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Yale Scientific Magazine










Yale researchers demonstrate drug

delivery efficacy via a bioadhesive

class of nanoparticles designed for

administering cancer treatment.




Using new analytics to understand

tiny mineral crystals, a Yale G&G team

discovers evidence for the effect of

volcanic activities on global climate.




A recent Yale study supports that

overimitation is distinctly human,

as dogs and dingoes are more

inclined to evade irrelevant actions.




Researchers from Yale and other

institutions unearth the origins of

the Tully Monster, a Carboniferous

creature with unusual morphology.





Uniting quantum mechanics and

computer science, Yale researchers

make progress towards constructing

more powerful quantum computers.

More articles available online at www.yalescientific.org

December 2016

Yale Scientific Magazine


q a


CO 2

Past the point of no return?


Climate change has been ranked a top

global threat, with indicators such as carbon

dioxide (CO 2

) levels illustrating its

rapid progression. Each year, CO 2


are lowest in September—but this year,

even at their annual minimum, CO 2


stayed above 400 parts per million

(ppm). Scientists consider 400 ppm to

be the “fail-safe” ceiling for CO 2


Beyond this concentration means that

Earth has permanently surpassed 350

ppm, the highest level needed to maintain

climate stability. So when the Mauna

Loa Observatory, a global monitoring facility

in Hawaii, discovered that CO 2


remained unusually high this year, the

news was concerning for many experts.

“We won’t be seeing a monthly value

below 400 ppm this year—or ever again

for the indefinite future,” said Ralph

Keeling, director of the Scripps Institute

for Oceanography, after he analyzed the


►Smoke is emitted from factory smokestacks

beside a highway.

daily Mauna Loa recordings.

With global CO 2

continuing to rise,

has our atmosphere been irreversibly

altered? Joshua Galperin, research

scholar and lecturer in law at Yale Law

School and the Yale School of Forestry

and Environmental Studies as well as

the director of the Environmental Protection

Clinic, believes we can address

the problem if both policymakers and

citizens make changes. “[Policymakers]

need to be imaginative,” Galperin said.

Specifically, he promoted the elimination

of coal power as a starting point

for energy reformation.

Galperin further suggested that citizens

use their skills in economies “built

on carbon” to ensure integrity as they

retract from carbon. He also emphasized

the need for hope at the forefront

of our actions to combat climate


Three’s a Crowd—How can a baby have three parents?


Modern technology has allowed for the

creation of “three-parent” babies by incorporating

genetic material from three individuals

in the creation of a single embryo.

For parents whose children are at risk of

inheriting a mitochondrial disorder, genetic

material from a third person can

help them conceive a healthy child. Mitochondria

are maternally inherited organelles,

so if a mother’s mitochondrial DNA

is mutated, her children are at risk of developing

defects that frequently result in

infant death.

Researchers first attempted to prevent

mitochondrial diseases in the 1990s by

injecting mitochondrial DNA from a donor

into another woman’s egg, along with

sperm from her partner. Some of these

children developed genetic disorders, and

the US Food and Drug Administration

stopped the procedure.


►Sperm cells surround and fertilize a human

egg as seen under a light microscope.

A recently approved method now used

in the United Kingdom is pronuclear

transfer: the mother’s and a donor’s egg

are fertilized with the father’s sperm,

both nuclei are removed from their respective

eggs, and the mother’s nucleus

is transferred to the donor’s egg. The embryo

then possesses mitochondrial DNA

from the donor, as well as nuclear DNA

from its parents. In this way, the child

has genes from three different parents.

Recent successful three-parent-births

give hope to parents who have lost children

to mitochondrial disorders.

“Mitochondrial diseases were incurable

until now. The opportunity to use

mitochondrial replacement as a form of

cell therapy to provide a ‘cure’ should be

embraced,” explained Pasquale Patrizio,

Director of Yale Fertility Center & Fertility

Preservation Program.


The year began with the thrilling discovery of gravitational waves. We said that

was just the beginning, and indeed what a year it has been for science and for us

at the Yale Scientific. From breakthroughs in cancer therapy in To Immunity and

Beyond (89.2) to advances in quantum computing in Welcome to the Quantum Age

(89.3) to new approaches to art restoration in Decko Gecko (89.4), it has been an

absolute joy sharing these fascinating scientific stories with you, our readers.

On this issue’s cover, we are excited to feature research conducted at Yale that

harnesses nanotechnology to target drugs to cancer cells with greater potency and

fewer side effects (pg. 15). Not to be outdone, another Yale team has discovered a

new drug candidate for lung cancer that acts through a novel mechanism (pg. 8).

Meanwhile, across the Pacific Ocean, a group of researchers in Melbourne are exploring

a novel approach to treating antibiotic-resistant bacteria (pg. 30).

This year also marks the 150th anniversary of the Yale Peabody Museum (pg. 25).

Museums like the Peabody inspire awe with their remarkable collections of fossils

and minerals. Easier to forget is the fascinating research that goes on behind the

scenes. The intriguing tale of the Tully Monster, a fantastic creature that has finally

been assigned its proper place in the tree of life, pays tribute to those efforts (pg. 20).

In many ways, the past holds insights for the present. In this issue, we dive into

the changes in carbon dioxide levels that have taken place across geologic time as

volcanic activity rose and fell. What we see is troubling, with surging carbon dioxide

levels driving a majority of species to extinction (pg. 12). As greenhouse gas levels

continue to rise, we evaluate where we stand today (pg. 4) and report on the quest

for cleaner sources of energy (pg. 10).

We worry about the future of climate change research as a new administration

takes over in January. Still, we take heart in the progress that scientists and engineers

around the world have already made, and we remain quietly optimistic that

scientists will respond to the increased urgency for clean-energy solutions with a

wave of innovation.

At our magazine, it is also time for us to pass on the baton to a new masthead.

We are struck by their boundless energy and their refreshing ideas, and we have full

confidence that they will carry this publication to greater heights.

Thank you for reading these pages. It has been our privilege and pleasure.

Yale Scientific

Established in 1894


DECEMBER 2016 VOL. 90 NO. 1 | $6.99








Lionel Jin


The cover, designed by arts editor Ashlyn Oakes, shows

the artist’s interpretation of nanoparticles as they deliver

drugs to cancerous endometrial cells. Endometrial cancer

is resistant to many forms of chemotherapy and must

be combated using powerful drugs which often have severe

side-effects. In order to relieve some of those side

effects and increase drug potency, Yale researchers have

developed sticky nanoparticles that attach to the surface

of tumor cells, delivering drugs in a targeted fashion to

the tumor and promising safer, more effective treatments

to a debilitating disease.


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Sarah Adams

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Kevin Chang

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Jasper Feinberg

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in brief

Modeling Mars: Life-Supporting Earthquakes?

By Isa del Toro M.


►A topography map of Mars with different

color intensities indicating the depth

of craters and highlighting areas of possible

seismic activity on its surface.

There’s a new hypothesis on the block related

to the possibility of life on Mars. Research

conducted by Sean McMahon of the Yale Geology

and Geophysics department, in collaboration

with John Parnell and Nigel Blamey,

looks into Earth’s subsurface hydrogen levels

and how these indicate potential microbial

activity on Mars.

Hydrogen serves as an energy source for

certain types of organisms. Subsurface hydrogen

gas is created on Earth due to the grinding

of rocks along ancient earthquake fault

lines. McMahon’s experiment sought to determine

whether these gas levels were enough

to have spurred microbial life. Using crushfast-scan,

a technique that involves crushing

rocks to expel the gas contained with them

and measuring the released gas composition,

the researchers concluded that the hydrogen

contained in these rocks was sufficient to fuel

anaerobic life on Earth. Many types of rocks,

including the basalt found on Mars, can likewise

create hydrogen, leading researchers

to determine that quake activity on Mars

could fuel microbial life. In 2018, NASA’s

InSight mission will collect data concerning

seismological activity on Mars. This data

will allow the researchers to re-evaluate the

“Marsquake” models they used in their conclusions

and determine whether their models

fit Mars’s actual surface.

McMahon’s results are an exciting find.

They shed light on another possibility of life

on Mars, which would have important consequences

on how we approach the idea of human

activity on the Red Planet, as well as our

understanding of how life came to be in the


The Gruber Cosmology Conference at Yale

By Urmila Chadayammuri


►Professor Manuela Campanelli of

the University of Rochester presents

her pioneering simulations of black

hole mergers.

The third annual Gruber Cosmology

Conference took place at Yale on October

7th, honoring discoveries advancing our

understanding of the universe. This year’s

Gruber Prize recipients were Rainer Weiss,

Kip Thorne, and Ronald Drever, the leading

scientists on the LIGO collaboration, which

made the groundbreaking discovery of

gravitational waves. The conference began

with a history of gravitational waves, after

which Weiss explained how the LIGO project

worked. Speakers also highlighted upcoming

detectors in Europe, India and Japan, which

aim to pinpoint the origin of gravitational


The afternoon session outlined the impact

of the discovery. Thorne described the

new science we can probe with the help of

gravitational waves, from learning about how

the very early universe grew, to understanding

spinning and colliding black holes. Harvard

radio astronomer Shep Doeleman closed the

conference with prospects for how we can

directly image black holes and their power as

gravitational lenses, which bend light from

sources behind them, to directly image black


The presenters all spoke of their work as a

conversation across centuries with the father

of general relativity, Albert Einstein. What

would Einstein have said if he heard of the

LIGO observation? Thorne guessed he would

try understanding the black hole merger that

caused it, while Weiss thought he would ask

how the equipment worked. Doeleman took

a step back. We knew general relativity was

correct before the gravitational wave detection,

he said, as GPS would not work without it. If

we were to present a map app to Einstein, he

would most likely wonder, “What is a phone?”

6 Yale Scientific Magazine December 2016 www.yalescientific.org

in brief


The Miller laboratory of Yale’s Department

of Chemistry recently made a discovery

in peptide catalysis that could change how

we think about enzymes. This discovery

capitalized on the laboratory’s previous

discovery of two peptide catalysts. Enzymes,

or protein catalysts, are characterized by high

specificity. Alford, the study’s first author, and

his colleagues demonstrated that two short

peptides, which are comprised of protein

building block called amino acids, can catalyze

two distinct, complementary reactions called

oxidation reactions. This remarkable capacity

is presumably due to the synthetic peptide’s

overall structure: by varying just a few key

amino acids outside of the active site where the

reaction takes place, the same active residue can

switch between catalyzing two very different

reactions. This control of catalytic activity by

Shrinking Enzymes

By Giorgio Caturegli

modifying secondary structure is a hallmark

of enzymes but has had limited application

in organic synthesis. “This finding is a really

interesting manifestation of what the [Miller]

group tries to do…using tools that nature has

to understand natural processes,” said Nadia

Abascal, a coauthor. Synthetic reactions can

be studied to gain insight into processes in

nature, which may follow a similar mechanism

to the reactions observed in this study.

Especially notable is the fact that peptides

are orders of magnitude smaller than

enzymes, and their small size and precise

control could allow for synthetic applications

in pharmaceutical and materials research.

The Miller group’s recent finding in peptide

catalysis is important to both understanding

natural biochemical processes and developing

synthetic applications.


►Miller’s laboratory discovered two

peptides that can catalyze two different

reactions based on secondary

structure and reaction conditions.

A New Excuse for Playing Video Games?

By Jasper Feinberg

Imagine if video games were a key to

improving learning. Yale psychiatry professor

Bruce Wexler believes they are. A study found

that a video game-based learning regimen

called Activate, developed by Wexler, improved

the test performance of 583 schoolchildren

compared to those without the regimen and

those with one-on-one tutoring. The curriculum

includes computer games aimed at cognitive

improvement and a five minute warm-up

computer activity designed to prepare students

for learning.

The Activate program harnesses

neuroplasticity. The structure of the brain

is shaped after birth from environmental

stimuli that reorganize neuronal connections.

