths. With renowned research laboratories

surrounding him, McQuaid reached out to nearly forty researchers.

Most did not respond or were not interested.

One researcher, however, was receptive to his hopes to work in a

laboratory: Goutham Narla, a scientist studying cancer biology and

genetics at Mt. Sinai Hospital. Narla invited McQuaid to work in his

laboratory the summer before his junior year of high school, and

McQuaid continued to work there throughout the school year. Later,

when Narla moved to work at Case Western in Ohio, Narla invited

McQuaid to continue doing research there as well. The summers

he spent researching the tumor suppressor protein KLF6 formed the

foundation for his successes in science research competitions during

his senior year, during which he became one of the forty national finalists

in the Intel Science Talent Search.

However, McQuaid felt some frustration about his summer research

experience at Case Western. “Just as I was figuring things out and getting

good work done, I was back in New York. I felt that if I had a year

there, I could generate some useful research,” said McQuaid. Under

Narla’s guidance and with the reassurances to his parents, McQuaid set

out in August of 2013 to spend a year at Case Western researching how

to repurpose tricyclic neuroleptics—a class of molecules used in antidepressant

drugs. Specifically, McQuaid studied how a segment of one

of these molecules induces anticancer effects in cells. “That segment

activates an enzyme called PP2A (Protein Phosphatase 2A), which removes

phosphate groups from proteins to regulate their activity,” Mc-

Quaid said. PP2A is expressed ubiquitously, but because it is inactivated

in cancer cells, they can proliferate freely.

With that knowledge, McQuaid developed a combination therapy

with his drug and another FDA-approved anti-cancer agent that can

functionally synergize with the activation of PP2A. McQuaid filed a

patent for this technology and included his discovery with the patent

of his mentor’s company. The company’s entire technology was licensed

to other companies for 252 million dollars.

Though this achievement was extremely gratifying for McQuaid,

he found himself burnt out after long days in the laboratory, working

from ten in the morning until after midnight. “My research lifestyle

was not sustainable at Case Western, and I needed to take some time

off. Class restrictions made long working hours in the lab difficult,”

McQuaid said. As a result, he chose not to do research at Yale until his

junior year. He eventually pursued working with Craig Crews, head

of the Crews laboratory, which partly brought him to Yale in the first

place. There, he researches Proteolysis Targeting Chimeras (PROT-

ACS), a technology developed by Crews based on small molecules that

target and degrade specific disease-relevant proteins.

Outside of class, McQuaid is involved with the Yale Undergraduate

Research Association (YURA), for which he is currently co-president

and has helped to lead the first undergraduate research conference at

Yale this past February. He is also involved in increasing global public

health awareness through the Foundation for International Medical

Relief of Children (FIMRC) and is a counselor for Camp Kesem, a

camp for kids who have or have had a parent with cancer. In the future,

he hopes to conduct research in oncology, but his experience shadowing

his mentor Narla in the clinic at Case Western kindled his interest

in pursuing an MD-PhD as well.

Without a doubt, McQuaid is truly passionate about cancer research

and the public health causes he helps drive on campus. But

rather than becoming overly focused on something, he also recognizes

the importance of reserving time for oneself—an important

reminder for researchers and students alike. “No matter how much

you love something, you’ll get tired of it if you don’t find a balance

and have other parts of your life to focus on and develop,” Mc-

Quaid said. With that in mind, McQuaid hopes to continue helping

others through his research for a long time to come.

36 Yale Scientific Magazine March 2017 www.yalescientific.org





Alanna Schepartz, professor of Chemistry and of Molecular, Cellular,

and Developmental Biology (MCDB), has combined her knowledge

from the fields of biology and chemistry in her current research, which

may revolutionize our understanding of the roles chemistry plays in biological

functions. Having studied at Columbia and Caltech, Schepartz

arrived at Yale in 1988 and has since been named the Milton Harris ’29

Ph.D. Professor of Chemistry along with a full-appointment in MCDB.

Now, Schepartz’s work focuses primarily on how proteins encode information

to influence functions inside the cell.

From the beginning, Schepartz’s family was involved in the fields of

science and mathematics. Her mother, a gifted mathematician, was part

of a team at Merrill Lynch that developed a computer program (known

as the “Million Dollar Baby”) capable of processing complex financial

operations in a matter of minutes. Meanwhile, her father, an enthused

geologist, had a hobby of collecting minerals and rocks from various locations

and often encouraged the family to join his road trips. Thus, at

an early age, Schepartz was exposed to various disciplines and decided

to explore more areas.

When Schepartz enrolled in SUNY Albany for undergraduate studies,

she was unsure about her career path. Not until sophomore year

did Schepartz realize her passion, when she took Introduction to Organic

Chemistry. “To me, it was just like a puzzle ready to be solved,”

said Schepartz. She had a firm understanding of organic concepts and

performed very well in the class. Schepartz performed so well that she

was invited to conduct research at a SUNY Albany lab during the summer

after sophomore year. Upon graduating, her colleagues at the lab

presented her with a departing gift: a red plaid briefcase with ‘Professor

Alanna’ inscribed on the side. “It was more influential than I had originally

thought,” admitted Schepartz. The moment persuaded Schepartz

to choose chemistry as a career; however, her path experienced a turning

point at Columbia.

Entering graduate school, Schepartz felt unqualified. “Everyone there

had better preparation than I did,” disclosed Schepartz. Nonetheless, she

still enjoyed her time and delved into her research. One Sunday night

while Schepartz was working in the lab, her advisor Ronald Breslow

stopped by to pick up some items before he left for a research trip abroad.

He asked Schepartz, “What would you like to do with your life?” and

Schepartz replied that she was still undecided. In response, Breslow said,

“You should consider teaching at a great institution,” and proceeded to

name a couple of well-known colleges including UC Berkeley and Yale.

His encouraging comment went a long way: Despite initially being behind

her colleagues, Schepartz was honored by his belief in her and was

thus motivated to pursue a chemistry career in academia.


►Alanna Schepartz is the Milton Harris ‘29 Ph.D. Professor of

Chemistry and Professor of Molecular, Cellular, and Developmental

Biology at Yale

As of now, Schepartz is conducting experiments that intertwine concepts

from chemistry and biology. Her latest research focuses on how

protein receptors in a cell membrane can identify the target molecules,

or ligands, that bind to it. One such ligand known as the Epidermal

Growth Factor (EGF) binds to its corresponding receptor and activates

signal transduction pathways inside the cell that stimulate growth.

When mutated, EGFR can cause cells to grow uncontrollably and form

tumors, contributing to numerous human cancers. Scientists have previously

attempted to halt EGFR activity by applying inhibitors in one

of two ways: either targeting the active site where EGF binds to EGFR

or obstructing catalytic Adenosine Triphosphate (ATP) from binding

to the intracellular domain of EGFR. In her lab, Schepartz is developing

a new method to control mutant EGFR. Activated EGFR has an altered

conformation (otherwise known as coiled-coil formation). Disrupting

this altered conformation subsequently prevents EGFR from

becoming active, thus halting cell growth.

Throughout her career, Schepartz has followed her passion in

chemistry and STEM. Futhermore, Schepartz’s persistence and determination

has allowed her to reach her position as an esteemed

researcher in both chemistry and biology.


March 2017

Yale Scientific Magazine



book review




Several billion years ago, billions of light-years away, two stars

lived in orbit around one another. As time went on, the two of

them eventually died, becoming two black holes orbiting each

other, sucking in everything around them, and creeping towards

each other, millennia after millennia. They continued to orbit—

darker than the empty space around them—until they collided and

launched gravitational waves out in every direction and shook the

fabric of spacetime.

Such is the theorized history of the universe until the present

day. Gravitational waves—ripples in spacetime caused by the

presence of massive objects in the universe—rocketed towards

us at the speed of light for more than one billion years. During

this time, we advanced enough to detect the distortion that these

waves produced, which is the size of a thousandth the width of a

proton. We built two Laser Interferometer Gravitational-Wave

Observatory (LIGO) sites to measure these waves and on Monday,

September 14th, 2015, they both recorded a burst as gravitational

waves passed over the earth.