Activate stimulates areas of the brain often

underdeveloped in children who grow up in

poverty or have neurodevelopmental problems

like attention deficit hyperactivity disorder

(ADHD). To accomplish this, Wexler used

neuroimaging studies to identify the regions

of the brain corresponding to certain cognitive

tasks. Wexler describes Activate as “a school

lunch program for the brain” customized to each

individual student.

The social implications of this educational

strategy are vast. First, Activate has the potential

to close the achievement gap by helping students

with different educational backgrounds. As a

technology-based tool, it is cheaper than many

current solutions. Wexler’s research is also an

effective treatment for depression and, in some

cases, ADHD.

Going forward, C8 Sciences, a Yale startup

dedicated to spreading Activate, hopes to

increase awareness and continue improving

the program. Activate has been translated into

multiple languages, and appears primed to



►A student using Activate, a gamebased

learning program shown to

improve test performance, in her

school’s computer lab.


December 2016

Yale Scientific Magazine



molecular biology


New drug reduces lung cancer cell growth


Wouldn’t it be nice if killing lung cancer cells was as easy as

flipping a switch? As it turns out, effectively targeting these

cells is more like a dimmer rather than a switch, but it can

be done, according to new research spearheaded by Joseph

Contessa, associate professor of Therapeutic Radiology and

Pharmacology at the Yale School of Medicine. Contessa led

the discovery of a drug that reduces non-small cell lung cancer

(NSCLC) tumor cell growth, proliferation, and survival,

without causing toxic effects to healthy cells.

NSCLC comprises about 80 to 85 percent of lung cancers and

generally spreads more gradually than small cell lung cancer.

Much cancer biology research surrounds the role of receptor

tyrosine kinases (RTKs), cell surface receptor proteins, in the

behavior of tumor cells. RTKs stimulate signals within cells

that direct the cell to grow, divide, and proliferate, and can

trigger survival signals in toxic environments. In cancer cells,

RTK genes are overexpressed, causing more RTKs to appear

on the cell surface, leading to more resilient and fastergrowing

cancer cells.

Contessa’s lab aimed to better understand how RTKs

affect tumor growth and survival, and therefore explore how

scientists can target these receptors to control tumors. Prior

hypotheses extrapolate that if one can block the function of

RTKs, turning them “off,” tumors can be treated with more

success. Current drugs and compounds such as Gefitinib

and Erlotinib target specific RTKs but do not work as well as

hypotheses predict. Early in his research, Contessa postulated

that these drugs failed due to redundant signaling, or the

presence of dominant and backup receptors that all signal

NSCLC tumor cell growth and proliferation. Therefore,

drugs and compounds that only target one receptor are

ineffective in treating the NSCLC tumor cells.

Thus, Contessa looked for ways to target multiple

receptors without creating a toxic environment for normal

cells. He found that all of the receptors are glycoproteins—

they have sugar chains attached to them. Contessa then

hypothesized that by interrupting glycosylation—the

addition of sugar chains—the function of the glycoprotein

RTKs could be blocked.

“What people thought before was that adding these sugar

chains was a switch like a light switch, turning on and turning

off. What we’ve shown is there’s actually a spot that you can

hit it that’s more like a dimmer switch, where you can just

turn it down. What we found is a small molecule, a drug-like

compound, that can act this way—it can turn the dimmer

switch down,” Contessa said.

This drug, N-linked glycosylation inhibitor-1 (NGI-

1), targets non-small cell lung cancer cells by inhibiting an

enzyme that attaches sugar chains to RTK precursors and

creates the mature glycoprotein RTKs. Contessa’s research

showed that this drug reduces the expression of epidermal

growth factor receptor (EGFR), a specific RTK, on the surface

of the lung cell. In the drug-treated cells, the EGFRs were

found inside of the cell, indicating that NGI-1 prevents the

transport of RTKs to the cell surface.

Contessa’s research further confirmed that NGI-1 is

specific; although it inhibits RTK signaling, it does not

inhibit the transport of all glycoproteins to the cell surface, so

glycoproteins essential to healthy cell function are unaffected.

“It means that tumor cells that are highly dependent on

RTKs become very sensitive to this drug,” Contessa said.

His research shows that NGI-1 arrests cellular growth and

division in RTK-dependent NSCLC tumor cells.

The project was not without difficulties. “The whole project

was a challenge… it was a collaborative effort, and we worked

with a couple different groups,” Contessa said. The process

sounds easy—a step-by-step path towards a new method of

battling lung cancer. In reality, this one drug resulted from

five years of dedicated research and testing, screening over

350,000 drugs.

“You’re kind of on this detective hunt. You’re screening and

you find this inhibitor, and then you don’t know exactly how

it works. So you have to call on some expertise to help you,

and then hopefully you get a little lucky and you figure out

the mechanism and you can advance it to your experimental

models,” Contessa reflected.

Contessa’s detective mindset, along with the advice of

many collaborators and a bit of luck, led the researchers

to a potential drug candidate for battling NSCLC tumors.

Contessa looks to translate their successes in laboratory cell

models into successes in live animal tumor models, and we

will hopefully see NGI-1 in future clinical studies.


►A member of Joseph Contessa’s lab at work at the Yale

School of Medicine.

8 Yale Scientific Magazine December 2016 www.yalescientific.org

computational biology



Tinkering with the building blocks of life




►Before the advent of computational methods, biologists

and biochemists had to rely on bouncing x-rays off of protein

crystals in order to determine the 3D structure of a protein.

Proteins play an important role in all life processes. From

catalyzing reactions to protecting our body to supporting

cell structure, proteins have a wide variety of functions

based on each specific protein’s structure. Naturally-occurring

proteins are perfectly evolved for their specific functions

in each organism. Synthetically designed proteins,

however, have the potential to solve the multitude of global

problems facing the world today. For example, engineered

bacteria can make enzymes that help decompose plastics

and reduce landfill waste, or produce designer proteins that

can harvest energy from sunlight for clean energy.

Direct experimental methods for designing synthetic

proteins can be used for creating new proteins with the

desired activities, but they are expensive and labor intensive.

Another strategy is to employ computer simulations,

which have the potential to greatly streamline the process

and reduce costs. However, despite a number of successes,

computational protein design software still frequently

makes inaccurate predictions of protein structure and interactions.

To solve this problem, two Yale groups are combining

their expertise in an interdisciplinary effort led by Corey

O’Hern, an associate professor of Mechanical Engineering

& Materials Science, and Lynne Regan, a professor of Molecular

Biophysics & Biochemistry and Chemistry.

In a recent Protein Engineering, Design, and Selection

paper published in July 2016, the team of researchers described

a new computational model that helps solve the

“repacking” problem, allowing them to accurately predict

how each amino acid side chain fits into the core of a protein.

Amino acids are the fundamental building blocks of

proteins, so understanding how they are positioned within

proteins is crucial to understanding protein structure. “It

may sound trivial, but it is not because you have to try all

side chain conformations to determine which one will fit.

Our simple model performed as well as the state of the art

software in repacking amino acid side chains,” O’Hern said.

Other approaches include all possible energetic contributions

to protein structure, such as steric interactions, electrostatic

effects, van der Waals attractions, and hydrogen

bonding. In contrast, the O’Hern and Regan team used a

somewhat unconventional approach to modeling proteins

by only considering steric interactions—repulsive forces

that prevent atomic overlaps. In their approach, the amino

acids are modeled as 3D puzzle pieces that are arranged to

fit into the protein core without overlaps. The model can

accurately predict how each amino acid must be positioned

to best fit into the core, just like the way Tetris pieces in

the 1980s video game need to be in certain orientations to

tightly fit together and not overlap.

“Our intention was to determine how far we could go in

protein structure prediction using the simplest model and

only add in additional factors when the simplest model can

no longer predict the experimentally observed data. That

was our idea: a bottom-up approach rather than throwing

everything in at the beginning,” Regan said. “Surprisingly,

we found that our model performs extremely well simply

by avoiding steric overlaps. We didn’t need to explicitly put

in any attraction or hydrogen bonding [or other factors].”

The team discovered that their simple model worked well

on many more amino acids than they anticipated. Even

so, they were able to identify its limits and simultaneously

learn much about the dominant forces that determine protein

structure. This point is well illustrated by comparing

the two hydroxyl functional group-containing amino acids,

threonine and serine, which are typically considered

similar in biochemistry textbooks. Although the position

of the threonine side chain can be predicted by steric interactions

alone, inclusion of hydrogen bonding is required to

correctly position the serine side chain. O’Hern and Regan

propose that this is because the steric interactions of the

additional methyl group on threonine are dominant.

The team has already expanded their original studies to

successfully repack multiple amino acid side chains simultaneously,

and they are working on calculating the energetic

cost of mutating amino acids in protein cores and at

interfaces. The O’Hern and Regan team are poised to apply

their novel approach and combined expertise to design

proteins for sustainability, biomedical, and pharmaceutical


December 2016

Yale Scientific Magazine



materials science


Organic solar cells reach new heights in efficiency


The old solar cell revolution has come to a halt. The types

of solar cells that are now widespread were commercialized

more than 50 years ago. Despite scientific improvements and

increased attention to solar energy, the cost of conventional

solar cells remains high due to the high cost of silicon, which

converts solar energy into electric energy by producing

electrons when light hits the silicon layer in the solar cell.

Understanding the negative effects of fossil fuels and the

necessity for cheaper renewable energy, scientists have worked

on engineering new solar cell designs using different materials.

Currently, in contrast to the inorganic solar cells that dominate

the field, organic polymer solar cells have been getting much

attention due to their mechanical flexibility, large area, light

weight, and low costs in mass-scale production. Organic

polymer solar cells differ in that carbon-based polymer is used,

and not the conventional silicon. The main hurdle that many

researchers face in developing organic polymer solar cells is

their low efficiency. Although slow improvements have been

made, the most common design, single-junction cells with

only one electron-producing active layer, has only an eight

to ten percent power conversion efficiency—far less than the

commercially required efficiency of over 20 percent.

Recently, researchers in professor Andre Taylor’s

transformative materials and devices lab broke through the

10 percent boundary by incorporating multiple cocrystalline

squaraines into the solar cell’s active layer. These cocrystalline

squaraines are organic fluorescent dyes that absorb light

and produce electrons, which are then picked up by the

interlayer to produce a current. Tenghooi Goh, a recent PhD

graduate, explained that their new design, which contains a

greater number of electron donors, allows the solar cell to

absorb a wider range of wavelengths, or types of light. Typical

polymer cells only absorb specific types of light and waste

the light outside that range, resulting in decreased efficiency.

However, Goh said that incorporating more materials is

extremely complicated, as undesirable interactions between

incompatible chemicals can occur. “Mixing things are not as

simple and direct as it may suggest. In a lot of times, if you

mix two incompatible things together…they actually drive

down the efficiency instead of having a positive effect,” Goh

said. Even with the setback, Goh stated this was a path to a

fundamental breakthrough in organic polymer solar cell

efficiency. Thus, the researchers focused on minimizing this

potential destructive interaction.

Previously, Goh and Taylor’s team successfully combined

squaraine and high efficiency polymer component, thanks

to certain properties of the system. Chromophores, or lightsensitive

molecules, transfer energy between an acceptor

and donor molecule through Förster resonance energy

transfer (FRET). Goh referred to FRET as “a mechanism like

photosynthesis, with electrons jumping over non-conducting

gaps.” Therefore, FRET stabilized the final mixture by allowing

energy to be transferred between materials, ultimately helping

the team mix together potentially incompatible components

so that the wide wavelength of light was preserved. The energy

transfer between two squaraines, ASSQ and DPSQ, along with

high performance electron donating compounds in active

layers, helped stabilize the final mixture in the active layer.

The team found that photovoltaic efficiency increased

by over 25 percent on average between solar cells with and

without ASSQ and DPSQ incorporated. In addition, multiple

FRET pairs with rapid and efficient energy transfer were

observed through spectroscopy techniques, which measures

rapid changes in the absorbance of certain wavelengths of light.

Such observations corresponded with the abovementioned

explanation validating that FRET was indeed responsible for

the stable combination of components.

The solar cells have their shortcomings—Goh pointed

out that the organic polymer solar cells are not free from

environmental consequences such as harmful solvent waste.