Janna Levin’s recent novel, Black Hole Blues and Other Songs

from Outer Space, explores the decades-long project that began as

the dream of Rainer Weiss and culminated in the two enormous

interferometers. The book documents the stories of three eminent

scientists—Kip Thorne, Rai Weiss, and Ron Drever—known as the

troika, as it unravels the field’s highly complex theories and serves

as tribute to “a quixotic, epic, harrowing experimental endeavor,” as

described in the book.

Written by an eminent theoretical

astrophysicist, Black Hole Blues makes

the science of this endeavor accessible

to readers of all scientific backgrounds.

The book reads very smoothly; Levin

follows the process from its humble

origins to its victorious discovery,

spending equal time on the science

and the story behind the endeavor.

The plotline does not feel bogged

down by technical jargon or by the

complicated physics associated with

the black holes. The science behind the

story is certainly important, but the

writing manages to place the reader

into the narrative; the trials faced by the team are our own, and the

excitement they feel as the project advances is shared.

Levin presents the scientists as real human beings—flawed in

various ways—and records conversations between them, giving

the reader insight into the team dynamic. Within any team,

there are conflicts and power struggles as well as deep bonds and

friendships, and Levin portrays both ends of the spectrum from

several perspectives. The reader is presented with deep insights

into the minds and relationships of the various physicists, which

personalizes the narrative and makes the characters seem real

rather than heroes on a pedestal.



Have you ever considered what a Special Operations soldier would do

if he suddenly found himself battling diarrhea in the field? Neither have

most Americans. But one author took it upon herself to investigate the

grosser and more obscure problems the military faces. In her latest book,

Grunt: The Curious Science of Humans at War, pop science writer Mary

Roach takes readers into the fascinating but often less-than-glamorous

world of the scientists who work to keep American soldiers alive.

Though it contains a wealth of interesting facts and engaging

witticisms, the book lacks a clear organizing principle or narrative

structure, leaping somewhat haphazardly from topic to topic. Roach

freely admits to “cherry-picking” subjects based on what she finds most

interesting, assuming her readers’ interests will align with her own. In the

case of Grunt, these interests range from the design of military uniforms

and bomb-proof vehicles to the development of stink bombs and shark

repellant. While her thought processes are difficult to follow, Roach’s love

for the thorough research behind her books is evident in every page. She

is unable to resist including numerous footnotes with interesting details

that don’t fit into the narrative of the main text, such as the Medicare

reimbursement code for maggots (CPT 99070) or her favorite amputee

organization name (Stumps R Us).

Reflecting upon her writing process, Roach notes that Grunt stands

out among her books. “There is a gravity to the material and a certain

treacherousness in applying a lighthearted tone,” Roach said. As a reader,

it is easy to appreciate her carefulness not to stray from humor into

disrespect or irreverence. For example,

other reviewers of the book have noted

her delicate and earnest handling

of the subject of penis wounds and

transplants. Refraining from bawdy

remarks, Roach preserves the dignity

of the wounded and explains why these

surgeries should not be trivialized.

In the early chapters, her musings

on uniform design take a somber turn:

“From first inspection to Arlington

National Cemetery, soldiers look like

those around them: same hat, same

boots, identical white grave marker.”

And the book’s final chapter, which

offers a glimpse of medical examiners’

morbid but crucial work, has a heaviness to it—the absence of Roach’s

usual quips forcing the reader to consider the weight of the lives sacrificed

and the importance of protecting those who remain.

Roach says that, when the book began, she had no agenda; however,

as the research progressed she became increasingly—and rightfully—

impressed by the people she met. “I didn’t set out with the explicit

mission of showing the world that these people do worthwhile work, but

if that is a result of the book, then I’m really happy,” she said.

38 Yale Scientific Magazine March 2017 www.yalescientific.org





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