Even so, this research can provide greater benefits by lowering

costs of production, leading to more widespread usage of

solar cells and decreased fossil fuel usage. The efficiency of

Goh’s team’s solar cell was recorded to be up to 10.7 percent,

widely considered a milestone in efficiency of organic polymer

solar cells. Furthermore, he added that this is before efficiency

optimization by researching and modifying the layers

surrounding the active cell. Goh is very hopeful about future

research. “In the future, if we combine the pinnacle of different

research together, we can probably reach greater efficiency.”


►Research in Andre Taylor’s lab focuses on organic solar cells, which

consist of thin films with unique light-absorbing and energy-transfer

properties that allow them to harness solar energy more efficiently.

10 Yale Scientific Magazine December 2016 www.yalescientific.org




The connection between metabolism and disease outcome




►Yale researchers in Professor Ruslan Medzhitov’s lab found

connections between metabolism and infection that may lead to

new approaches to nutrition for the critically ill.

As winter settles in, perhaps the only seasonal “foods” more iconic

than hot chocolate and s’mores are cough drops and tea. Why do

some people want to weather colds holding steaming bowls of comforting

soup, while others suffer queasy stomachs and leave dinner

plates untouched? The seemingly paradoxical appetite changes associated

with sickness are a well-recognized and evolutionarily ancient

trait, but up until now scientists could only speculate about

their cause and purpose.

Yale researchers led by Ruslan Medzhitov, professor of immunobiology

at the Yale School of Medicine, have found that the answer

to this puzzle lies with the causes of infection. The key insight of

their research is that not all sicknesses are created the same. Fighting

viral versus bacterial infections requires completely opposite

nutritional needs. The findings of their research hold the potential

to transform how healthcare approaches nutrition in illness.

The researchers began by tracing out how anorexia, or loss of appetite,

affects disease outcome in bacterial infections. Researchers

infected mice with Listeria monocytogenes, a common cause of

food poisoning. Mice that were fed during infection died; those

who did not eat lived.

Similarly, the researchers infected mice with influenza virus, the

cause of the flu, and again varied caloric intake. Now the fortunes

were reversed: fed mice survived viral infection while those that did

not eat mostly died. These trends held true not only for infection

but also when the experiments were repeated for bacterial and viral

inflammation—whole body immune activation.

The real story linking nutrition and disease, however, emerged in

the search for the nutrient causing the outcomes. Between protein,

fat, and glucose, only glucose was required to induce the complete

effects of caloric intake. Moreover, blocking glucose utilization rescued

bacteria-infected mice while killing virus-infected mice.

Interestingly, glucose does not change the number of pathogens

or the strength of the immune response. Instead, glucose

shapes the role of metabolism in the body’s tolerance of the immune

response. Metabolism refers to all the chemical reactions

needed to sustain life; use of the immune system comes at a price.

“Depending on the type of inflammation or infection, there

are different metabolic processes that are necessary to survive the

critical illness condition,” Medzhitov explained. Specifically, bacterial

and viral infections generate different kinds of tissue damage

depending on the presence of glucose.

While glucose dominates metabolism in the fed state, during

a fasting state the body begins breaking down fat stores to utilize

molecules called ketone bodies for energy. Bacterial infections

cause an immune response that releases reactive oxygen species

(ROS), or “free radicals,” which kill pathogens as well as damage

host cells. Glucose exacerbates this negative side effect while ketone

bodies from starvation are protective. A parallel exists for

viral infection.

In response to the cellular damage caused by viral infection,

the unfolded protein response (UPR) targets and eliminates cells

producing abnormal proteins. This process is regulated by glucose—without

glucose, this stress-induced response leads to excessive

cell damage.

“We discovered that by blocking glucose utilization in viral infections

we prevented a normal response against viruses and instead

caused a response that ended up being destructive for the

host,” said Andrew Wang, first author and clinical fellow in medicine.

Shockingly enough, the battleground where glucose decided

life and death was not in the heart or the lungs, as may be expected

for a pulmonary illness like the flu, but rather in the brain.

PET scans and tissue studies revealed damage at critical sites in

the brain following bacterial and viral infection. Absence of glucose

increased neuronal damage in viral infections while for bacteria

the opposite was true. The damage was once again linked to

either overactivity of the UPR or overproduction of ROS.

Medzhitov and his team hope that these new findings can

improve nutrition for the acutely ill. Currently, all ICU patients

are fed intravenous liquid food that is 30 to 60 percent carbohydrates,

but Medzhitov’s study suggests that these formulations

need to be adjusted based on the cause of illness. The Yale

team is currently preparing clinical trials that test that premise.

Future studies by the team will continue using mouse models

to study different types of infections, including parasitic and

fungal. Their work will contribute to new holistic models of

healthcare treatment.

“The general implication is that there is a certain wisdom

to the body’s reactions and our preferences during illness, and

many of these are protective,” Medzhitov said. In sickness at

least, we can all benefit from listening to our bodies.

December 2016

Yale Scientific Magazine













environmental science


Surging carbon dioxide levels,

combined with increased radiation

from the Sun, dramatically increased

global temperatures. Ocean surface

temperatures reached upwards of 104

degrees Fahrenheit. Consequently, mass

extinctions occured, with marine and

terrestrial life suffering huge losses in


Until now, the scientific community

has struggled to determine the relative

importance of the two forces that drove

the Permian-Triassic mass extinction

event: volcanic activity and erosion. A

study led by Ryan McKenzie, a postdoctoral

associate at the Yale Department

of Geology and Geophysics, has now

proposed a solution. The study argues

that on the time scale of the past several

hundred million years, volcanoes have

been the principal driver of climate

change. These revolutionary findings are

key to understanding long-term climate

change, and thus, may prove informative

in our present-day combat against global

climate change.

The greenhouse effect

Carbon dioxide (CO 2

) is a double-edged

sword—both vital to life yet potentially

harmful. On one hand, much of Earth’s

plant life depends on CO 2

to produce

food for itself and consumers, like us. At

the same time, increasing CO 2

levels since

the industrial revolution have led to rising

global temperatures, which pose a risk

to the global ecosystem. How does this


The Earth’s atmosphere normally

reflects much of the Sun’s invisible

infrared radiation back into space,

thereby preventing surface temperatures

from becoming too high. However,

when sufficiently concentrated in the

atmosphere, CO 2

can form a blanket of

sorts, which traps some of this radiation

and prevents it from leaking back to space.

Thus, CO 2

is aptly termed a greenhouse


Various processes regulate the levels

of CO 2

in the atmosphere. Volcanic

eruptions, which release gases from the

Earth’s interior, contribute to atmospheric

greenhouse gases and raise global

temperature levels. Chemical weathering,

on the other hand, has the opposite

effect. When CO 2

reacts with water vapor,

carbonic acid is formed. This weak acid

then eats away at rocks and other surfaces.

Other forms of chemical weathering

include burial of carbonate minerals,

along with burial of organic carbon. Thus,

chemical weathering is a CO 2

sink and has

the ultimate impact of decreasing global


The scientific community recognizes

these two forces—volcanism and

weathering—as the principal drivers of

long-term climate change. Due to these

two processes oscillating and changing

pace over time, the content of CO 2

in the

atmosphere is in constant flux. Thus, the

Earth’s temperature has risen and fallen

multiple times within its history, creating

various periods of global warming

followed by global cooling in the form of

ice ages.

The unearthing begins

The study began with McKenzie’s

fascination with the links between climate

change and biodiversity. “I became

interested in the anomalies characteristic

of the Cambrian period,” McKenzie said.

“A lot of species extinction occurred,

which many people attribute to the

Cambrian having one of the highest

atmospheric carbon dioxide levels of the

past six hundred million years.” McKenzie

set out to discover the root cause of this

carbon dioxide flux.

First, McKenzie and team needed to

obtain a record of Earth’s volcanic history.

The Earth is made up of multiple tectonic

plates, which are large pieces of the Earth’s

crust. When an oceanic plate collides

with a continental plate, a subduction

zone is formed. The oceanic plate sinks

deeper into the earth, liberating water in

the process. This water gradually seeps

upward, melting the hot mantle rocks

and forming magma in the process.

This magma finally rises to the surface

and forms a chain of active volcanoes.

Unfortunately, however, it is often difficult

to track the formation of these volcanic

emissions through Earth’s history because

erosion and destruction of volcanoes

obscures the important data. In addition,

the commonly used sea-level approach to

track volcanic rates through time relies

on too many vague assumptions. This is

where zircons come in.

Zircons, otherwise known as zirconium

silicate, are grains of sedimentary rocks

that crystallize from magma. Young zircon

is especially prevalent in the subduction

zones of continental volcanoes, such as the

Andes and the Cascade volcanoes. Zircon

grains are able to withstand high degrees

of erosion, so they represent untampered

records of volcanic activity. Fortunately,

due to zircon’s uranium impurities, the

age of zircon samples can be determined

very precisely through radioactive

isotope analysis. Thus, if one can trace an

abundance of young zircon to a specific

period, this period likely experienced

massive continental volcanic activity.

McKenzie and his team used this property

of zircon to contribute to a precise record

of continental volcanic activity throughout

the geologic timeline. The team could now

accurately map the relationships between

carbon dioxide levels and volcanic activity.


►Dr. Ryan McKenzie stands with a fuming

Mt. Bromo in Indonesia. McKenzie analyzed

sedimentary rock to more closely link volcanic

emissions to long-term climate change driven

by carbon dioxide concentration.


December 2016

Yale Scientific Magazine



environmental science

Mapping the Earth


►Shown is a photo of Mt. Vesuvius in

Italy. Data on sedimentary rocks in the

area contributed to McKenzie’s analysis of

volcanic activity.

“In addition to the scientific literature,

we did extensive work in India, Myanmar,

and North China to fill in the existing gaps

within zircon data sets,” McKenzie said.

Compiling analyses of close to 120,000

zircons, McKenzie’s team found a promising

pattern. The Cambrian, Jurassic, and

Cretaceous periods, which saw high levels

of CO 2

, had very high proportions of young

zircons. In contrast, the Neoproterozoic,

Carboniferous, early Permian, and

Cenozoic periods, when CO 2

levels were

low, had low proportions of young zircons.

“We were able to establish a crucial link

between the oscillations of volcanic gas

activity and the flux of greenhouse gas

levels,” McKenzie said.

The findings of this study fit well into the

geographic framework of continental shifts.

Multiple times throughout Earth’s history,

continents have rifted and amalgamated.

Rifting periods—times when continents

separate from each other—create extensive

subduction zones, which in turn fuel

continental volcanic activity, increasing

zircon and CO 2

abundance. On the other

hand, amalgamation periods—times when

two continents combine—lead to a loss of

subduction zones, reducing volcanic activity

and therefore zircon and CO 2


Thus, the results of McKenzie’s study

could be verified by existing knowledge

about continental shifts. Ultimately, the

techniques used in this project provide

strong proof of the versatility of zircon as

an indicator of volcanic CO 2


Thus, with this innovative zircon

technique, McKenzie’s team has provided

compelling evidence that volcanism has

been an important driver of climate change

over the past 700 million years. “Many of

the specialists in this field were initially

skeptical of this work, so we faced the

challenge of revising popular opinion,”

McKenzie said. While McKenzie and his

group have primarily focused on volcanism

as a key driver, they still recognize the

importance of weathering in contributing

to CO 2

changes. However, they argue that

weathering can be interpreted simply as a

secondary effect of volcanoes. Volcanoes

contribute the primary influx of CO 2


the atmosphere, so they exert the greatest

first-order control over long-term climate


However, volcanoes do not just act in one

direction. Volcanoes result in both global

warming and global cooling. According

to other studies, a fuller consideration of

the effect of volcanism on climate change

must include the long-term effects of

volcanic rocks. Indeed, volcanic activity

can certainly lead to immediate increases

in CO 2

emissions, leading to higher

temperatures. However, during periods of

volcanic dormancy, the volcanoes can be

weathered. This weathering removes great

quantities of CO 2

from the atmosphere,

leading to a global cooling events. Thus,

if considered on a long-term time scale,

each volcano is both a carbon source and

a carbon sink. Indeed, volcanism is a major

force that regulates long-term climate


Future digs

Modern-day, human-driving global

warming is a formidable challenge,

especially given the jump in CO 2


in such a short period of time. But placing

ourselves in geological time, we would see

that global warming has occurred multiple

times since the formation of the Earth’s

atmosphere as CO 2

levels oscillated with

the rise and fall of continental volcanic

activity. Global warming has defined the

landscape of existing biodiversity and

geography on Earth, notably during the

Permian-Triassic extinction when 70

percent of land species and 90 percent of

marine species went extinct. Importantly,

global warming of the past educates us on

the critical interactions that occur between

carbon sources and carbon sinks, which

is a part of present-day human-driven

climate change as well as the climate

variation of the past.

Moving forward, McKenzie’s research

group refuses to be constrained to

one specific goal. “Up until now, the

constraints of our data have been limited,”

McKenzie said. “We hope to look at more

high-resolution data sets and put more

real numbers to this data.” Indeed, to fully

uncover the Earth’s rich history, we must

be willing to constantly dig deeper.



KEVIN BIJU is a sophomore Molecular Biophysics and Biochemistry major in

Morse College. He is the Alumni Outreach Coordinator of the Yale Scientific

Magazine and is interested in the cross-talk between evolution and genetics in

biomedical research.

THE AUTHOR WOULD LIKE TO THANK Dr. Ryan McKenzie for his thoughtful

interview, as well as his research team’s dedication.


M. R. Burton, G. M. Sawyer, D. Granieri Deep carbon emissions from

volcanoes. Rev. Mineral. Geochem. 75, 323–354 (2013).

14 Yale Scientific Magazine December 2016 www.yalescientific.org











December 2016

Yale Scientific Magazine



biomedical engineering

Eyes on the prize, you jump into a river, furiously swimming for the shoreline.

Yet, the second you reach for it, the current pulls you away. This is the

challenge cancer drugs face in the human body: rapid clearance from the

treatment site. The protection and safe delivery of these drugs as they travel

to their target region are important factors in the drug’s success.

In order to combat this problem of rapid

clearance, a group of Yale researchers

has been studying therapeutic drug delivery

through the use of sticky biodegradable

nanoparticles. This technique targets tumors

more efficiently by releasing drugs directly

into the cancerous regions. The Yale study

found that bioadhesive nanoparticles were

capable of remaining in the tumor regions for

long periods of time, demonstrating the potential

for drug delivery through nanoparticles

to fight cancer.

Promising potential

Surgery and chemotherapy are common

treatments for aggressive tumors arising from

the ovary and uterus. Unfortunately, many

patients undergoing these therapies redevelop

tumors or, in the case of chemotherapy,

see their tumors become resistant to the

treatment. For a little over the past decade,

nanoparticles have emerged as a delivery

system for agents such as drugs, targeting a

larger portion of the drug to the tumor and

causing less severe side effects. Nanoparticles

can be engineered to enclose these drugs,

protecting them on their way to the target site

in the body.

Nanoparticle size plays an important role in

the drug’s ability to stay in the region of the

tumor. Too large a particle results in the drug’s

accumulation in the lower abdomen, while

too small of a particle results in a greater

chance of abdominal fluid clearing the drug

out of the system. With successful control

of nanoparticle size, however, nanoparticles

have the potential to allow for safer and more

effective cancer treatment.

A sticky finding

Mark Saltzman, a professor at the Yale

School of Engineering and Applied Science,

is working to harness the potential

of nanoparticles. His team developed

nanoparticles with an outer coating of a

polymer known as hyperbranched polyglycerol

(HPG). HPG nanoparticles are like

branched trees, where each branch is terminated

in water-loving groups that make the

particles water-soluble. This specific HPG

outer coating has proven to be more effective

than even the most highly regarded

particle coating, possessing higher stability,

lower risk of absorption in the body by proteins,

and longer circulation in blood.

Experimenting with nanoparticles of

different sizes, the team found nanoparticles

measuring around 100 nanometers to

be most effective in distributing throughout

the body cavity and dispensing their

encapsulated drug to the target site. The

longer the time in the body, the longer the

nanoparticles will release the therapeutic

drugs into the tumors.

Initially, Saltzman and his laboratory

team worked with non-sticky nanoparticles

that would circulate around the body

for extended periods of time and eventually

accumulate in the tumor. However, Yang

Deng, a postdoctoral associate working in

the laboratory, had an interesting finding.

With organic chemistry techniques, he was

able to make the nanoparticles that stick to

protein-coated surfaces. This was done by

using sodium periodate to transform the

outer coating of the particles, generating

aldehyde groups which are able to form

bonds with other proteins.

Once the team discovered these sticky

particles, the race was on to find suitable

applications. The team was able to invent

a new kind of sunblock that lasted longer

on the skin, taking advantage of how the

nanoparticles could stick to the skin’s top

layer. However, the researchers also realized

they could apply these sticky nanoparticles

to areas such as cancer treatment. This is

where Alessandro Santin came in.

Alessandro Santin, a professor at the Yale

School of Medicine, treats patients with gynecological

tumors with origins in the uterus

and ovaries. In some cases, the tumor

spreads out of the reproductive tract and

into the abdomen, where it would grow in


►A member of the Saltzman lab prepares

reagents for her experiment. The Saltzman

lab has pioneered the use of nanoparticles

for drug delivery.

little clusters of cells that stick to the membrane

surfaces of the abdomen.

Saltzman believed his sticky nanoparticles

were relevant to Santin’s work for

a variety of reasons. “If they’re sticky,

we thought they would stick to the same

membranes that the cancer cells stick to

and they should get all over the abdomen,

and eventually stick to the same surfaces

tumor cells stick to,” Saltzman said.

Saltzman and his team hypothesized that

the sticky nanoparticles they had created

could be applied to deliver drugs to tumors.

16 Yale Scientific Magazine December 2016 www.yalescientific.org

iomedical engineering


Targeting tumors with drugs

Saltzman, Santin, and their team sought

to apply the their invention to cancer therapy.

First, they tested how adhesive the sticky

nanoparticles were compared to nonadhesive

nanoparticles. To do this, they tested both

particles in human umbilical cords, measuring

how long they remained on the luminal

surface. As a marker to quantify the level of

adhesiveness, both particles were loaded with

a dye, which emitted a fluorescent signal corresponding

to the amount of particles in the

region. The results showed that the bioadhesive

nanoparticles had a longer signal time

than that of their non-sticky counterparts.

Now, the researchers could proceed with

loading a drug into these nanoparticles.

Epothilone B (EB), a drug that inhibits

microtubule function, can prevent cancer

cell division . The researchers chose to load

EB into these sticky nanoparticles because

of its efficacy against both ovarian and uterine

cancers. However, the drug comes with

its dangers. “The problem with this drug is

that it’s so potent at killing cancer cells that

it’s toxic,” Saltzman said. Therefore, a way

to introduce the drug to the cancerous region

gradually and more directly is crucial.

Saltzman hypothesized that by injecting

these EB-loaded bioadhesive nanoparticles

into the space between the membranes that

line the abdominal cavity, they could get

the nanoparticles to form bonds with the

proteins on the tissue surfaces. This would

increase the length of time over which drug

would be delivered to the tissue.

Traditionally, nanoparticles injected in

this manner would be quickly cleared from

the abdominal region. With the bioadhesive

nanoparticles, however, the protein bonds

formed with the cells layering this region

held the nanoparticles in place. “We showed

that if you take the particles and you expose

them to a protein-coated surface, they stick

very well,” Saltzman said. If successful, this

would increase the bioavailabilty of the drug.

To test if this indeed happened, the researchers

created a mouse model with human

tumors in the abdominal region to simulate

the environment in a human cancer

patient. They loaded EB into the nanoparticle

vectors and injected them into the mice.

The results were promising: at the end of four

months, the mice subjected to this treatment

had a 60 percent survival rate, whereas only

10 percent of mice survived in the control

groups. “We showed that by putting it in our

bioadhesive nanoparticles, we can keep it in

the abdomen for a long time with very little

toxicity, particularly compared to the drug

itself,” Saltzman said.

Sticking with it

The results of the Yale study offer the potential

for more efficient methods for delivering

drugs to target tumor cells. In the

future, the researchers hope to increase the

efficiency of drug delivery. For example, Santin

is working on designing homing peptides

that would target tumors specifically. “Doing

so may increase the antitumor activity of the

nanoparticle treatment,” Santin said.

Yet, more research needs to be done on the

deliver system used in the study. Saltzman

states that the researchers did not see a specific

immune response when they observed

general markers of immune activation, but

that there are still more areas of concern to

be addressed before the drug delivery system

is ready to be used for cancer patient treatment.

According to Santin, the researchers

are working on an investigator-initiated trial

using the drug. “This clinical trial will help to

understand the potential of this novel agent

in the treatment of chemotherapy-resistant

ovarian cancer,” Santin said.

The results of the team’s work indicate the

potential for bioadhesive nanoparticles as

drug delivery agents to cancerous tumors.

With more research on safer cancer treatment

methods, nanoparticles may become a

powerful weapon in our arsenal against devastating




JESSICA TRINH is a freshman and prospective biomedical engineering major

in Branford. She enjoys volunteering for Synapse, Yale Scientific’s volunteer

outreach program, being the Director of Operations for Resonance, Yale

Scientific’s high school outreach program as well as the Communications

Chair for Yale’s chapter of STEAM.


Alessandro Santin for their time and enthusiasm.


December 2016

Yale Scientific Magazine





When, as a child, we were learning

to tie our shoes, we painstakingly

followed the directions of our

parents or a nursery rhyme. When we were

picking up dining etiquette, we carefully

observed the way others use the utensils.

When we navigate our first day at school

or at the workplace, we are quick to do as

our colleagues do. Imitation is the foundation

of our socialization. But sometimes,

our tendency to replicate others extends

beyond necessary or efficient actions, a

phenomena scientists call overimitation.

Overimitation is a human-specific form

of social learning in which we faithfully

copy irrelevant actions. It is largely responsible

for the ability of our species to

have so many rich cultural traditions and

advanced technology because we are able

to handle more information by accepting

the way that other people behave.

The purpose of a recent Yale study was

to explore whether dogs and dingoes also

display overimitation. There are many

reasons to expect that dogs might follow

human cues. For one, they follow human

gaze and directions, and studies have repeatedly

shown that dogs are prone to look

for a human lead. Surprisingly, the results

revealed that canines do not display this

behavior, suggesting that humans are the

only species to demonstrate this behavior.

The merits of overimitation

One of the most obvious drawbacks of

overimitation is that it can cause a person

to be misled. However, the benefits are

much greater. Consider activities as mundane

as washing your hands or brushing

your teeth. It is important for health reasons

that young children replicate these

behaviors at a young age, regardless of

whether they understand the reasoning

behind the action.

Thinking even further back, consider the

Stone Age. Learning how to start a fire may

have been more likely to persist because

individuals had a tendency to overimitate

the demonstrator. A stick must be spun

quickly for a long time to create a spark. If

the learner did not have the inclination to

continue spinning the stick, despite its apparent

uselessness, then they may not have

been able to start a fire. Without the ability

to start fire, our species would not have

moved on to designing simple machines

and advancing technology.

Overimitation may also be particularly

responsible for the depth and longevity

of human culture. Other species do not

have traditions. Humans maintain rituals

by passing their knowledge on through

generations, although it might not be

necessary or relevant. Consider religious

practices or decorative dressing that have

survived for centuries; without overimitation,

these practices could have been discarded

as ornamental and extraneous.

A drawback of overimitation is that it

can sometimes constrain our exploration.

Overimitation may dampen human trial

18 Yale Scientific Magazine December 2016 www.yalescientific.org

cognitive science




ANNA WUJCIAK is a senior Biomedical Engineering Major in Saybrook

College. She works in Jay Humphrey's lab studying cardiovascular

biomechanics and is a member of the Women's Club Water Polo Team.

THE AUTHOR WOULD LIKE TO THANK Laurie Santos, Angie Johnston,

and Paul Holden for their time and passion for their research.


►Dingoes look very similar to dogs. Yet,

there are stark differences, both physical and

psychological, between the two species of



Smith, B. & Litchfield, C. (2010). Dingoes (Canis dingo) can use human social

cues to locate hidden food. Animal Cognition, 13, 367-376.

and error behavior, while other species are

more inclined to engage in this behavior

because they do not automatically accept

the information others have given them.

Canine independence

At the Canine Cognition Center at Yale,

professor Laurie Santos, PhD candidate

Angie Johnston, and research assistant

Paul Holden explored whether dogs displayed

overimitation. Dingoes were studied

similarly at the Dingo Discovery Center

(DDC) in Australia. Dogs were then

compared to dingoes, a closely related but

non-domesticated species, in an effort to

explore the role of domestication.

In four different trials, animals were

tasked with opening a box to retrieve the

treat inside. These boxes, which Holden

designed at the Yale Center for Engineering

Innovation and Design, were equipped

with a lever on the side and a treat underneath

a flip lid. Although the flip lid was

necessary for getting the treat, the lever

was completely ineffective. At the beginning

of each test, a human completed both

the relevant and irrelevant steps in the

process of opening the box three times

as a display for the animal. The box was

considered solved if the animal was able to

retrieve the treat.

Results showed the dogs and dingoes

filtered out the irrelevant lever action,

even though it was demonstrated to them.

With each of the four tries the test subjects

had with the box, the rate of using the irrelevant

lever decreased and the rate of

solving the box increased. This indicated

that both species of canines were learning

which actions were relevant and which actions

were not based on their own learning


Although neither canine species displayed

overimitation, there were differences

in the two species. “Dingoes were

using the lever less than dogs,” Holden

said. “At first glance, dogs and dingoes

look quite similar, but they’re actually very

different.” Dingoes are clever problem

solvers because they are more attentive

and independent, Johnston added. Dogs

have become domesticated over time due

to their companionship with humans, and

therefore they tend to look toward their

human more often when a problem arises.

As dogs have come to rely on humans

more, they may have also become less

adept at independent problem solving,

which might explain why they used the lever

more frequently than dingoes.

A human behavior

The brain mechanism behind overimitation

is not yet well understood. Although

it is outside the scope of Santos’s psychology

lab, other researchers are exploring the

complex brain processes that control decision-making

and overimitation.

Unfortunately, outside of dogs, dingoes,

and chimpanzees, not many species have

been tested for overimitation behavior.

Dogs were selected as a species to study

specifically at Yale because they are highly

social. Chimpanzees have previously been

studied because of their high intelligence

and social tendencies. Scientists assume

that since the closest relative to the human,

the chimpanzee, does not display

this behavior, it is human specific. The absence

of overimitation in chimpanzee behavior

also indicates that humans evolved

this trait sometime within the last seven

million years since our species diverged.

Corvid species, which include birds and

crows, may be valuable to explore next,

as they are also very intelligent creatures.

“Most animals exhibit innate behaviors

that they’ve developed over many years

of evolution,” Johnston said. For example,

think of squirrels who bury nuts every


If not from overimitation, how do other

species pass on information? Johnston

explained that animals learn through observation,

as opposed to the intentional

instruction method of passing information

like humans. Some information, such

as locomotion, is instinctual. “It’s not that

other animals can’t imitate, it’s just that

they only do it when they need to, whereas

humans tend to do it much more often

than necessary. Animals are better at

prioritizing the information they really

need,” Johnston said. While humans have

complex technology and intricate cultural

practices, other species have more basic

tasks that they can typically address on

their own. Our species is the only one

with a culture that forces us to rely on others.

There are two general hypotheses about

the driver of human overimitation. The

first is that humans can’t help but overimitate.

The second is that humans assume

that the actions they observe are the culturally

appropriate way to behave. “My

thoughts are that it’s really a combination

of both of these hypotheses that cause humans

to overimitate,” Santos said.

Overimitation, for better or worse,

seems to be a distinctly human behavior.

It assists our species to pass on complex

cultural information and maintain a high

degree of advanced technology. It certainly

appears that overimitation is one of the

reasons that humans differ so greatly from

all other species.


December 2016

Yale Scientific Magazine



evolutionary biology








by Andrea Ouyang | art by Emma Green

One of the miracles of science is its

ability to extend human memory. As

our computational and technological

capabilities expand, the searchlight of history

broadens our vision into our past and uncovers

new revelations and mysteries alike. Few fields,

then, provide more fascinating applications of

science than the tireless efforts to trace the evolutionary

relationships of creatures, dead and

alive, who populate the tree of life.

Enter Tullimonstrum gregarium.

In the 1950s, Francis Tully discovered a bizarre

fossil in Mazon Creek, Illinois—a site

known for the quality and diversity of creatures

preserved in its deposits, formed 300 million

years ago in the Carboniferous period. For half

a century, no one was quite sure what to make

of the fossil, dubbed the Tully Monster and

declared the state fossil of Illinois in 1989. This

oddly shaped sea creature did not fall under

any neat category, with its pair of cuttlefish-like

fins, long proboscis, and small sharp teeth. Indeed,

paleontologists variously suggested the

organism belonged to animal groups ranging

from wormlike animals to mollusk-like creatures

and even to fish.

A Yale-led research team, led by then graduate

student Victoria McCoy, has at last identified

the Tully Monster. Combining morphological

analysis and close examination of

features resulting from the fossilization process,

the researchers found that the Tully Monster

was most likely a vertebrate with lamprey-like

features. The study, published in April, has put

to rest the mystery of the Tully Monster while

also opening new avenues to further explore

the life of this extraordinary animal.

The exemplary enigma

For a long time, the phylogenetic origins of

the Tully Monster were unknown.

“It’s a classic example of what we generically

call a ‘problematic fossil,’ which is a way of

saying we don’t really know, or didn’t know,

what it was or where it sat in the grand scheme

of things,” said co-author Derek Briggs, a professor

of Geology and Geophysics at Yale and

curator at the Yale Peabody Museum. "There

were a number of these problematic fossils in

older rocks, particularly during the Cambrian

explosion 530 million years ago," Briggs said.

This explosion of life saw the evolution of

animals that would look alien to us today, but

which were actually early offshoots of lineages

leading to modern groups. Subsequently, most

of these peculiar-looking fossils disappeared,

replaced by groups more recognizable to paleontologists


“What we see in the fossil record later on are

generally things that we can identify, or at least

relate to living groups,” Briggs said. “The Tully

Monster was one of those exceptions.” Present

in Carboniferous rocks dating from about 300

million years ago, the Tully Monster was considered

one of the problematica, or fossils that

are difficult to classify. Besides its aquatic environment,

no one really knew anything about it.

Previous solutions to this “problem of the

problematica” included simply classifying the

problematica as phyla that went extinct—in

other words, they were considered a long, divergent

branch of the evolutionary tree of life

that had been cut short, rather than a branch

more closely nested in ancestral animal groups.

Though modern computational approaches to

20 Yale Scientific Magazine December 2016 www.yalescientific.org

evolutionary biology


classification have resolved lingering questions

about many previously problematic fossils, the

Tully Monster had largely resisted phylogenic


The mission begins

In 2015, McCoy was leading the Briggs lab

group’s annual project, on which all the researchers

in the group were collaborating.

“The Field Museum independently thought

that they would want someone to look at the

Tully Monster, so I independently met with

the Field Museum and curators and collection

managers at the Geological Society of America

meeting,” McCoy said. “We both kind of

simultaneously said we’d like to work on the

Tully Monster.”

The Field Museum, in Illinois, is the closest

major museum to Mazon Creek, where the

majority of Tully Monster fossils have been

unearthed. Its close relationship with local collectors

has helped it acquire a vast collection

of Tully Monster fossils—at over 2,000 specimens,

the largest in the world—which made it

the ideal location to work on the project, according

to Briggs.

It’s elemental, not elementary

Part of what helped the Yale team succeed

where others had failed was meticulous attention

to detail. The fossilization process, though

permitting long-term preservation, can make

morphological features difficult to decipher as

organisms decay and fossilize.

In total, the researchers examined around

1,200 Tullimonstrum specimens, organ by organ,

for general morphological features. As an

example, at the end of the Tully Monster’s proboscis,

the team counted and measured teeth

structures and studied how they were situated

in the Tully Monster’s claw structure. They also

looked at features such as whether the eye bar

sat at the top of the head or went through the

center of the body.

The second component of the research involved

studying features of preservation where

the Tully Monster was discovered. The fossils

were preserved as a discolored film on surrounding

rock where the organism had been

buried, and what appear to be morphological

features sometimes are merely discoloration

from the fossilization process.

This combined analysis of morphological

and preservational features in the Tully Monster

helped McCoy and the team conclude that

the Tully Monster had a notochord, a cartilaginous

skeletal rod and evolutionary precursor

to the spine that classified the fossil as vertebrate.

The researchers had noticed a long line

running down the middle of specimens, previously

identified as the gut of the organism.

While it was entirely possible that the line was

the fossil imprint of either a gut or a notochord,

examining preservation in conjunction with

morphology allowed the researchers to determine

which feature it was.

To further test the vertebrate hypothesis,

the researchers took specimen samples to Argonne

National Laboratory for synchrotron

analysis, a technique that allowed the team to

determine which elements in a sample were

enriched, what differences existed in the elemental

composition of different tissues, and

when they were preserved in the fossil. The

synchrotron data indicated that Tully Monster

eyes were often preserved in pyrite mineral, a

preservational feature shared only by the fish

—the other chordates—at the fossil site. This

was particularly strong evidence that the Tully

Monster was preserved similarly to fish, rather

than other proposed animal groups, such as

worms or mollusks.

The researchers also found that Tully Monster

teeth had a distinct composition from that

of the rest of the bifurcated, claw-like structure

at the end of its proboscis. This discovery also

pointed to chordate affinity, since arthropods,

another previously proposed position for the

Tully Monster, have teeth-like spikes made of

the same material as their claw. Fish teeth, on

the other hand, are biomineralized—minerals

were produced in those tissues to harden them,

making teeth tissue distinct from the rest of the

fish’s mouth.

The teeth were pyritized, or replaced with

iron sulfide, suggesting they were composed

of sulfur-rich material, but not biomineralized,

in contrast to most cartilaginous fishes,

like sharks, whose fossils typically contain

calcium or phosphate compounds. The sulfur-rich

soft tissue was likely made of keratin,

a sulfur-containing protein that is the main

component of fingernails. Interestingly, keratin

is also a component of hagfish and lamprey

teeth, which do not biomineralize, so the

researchers could conclude not only that the

Tully Monster was a chordate, but also that

it preserved similarly to soft-bodied fish like

lampreys and hagfish.

A fossil’s future

Future studies of the Tully Monster include

understanding its ecology and interactions

with its environment and other organisms of

the Carboniferous. It is unknown whether it

was a parasite (like modern lampreys) or a

scavenger, an ambush predator or one that

could sustain periods of continuous swimming.

Its many morphological oddities make

it particularly compelling to study, according

to McCoy.

Luckily for researchers, the Field Museum

recently acquired more Tullimonstrum fossils,

a collector’s gift that could provide researchers

the opportunity to explore and refine

their findings against the new specimens. An

important step, according to Briggs, is to examine

the new collection and see whether it

supports the team’s conclusions. While the

Tully Monster may be long dead and gone,

the story of its existence is sure to fascinate

generations to come.



ANDREA OUYANG is a sophomore and prospective MCDB major in

Davenport College.

THE AUTHOR WOULD LIKE TO THANK Dr. Victoria McCoy and Professor

Derek Briggs for their time and enthusiasm in speaking about their work.


Clements, T. “The Eyes of Tullimonstrum reveal a vertebrate affinity.” Nature

532, 500-503, 2016.

Richardson, E.S. “Wormlike Fossil From the Pennsylvanian of Illinois.”

Science 151 (3706), 75-76, 1966.


December 2016

Yale Scientific Magazine





the Quantum Computing Toolbox

By Noah Kravitz

Art by Yanna Lee

22 Yale Scientific Magazine December 2016 www.yalescientific.org



In 2011, Canadian tech company

D-Wave stunned the world by announcing

that it would market a

functioning quantum computer. Soon,

companies ranging from Google to NASA

bought versions of the device, and scientists

began scrambling to evaluate what

potentially was the biggest technological

breakthrough of the century. One

third-party test, in which the new quantum

computer solved a complex math

problem 3,600 times faster than a cutting-edge

IBM supercomputer, seemed

to substantiate D-Wave’s claims of quantum

computation. Other tests found

no evidence of quantum activity at all.

Quantum computing, an idea which has

captivated physicists and computer scientists

alike since its conception in the 1980s,

has proven difficult to realize in practice.

Because quantum computers rely on the

uncertainty built into the laws of quantum

physics, they are extremely sensitive to

their environments. A small imperfection

in even a single component of the design

can be devastating. One technical challenge

is that heat energy can disrupt the

fragile quantum states, so quantum technology

is usually cooled almost to absolute

zero (-273 degrees Celsius). D-Wave’s

quantum computer is small enough to

hold in the palm of your hand but has to

be housed in a 10-foot-tall refrigerator.

Yale researchers, led by Professor of

Electrical Engineering and Physics Hong

Tang, have developed a new version of a

device called a piezo-optomechanical resonator

that could allow quantum computers

to operate at higher temperatures. The

paper, which is co-authored by graduate

students Xu Han and Chang-Ling Zou, describes

an improved method of connecting

information in physical and electrical

domains. This advance could be used as

the basis for reliable memory storage for

quantum computers—an important step

towards stronger quantum computing.

From Schrodinger’s cat to national


Quantum computing fundamentally

differs from classical computing in that

it relies on the non-intuitive quantum

properties of light and matter. In familiar

classical computation, information is

stored as bits which can take on the values

0 and 1—they are simple on/off electrical

switches, and it is easy to check their

positions. The computer then performs

tasks using sequences of logical operations

on the bits. For example, it might

say that if bit A is 0, then bit B should

be set to 0, but if bit A is 1, then bit B

should be set to 1; or that bit C should be

set to 1 only if bits A and B are different.

In quantum computing, by contrast, the

situation is not so straightforward. First of

all, information is stored in qubits (short

for “quantum bits”) which have more than

two possible values: 0, 1, and a combination

of 0 and 1. These qubits are particles

with distinct measurable quantum states

corresponding to “0” and “1,” but one of

the principles of quantum physics is that

sometimes we can predict the result of

a measurement only in terms of probabilities.

So in quantum mechanics, even

though sometimes we might know that

we will always measure the particle as “0,”

there can also exist a scenario in which

there is a 50 percent chance of finding the

particle in the “0” state and a 50 percent

chance of finding it in the “1” state. The

surprising part is that, mathematically

speaking, the latter particle is actually in

both states equally until we measure it as

being in one or the other, and it is meaningful

to think of such a qubit as having

value ½ representing a “mixed” state even

though ½ is not a possible measurement.

Another useful property of quantum

mechanics called entanglement links the

measurements of different particles. For

example, if particles A and B are entangled,

then we might know that whenever

we measure both particles, we will get one

“0” and one “1.” In this case, measuring

one qubit immediately determines the

value of the other, and it is possible to use

this property to “teleport” information!

The unique logical underpinnings of

quantum computation allow quantum

computer to approach old problems in

new ways. Since qubits are more complex

than regular bits, quantum algorithms are

often more streamlined than their classical

counterparts, especially when searching

for optimal solutions to problems. For

example, if we want to find a car that is

hidden behind one door out of a million, a

classical computer would have to check the

doors one by one, and, in the worst-case

scenario, it would have to make a million

queries. A quantum computer, by contrast,

can use a probabilistic algorithm to find

the car in at most only a thousand queries.

Quantum computation has potential applications

in many problems that would

take classical computers longer than the

age of the Earth. In the best-known example

of this principle of “quantum speedup,”

computer scientists have created a quantum

algorithm that can factor large numbers

(essentially a needle-in-a-haystack

problem like the car example above) exponentially

faster than is possible for any

classical algorithm. Although this problem

may not seem very exciting, it in fact underlies

many more complex processes such

as cryptography. Similar principles apply

to choosing cost-effective combinations of

building materials and even to identifying

keywords for news articles. Unsurprisingly,

quantum computation is often the best

way to model complex natural systems.

We have made significant progress over

the past few decades towards meeting the

challenges of quantum computing. As early

as the mid-1990s, we have manipulated

qubits and written codes to correct spontaneous

errors in quantum computers. In

the 2000s, we demonstrated long-distance

entanglement. In 2013, Hong Tang and his

team contributed to the corpus of knowledge

when they determined a method

for measuring quantum systems without

permanently altering them. Now, in 2016,

the Tang Lab at Yale has once again expanded

the quantum computing toolbox,

this time in the stubbornly challenging

field of information storage and transfer.

A new approach to quantum memory

You probably carry around in your

pocket a crucial piece of the new Yale

device: Smartphones contain the materials

that Tang and his team used to bridge

the mechanical-electrical gap. Piezoelectrics

are materials, usually crystals, that

accumulate charge when compressed,

twisted or bent. For instance, when

a piezoelectric sheet is creased, a net

negative charge forms at the fold, and

net positive charges form at the ends.

Conversely, when an external magnetic

field causes charges in a piezoelectric to


December 2016

Yale Scientific Magazine





►Professor Hong Tang (right), along with graduate students Chang-Ling Zou (left) and Xu Han

(not pictured), developed a piezo-optomechanical resonator that has applications to quantum

memory storage.

move, the object responds by changing

shape physically. In this way, vibrations

in physical objects and electrical fields

can easily be connected, or, as physicists

say, coupled. Piezoelectrics in smartphones

often power tiny speakers— they

convert electrical signals into sound

waves, which arise from physical pulses.

The Yale piezo-optomechanical device

consists of a pair of tiny resonators:

a silicon wafer and a wire loop situated

above it. “It is useful to think of a resonator

like a tuning fork because it responds

most powerfully to a particular resonant

frequency,” said Han, an electrical engineering

Ph.D candidate who worked on

the project. The two ends of the wire

loop do not quite connect, so electrical

charges tend to bounce back and forth

around the circle, which functions as an

electrical resonator in the microwave region

of the electromagnetic spectrum.

The wafer, which is about as thick as five

sheets of paper, functions as an acoustic,

or mechanical, resonator. This resonator

is coated with a thin layer of aluminum

nitride, a piezoelectric material,

which facilitates the exchange of oscillations—and

energy— between mechanical

and electrical components. “If you

want to transfer information between

two systems, it is necessary to have an

efficient coupling mechanism,” Han said.

The idea of coupling between mechanical

and microwave electrical domains

is not new; the Yale team’s innovation

is achieving stronger coupling on a

smaller scale. The key is using resonators

with a higher frequency: Whereas

other designs have used frequencies on

the order of a few million oscillations

per second, the Yale design runs at ten

billion oscillations per second. As a result,

the device is solidly in the so-called

strong-coupling regime —meaning that

the rate of information transfer is greater

than the natural energy dissipation

rates of the individual systems—and

transmitted signals are clearer and longer-lasting.

Yet high frequency comes at

the cost of increased construction difficulties.

“Since the device is small, it

is more susceptible to perturbations in

the environment,” Tang said. As a result,

the design carefully balances considerations

of compactness and robustness.

The researchers believe that applications

of their breakthrough lie mostly in the far

future. “This is fundamental research, so

it’s not immediately pertinent to daily life,”

Han said. Instead, the piezo-optomechanical

resonator’s real value is as a component

of more complex systems. Because of the

strong coupling achieved, it is well suited

for quantum uses where “noise” from ambient

heat (analogous to TV static) would

otherwise be disruptive. “For high-frequency

devices, the temperature requirement is

not as low,” Han said. Chang-Ling Zou, a

postdoctoral student in Tang’s lab, hopes to

develop this strength into a basis for quantum

memory storage, which is currently

unfeasible at most temperatures. Small

vibrating crystals would serve as physical

memory, and the resonators would convert

between these crystals and the computational

part of the computer, which would

likely operate in the microwave domain.

The Yale team is also looking to incorporate

visible light into their design. “The

next step is integrating an optical resonator

and using the acoustic resonator

as an intermediary between microwave

and optics,” Han said. Accomplishing

this feat could improve computer signal

processing, radio receiving efficiency,

and information transmission across

long distances via optical fiber cables.

Given its versatility, the piezo-optomechanical

resonator may find its way into

all kinds of applications. From analyzing

the stock market to sending trans-Atlantic

messages, you can expect to hear more about

this small device in big-time situations.



NOAH KRAVITZ is a freshman in Calhoun College. He is interested in

studying math, music, physics and philosophy.


Professor Hong Tang for explaining their research.


Li, Mo, W.H.P. Pernice, and H.X. Tang. “Ultrahigh-Frequency Nano-

Optomechanical Resonators in Slot Waveguide Ring Cavities.” Applied

Physics Letters 07 (2010).

24 Yale Scientific Magazine December 2016 www.yalescientific.org

evolutionary biology



Opening the David Friend Hall at the Peabody Museum


Nearly every observed galaxy has a giant black hole at

its center. Step into the Peabody’s new David Friend Hall

and it might take a minute for your eyes to adjust to the

darkness—and then another hour for your mind to adjust

to the dazzling marvels that surround you. From the

2000-pound, single-quartz crystal from Namibia to the

30-million-year-old sandstone concretion with smooth

undulating curves, each object in the hall aims to wows

visitors. Curators carefully chose every detail—from the

lighting to the case design—to showcase the world-class

treasures here in New Haven, Connecticut.

Dramatic lighting highlights specimens with dazzling

clarity and draws attention to the kaleidoscope of colors

filling the hall. This focus on showmanship was well

developed; David Friend (YC ’69), who donated three

million dollars for the exhibit, hoped to fill people with

a sense of wonder. “The function of a museum is not so

much to teach but to inspire a desire to learn,” Friend

said shortly before he cut the ribbon to officially open

the exhibit.

It is fitting for Yale to host this transformative mineral

exhibit, since modern mineralogy originated here. Just

as Carl Linneaus brought order to the natural world

by classifying plants and animals, Yale professor James

Dwight Dana brought order to the world of rocks and

minerals with a classification scheme that is still used

today. Geology has always been strong at Yale; Benjamin

Silliman, Yale’s first science professor, started the

American Journal of Science in 1818. Not only is the AJS


►Prominent members of the Yale and New Haven communities

attended the ribbon cutting ceremony with David Friend (YC

’69). The opening speeches set the tone for an exhibit that

would wow visitors.

the oldest scientific journal in the United States, it is one

of the most influential journals in the fields of geology

and mineralogy.

The Peabody Museum continues to challenge the

expectations for natural history museums with the David

Friend Hall. Rather than bombard visitors with text, the

exhibit isolates the singular beauty of sparkling minerals.

Educational materials for the displays are captured by a

smartphone application, where visitors can access and

browse background information. In addition, the gallery

will feature rotating exhibits: many gems are on loan from

private collectors, so new treasures can be featured in the

future. Although art galleries often feature loaned art,

the David Friend Hall is one of the first natural history

exhibits to do the same.

And the treasures are dazzling, indeed. Beside the

2000-pound quartz stands a giant geode from Uruguay,

completely encrusted by deep purple amethyst shards.

Nearby, a white-board-sized fossil of a fan-like frond

flanked by ancient fish demands your attention. The

crystals, ranging from a five-by-four-foot fluorite from

China to miniature “thumbnail” specimens in a display

case, vary in size, shape, and geographic origin. “If

you go around and look at every single crystal, they’re

from all over the world,” said Dave Skelly, the Director

of the Peabody Museum. Stefan Nicolescu, head of the

Peabody’s minerology collections, guided the selection

of minerals, consulting private collections throughout

the region and selecting specimens for their wow factor.

“The interest is to stir curiosity and to make people want

to know more about these things,” said Nicolescu.

The recent ribbon cutting ceremony thoroughly

explored this theme of curiosity and inspiration: “The

goal is to capture people’s imagination, particularly the

imaginations of budding young scientists, to get them

fascinated by the natural world,” said Jay Ague, chair of

Yale’s Geology and Geophysics department. They hope

to reach far beyond New Haven. Since its conception

150 years ago, the Peabody Museum has served as the

archetype for many natural history museums. The

curators of the David Friend Hall hope that their setup

will also set an example that diffuses globally.

For New Haven residents and Yale University students,

the hall breathes new life into an already brilliant

collection of natural history. “I think this exhibit will

certainly bring more students up [to the Peabody],”

said Dean Jonathan Holloway. The brilliant jewels may

prompt curiosity for understanding our world.


December 2016

Yale Scientific Magazine



human evolution




The female orgasm has always provoked biologist’s curiosity.

From an evolutionary perspective, the male orgasm has a

clear purpose: it is required for ejaculation and the subsequent

transfer of sperm. Explaining the female orgasm is more difficult,

since fertilization and reproduction will occur whether

or not a female orgasm occurs. In fact, female orgasms occur

more frequently during masturbation or homosexual intercourse

than during heterosexual intercourse. Natural selection,

the driving process of evolution, favors traits that yield a

survival or reproductive advantage to a species, so why has the

female orgasm evolved if it provides no apparent survival or

reproductive advantage?

Yale’s Günter Wagner and his colleague, Mihaela Pavlicev,

recently identified that the female orgasm—like the male orgasm—predates

the primate lineage. Thus, the human female

orgasm likely evolved from an older, functional trait and was

passed down through generations. Here, we will explore the

history of this trait and how its function has changed since it


For species whose ovulation is induced by copulation, it is

thought that orgasms stimulate the release of hormones such

us prolactin and oxytocin, triggering ovulation. In contrast,

women are spontaneous ovulators. Although they too release

prolactin and oxytocin during orgasm, their ovulation cycles

do not depend on these hormones.

Differences in ovulation cycles between species may have

evolved in tandem with anatomical differences. Wagner’s

study predicted that for spontaneously ovulating animals, the

distance between the clitoris and the vaginal opening can be

larger than for animals with copulation-induced ovulation,

whose clitorises should be within (or near) their vaginal openings.

In accordance with this prediction, external, non-penile

stimulation of the clitoris is required for many women to

achieve orgasm, because the clitoris is relatively far from the

vaginal canal.

Looking deeper into anatomical evolution, Wagner and his

colleague studied databases of veterinary literature comparing

female animal anatomy. In spite of a dearth of accurate studies

on female genitalia, they found enough data to support

their hypothesis. They discovered that in most species of reptiles,

birds, and mammals, a single canal is used for urination

and copulation. In these animals, the clitoris is often within or

nearby the copulatory canal. However, in the ancestors of humans

and other primates, the urogenital canal–the canal used

for urination and copulation–shortened until the urethra became

an entirely independent canal. As these two canals separated,

the distance between the copulatory canal and the clitoris

also increased.

Wagner realized copulation-induced ovulation occurred

most often in animals in which the clitoris was located within

or near the copulatory canal. Spontaneous ovulators, in contrast,

evolved to separate the clitoris and vagina. Together,

this information suggests that the common ancestor of many

mammals was a copulation-induced ovulator. However, as

spontaneous ovulation evolved in humans and primates, clitoral

stimulation as a means to induce ovulation became useless,

and evolution distanced the clitoris from the copulatory canal.

Though researchers have yet to prove that copulation-induced

ovulation is triggered by clitoral stimulation and orgasm,

the theory is pharmacologically testable. Future studies

could use drug-induced anorgasmia–the inability to achieve

orgasm–and the subsequent monitoring of an animal’s ovulation

cycle, to begin to answer this question.

In the context of spontaneous ovulation, clitoral stimulation

leading to female orgasm may serve another purpose. For example,

orgasm might improve pair bonding. Wagner emphasized

that, although the female orgasm may not make a clear

contribution to reproductive fitness, this does not reflect its

modern importance. “Maybe the way to think about the female

orgasm is as a type of art . . . which doesn’t have to have

a specific purpose but still has value,” Wagner explained, referencing

the way we value our ability to admire art despite its

non-existent connection with reproduction or fitness.

Wagner’s research has powerful and liberating implications

for both men and women, freeing them from preconceived

notions about the meaning of female orgasm during heterosexual

intercourse. The research will hopefully discourage unhealthy

notions, such as Sigmund Freud’s labeling of the clitoral

orgasm as “infantile,” or theories that claim the female

orgasm occurs more frequently with higher-quality males as

a mechanism for retaining larger quantities of their sperm.

Wagner and Pavlicev explain the difficulties associated with

achieving female orgasm during heterosexual intercourse as

an effect of evolution without any intrinsic implications regarding

the male’s value.


►The female orgasm releases the hormones prolactin and

oxytocin, which are theorized to trigger ovulation and fertilization.

26 Yale Scientific Magazine December 2016 www.yalescientific.org

materials science






►Marine debris, the result of human plastic waste, on the

beaches of Dar es Salaam, Tanzania. These large plastic

pieces are shredded by weathering into more dangerous, easily

ingestible microplastics.

The dangers of oceanic plastic pollution are well known:

throughout social media, trending videos portray turtles

trapped in plastic netting and decomposed birds with

plastic in their stomachs. The reality of plastic pollution is

heart-wrenching, and researchers are continuously producing

more evidence to demonstrate the extent of the problem.

Discoveries from the past 20 years have revealed that organisms

living in shallow waters and the middle layers of

the ocean ingest copious amounts of plastic. Most recently,

however, researchers at the University of Oxford discovered

that deep-sea organisms—rarely studied in this context until

now—are also consuming plastic at alarming rates. Their

finding is particularly concerning because it demonstrates

the vast impact of human plastic pollution: our trash has

reached one of the Earth’s most remote and fragile environments.

Conducted primarily by Michelle Taylor and Lucy Woodall

at Oxford, the research concentrates on microfibers, the

most common type of microplastic found in the environment.

Microplastics are small plastic pieces, usually less than

five millimeters in diameter (the width of a thumbtack), that

are created when larger plastic debris is weathered and broken

apart, while microfibers are a sub-class of fiber-shaped

microplastics that often come from fibers on clothing. They

are particularly dangerous for aquatic wildlife because they

can easily get trapped in an animal’s digestive track or gills,

lessening its feeding ability, damaging its digestive track, and

often leading to its starvation. Organisms also face contamination

by concentrated organic pollutants and metals that

are harbored by the plastics.

Taylor and Woodall’s research was inspired by earlier findings

that discovered microplastics in deep-ocean sediments.

“We were discussing what deep-sea animals eat, which is

mostly particle matter falling from shallower waters—something

called marine snow, and if this snow would have microplastics

in it,” said Taylor, a senior postdoc at Oxford.

The researchers explored deep-sea organisms in the equatorial

mid-Atlantic and southwest Indian Ocean by sending

a robot to the seafloor to scoop up organism samples. Reaching

such depths was a major challenge, but the research team

had access to a UK research ship and the Remote Operated

Vehicle Isis robot, which can reach depths of 6000 meters.

From their collected samples, they studied three distinct

phyla: Cnidaria (such as jellyfish and corals), Echinodermata

(such as starfish and sea cucumbers), and Arthropoda (such

as crustaceans). The researchers recorded the depth where

each organism was found, the type of microplastic it had interacted

with, and the microplastic’s location on or within

the organism. Most of the studied organisms, such as squat

lobsters, corals, and sea cucumbers, contained microplastics

in their oral areas, stomachs, and gills, indicating that

the plastics were either ingested or inhaled. For example, the

researchers found microplastics made of polypropylene, a

polymer that can carry compounds such as DDE, a pesticide.

The logical follow-up question is what we can do about human

plastic pollution, but the answer is difficult because of

the sheer prevalence of plastics in daily life. “It’s surprising

how much clothing we wear is made up entirely of acrylic or

polyester—I challenge you to check yours now,” said Taylor.

Scientists are currently designing safer plastics. Paul Anastas,

the Director of Yale’s Center for Green Chemistry and

Green Engineering, says research should focus on developing

biodegradable plastics that do not persist in the environment.

“There is a worldwide network of people producing

these solutions, and they need to be implemented much

more rapidly.” The twelve principles of green chemistry include

designing safer chemicals, using safer solvents, and reducing

energy use.

Governments, too, are taking measures to reduce the

amount of plastic waste released into marine environments.

In December of 2015, President Obama signed the Microbead-Free

Waters Act, banning the cosmetics industry from using

plastic microbeads, such as the exfoliating beads in facial

soaps that are washed down the drain and released into the


The public also has a responsibility to keep plastics out of

our oceans. We can trash the “throw-away” mentality that

leads us to use disposable plastic cups and utensils and opt

for reusable options like cloth bags at the grocery store. In the

meantime, Taylor hopes to see further research that probes

deep-sea plastic pollution.


December 2016

Yale Scientific Magazine




insight into




art by YANNA LEE

28 Yale Scientific Magazine December 2016 www.yalescientific.org


lizard escaping from a predator can lose its tail as a defense

mechanism—while the detached tail writhes on the ground

and confuses the predator, the lizard scurries away. During

the following months, the lizard grows back a new tail. How does

this regeneration occur? The answer lies in the behavior of stem

cells, specialized cells that can both renew themselves and generate

various other cell types.

Humans have stem cells, too, although they behave differently

from those in the lizard’s tail. Many distinct populations of stem

cells reside within each of us. Neural stem cells in our brains, for

instance, can become new neurons or glial cells. Blood stem cells

in our bone marrow can turn into new white blood cells, red blood

cells, or platelets coursing through our bloodstream. Since stem cells

are extremely versatile and can generate a number of new cell types,

a recent goal of researchers and clinicians has been to harness their

regenerative abilities for replacement therapies—restoring lost organs

and tissues in human patients.

Bo Chen, associate professor of Ophthalmology at Yale, studies

human retinal stem cells. Recently, his team figured out how to

reawaken the stem cell ability of a special group of dormant cells,

called Muller glial cells (MGs). MGs are found in the retina, a tissue

at the back of the eye that detects visual information in the form of

light. While MGs in humans are not true stem cells, they can behave

like stem cells under certain circumstances, such as extreme injury.

MGs are normally asleep, in an inactive state, but injury can reawaken

them and cause them to reenter the cell cycle and develop regenerative

stem cell abilities. Chen and his research team discovered

how to wake up MGs and cause them to proliferate without injuring

them, a strategy that could potentially help to restore retinal cells

damaged by disease.

In invertebrates, such as zebrafish, MGs are permanently active

retinal stem cells capable of regenerating damaged and lost cells. In

mammals, however, MGs typically remain dormant and incapable

of spontaneously re-entering the cell cycle without outside intervention.

While past studies have shown that severe retinal injuries

can stimulate MG proliferation and stem cell activation, Chen found

that injuring MGs was counterproductive to the goal of regeneration.

“We wanted to do something different: activating these cells

without inflicting any damage to the retina. Our goal was to make

neurons without having to kill any neurons in the first place,” Chen


The cell’s decision to remain dormant or become active depends

on a network of signaling pathways that is poorly understood.

Chen’s team suspected that the Wnt signaling pathway was involved,

since this pathway is also involved in embryonic development and

the regulation of stem cell behavior. Thus, the researchers decided

to test if they could reawaken MGs by increasing the activity of the

Wnt pathway.

In the traditional signaling pathway, Wnt proteins bind to cell receptors

to initiate a cascade that eventually results in inhibition of

the GSK3 protein. GSK3 normally degrades β-catenin, a signaling

molecule that causes a number of cellular effects. Therefore, when

the Wnt signaling pathway is activated, GSK3 is inactivated and

β-catenin accumulates inside the cell. The increase in β-catenin then

turns on a set of genes that can change the activity of the cell by

promoting proliferation. To study how Wnt signaling affects MGs,

Chen’s team used viruses to transfer the β-catenin gene into mouse

MG cells, thus mimicking the effects of an activated Wnt pathway.



After the team transferred the β-catenin gene into the cells, a

significant number of MGs began to reenter the cell cycle and proliferate.

To confirm the role of β-catenin, the researchers next deleted

the GSK3 gene, which encodes for the protein that degrades

β-catenin—again causing a buildup of β-catenin. Once again, they

observed significantly increased proliferation of MGs. They also

discovered that β-catenin directly affected the expression of a gene

called Lin28, which has been shown to regulate stem cell decisions.

Chen’s team had made a remarkable discovery, being the first

to activate the proliferative response of MGs without retinal injury.

Now that they were capable of waking up MGs, they wanted to

know whether their reactivated MGs were behaving like true stem

cells—that is, whether the MGs were capable of generating other

cell types. They transferred the β-catenin gene to a population of

MGs and gave them time to activate and differentiate. When they

analyzed the gene expression of the MGs, they found that the reactivated

MGs expressed similar genetic profiles to several retinal cell

types, suggesting that the MGs were able to differentiate in a stemcell-like


The impact of Chen’s study lies in its implications for stem cell

regenerative therapy. “Stem cell therapies are promising for treating

diseases of the human retina, where there is a loss of retinal cells,”

Chen explained. These diseases include macular degeneration and

glaucoma, both of which cause vision problems and can eventually

lead to blindness. If stem cells could be used to regenerate lost retinal

cells, then scientists and clinicians would have a novel tool to

treat these types of degenerative retinal diseases. “We can activate

this group of MG cells and potentially direct their differentiation

into any type of retinal neurons, which could replace lost cells. Essentially,

we are asking our retinas to repair themselves,” Chen said.

Although the preliminary results are promising, Chen and the

other scientists still do not fully understand the complex process of

MGs differentiation. For instance, the researchers still do not know

how reactivated MGs choose to become one cell type or another.

“The challenge now is that even when the MGs reenter the cell cycle,

they might not make the exact type of neuron we want,” Chen

said. He would like to better understand the signaling pathways that

guide MG differentiation in order to produce the cell types required

for regenerative therapy. In the future, Chen would like to test different

sets of factors that control MG differentiation. “We hope to use

these factors to guide the differentiation of the reactivated MGs to

make the types of cells that we want.”

Chen and his team are currently focusing on two types of neurons:

photoreceptor cells and ganglion cells. Both cell types are extremely

important in eyesight, detecting light from the environment and

converting it into electrical signals that can be routed to the brain.

If scientists such as Chen’s team successfully produce new photoreceptor

cells and ganglion cells from MGs, then these cell types could

be restored in patients who have lost them due to injury or disease.

Retinal stem cells are an important research topic, and Chen’s findings

will be extremely valuable for other researchers in the field. For

the first time, retinal cells regained stem cell abilities without injury.

As the discovery improves our understanding of the fundamental

signaling pathways behind stem cell differentiation, researchers

could soon harness the abilities of stem cells to heal damaged tissues

in patients. Chen is optimistic that other scientists will continue to

build upon his findings. “This type of research will ultimately greatly

benefit patients if we are successful,” he predicted.


December 2016

Yale Scientific Magazine





by Grace Niewijk || art by Anusha Bishop

“We talk about a pre-antibiotic era and an antibiotic era. If we’re not careful, we will soon be in a post-antibiotic era.

And, in fact, for some patients and some microbes, we are already there.”

- Tom Frieden, CDC Director

Scientists predict that, without a major pharmacological breakthrough,

deaths from antibiotic-resistant bacteria will surpass

cancer deaths by the year 2050. However, thanks to a team from

the Melbourne School of Engineering, that breakthrough may be a bit

closer. The team designed tiny, star-shaped polymers that were highly

effective against multiple types of bacteria without allowing resistance

development. Though more testing and development is required, scientists

are hopeful that these polymers could avert a deadly global

health crisis.

Just as humans can build up tolerance to poisons by exposing themselves

to incremental, sub-lethal doses over time, bacterial colonies

can develop resistance to antibiotic drugs when exposed to non-lethal

quantities. Although the biological processes are different, the result is

the same: substances that would normally prove lethal suddenly fail to

have an effect. In the case of antibiotic-resistant bacteria, this can mean

infections and diseases that were once easily treated suddenly become

deadly. Without antibiotics, even routine procedures like kidney dialysis,

appendectomies, hip replacements, and biopsies would suddenly

carry extremely high risk.

Manisha Juthani-Mehta, an infectious diseases physician at the

Yale School of Medicine, notes that drug-resistant bacteria have been

around for decades, but modern medicine is exacerbating their proliferation.

“We have far more [drug-resistant bacteria] now with prevalent

overuse of antibiotics,” she said. The agricultural industry is by far

the largest culprit of overuse, purchasing 80 percent of all antibiotics

sold in the United States every year. The drugs help promote plant and

livestock growth and protect crops and animals from diseases. While

these uses are important, they are not so crucial that cutting back

would be impossible. Overuse drastically increases the rate at which

drug-resistant bacteria develop and spread in the environment and in

30 Yale Scientific Magazine December 2016 www.yalescientific.org

iomedical engineering


the food supply. Nursing homes and hospitals are other major breeding

grounds for antibiotic-resistant bacteria. “In nursing homes, infections

are commonly suspected and antibiotics are frequently prescribed.

Older nursing home residents have multiple medical problems and are

often exposed to multiple rounds of antibiotics” said Juthani, whose

expertise involves infections in older adults. Although scientists and

government agencies have encouraged farmers and medical professionals

to limit antibiotic use, no strict regulations have been passed.

For some infections, we are running out of treatment options. “We

are more often stuck using very toxic, old antibiotics because we have

no choice,” said Juthani. In some cases, even these last resorts are failing.

Each time a bacterial infection becomes resistant to a particular

drug, physicians can only hope that a new, more effective drug will

be developed. Unfortunately, because bacteria generally develop resistance

to a drug very quickly and thereby render it obsolete, antibiotic

development is not profitable for pharmaceutical companies. “There

have only been one or two new antibiotics developed in the last 30

years,” said Greg Qiao from the University of Melbourne in a Science

Daily article.

That’s where the real stars come in. A team of Australian scientists—

including Qiao, Eric Reynolds, and PhD candidate Shu Lam—recently

published a paper in Nature Microbiology describing a promising alternative

technology to combat multidrug-resistant bacteria. Instead

of designing a traditional chemical drug treatment, the team developed

what they call “structurally nanoengineered antimicrobial peptide

polymers,” or SNAPPs, for short. The researchers were inspired

by natural antimicrobial peptides, which are small proteins that play

important roles in the immune systems of many organisms. Naturally

occurring antimicrobial peptides cannot be used in clinical settings

because they are often toxic to mammalian cells, but Lam and her

team wanted to use them as a model for designing a powerful and safe

antibiotic agent.

The scientists meticulously designed the polymers down to the level

of the individual building blocks—amino acids—that would make up

the peptides. Out of the many amino acids available to them, the scientists

chose lysine and valine. Lysine is a positively charged cation and

was selected because cationic peptides were already known to exhibit

antimicrobial activity. Valine, on the other hand, is uncharged and

therefore hydrophobic, meaning it does not interact favorably with

water or other polar molecules. Since hydrophobic materials interact

favorably with other hydrophobic materials, valine’s hydrophobicity

enables the SNAPPs to infiltrate the cell membrane, which is also

mostly hydrophobic. Instead of just creating long chains of amino acids

or allowing the polymers to self-assemble, the researchers attached

groups of 16 or 32 chains to a multifunctional core, which served to

promote water solubility and create the characteristic star shape. They

hypothesize that the star shape optimizes functionality because it promotes

peptide aggregation and localized charge concentration, which

leads to more effective ionic interactions with bacterial membranes.

After designing and successfully producing the polymers, the researchers

assessed the activity of the SNAPPs against different species

of bacteria. The SNAPPs were active against all bacterial species but

were especially effective against Gram-negative bacteria, such as E.

coli. Gram-negative bacteria are characterized by an outer membrane

that normally acts as a highly impermeable barrier, but the researchers

discovered that the SNAPPs could penetrate this membrane, since

they have a high affinity for specific molecules found on it. The treatment

was equally effective against antibiotic-resistant and susceptible

strains of bacteria. The effectiveness of SNAPPs against Gram-negative

bacteria is especially important because no antibiotic drugs currently

under development are effective against Gram-negative infections.

Before testing SNAPPs in living organisms, the researchers first performed

a biocompatibility assay to ensure that the polymers would

not attack mammalian cells. By incubating the polymers with sheep’s

blood and measuring death rates of blood cells, the scientists determined

that SNAPPs exhibit very low toxicity, even at concentrations

100 times higher than what is required to kill bacteria. After confirming

biocompatibility, they tested the effectiveness of SNAPPs by

treating mice with rampant bacterial infections. The results were very

promising—all mice treated with SNAPPs lived, compared to only

20 percent of the untreated mice. In addition, SNAPP treatment enhanced

the ability of white blood cells to infiltrate infected tissues, a

benefit not displayed by mice treated with traditional antibiotics.

The SNAPPs have multiple mechanisms of killing cells, making it

more difficult for bacteria to develop resistance against them. The

polymers’ partially hydrophobic composition allows them to infiltrate

the membrane, but once they have done so, the positively charged

amino acids disrupt membrane integrity and prevent regulation of ion

flow. The star-shaped polymers can even aggregate and rip apart the

membrane. The SNAPPs may also trigger the cellular processes that

induce apoptosis, or cell suicide. All these mechanisms of antibiotic

action are impressive individually, but when combined in a single molecule,

they are incredibly powerful and difficult for bacteria to fight.

Even after exposing 600 generations of bacteria to low concentrations

of SNAPPs, the researchers could not detect bacterial resistance to the

treatment. These results show great promise for SNAPPs as a longterm

solution to the rise of superbugs.

To bring treatments like SNAPPs into regular use, more research,

development, and eventually clinical trials are needed. Although many

industries and the public still fail to heed scientists’ warnings about antimicrobial

resistance, governments and research institutions are starting

to focus on the war against drug-resistant bacteria. On September

21st, the United Nations held a summit on antimicrobial resistance

and concluded that all countries must formulate a plan to combat it.

At the beginning of October, the CDC announced that a Yale School of

Public Health research team—along with 33 other teams—will receive

funding as part of a $14 million effort to research antibiotic resistance.

Hopefully, this collaboration between scientists and governments will

allow SNAPPs—and perhaps other new technologies—to better aid in

humanity’s battle against antibiotic-resistant bacteria.


►Scanning electron micrograph image of methicillin-resistant

Staphylococcus aureus (MRSA). MRSA is one of the most well-known

drug-resistant bacteria and is especially common in hospitals and

sports settings.


December 2016

Yale Scientific Magazine








32 Yale Scientific Magazine December 2016 www.yalescientific.org

From space, most stars never twinkle. Some dim periodically, betraying

the clocklike passage of planets. But there is one star that flickers

unlike any other seen before. Known as “Tabby’s Star,” this astronomical

enigma has captured the imaginations of thousands of scientists

and amateurs alike. Its mysterious blinking behavior was first spotted

by amateurs and was subsequently investigated by former Yale postdoctoral

fellow Tabetha Boyajian ’16. Because the behavior of Tabby’s Star

is completely unlike that of similar stars, scientists have resorted to an

array of wild theories as potential explanations—from a massive comet

chain to an alien megastructure. New research suggests that the star is

even more peculiar than previously thought, complicating attempts to

explain its behavior and reinforcing the need for continued study of its


Tabby’s Star (more formally known as KIC 8462852, and more colloquially

as the “WTF”—Where’s The Flux?— Star) was observed from

2009 to 2013 by NASA’s Kepler Space Observatory. This orbiting telescope

is designed to detect the shadows of exoplanets as they pass in

front of stars. But because of its foreign behavior, Tabby’s Star was not

detected automatically; it took the relatively untrained eyes of citizen

scientists—amateur astronomy enthusiasts who volunteered to pore

through Kepler’s data with their own eyes—to spot the bizarre signal.

“When they first showed the data to me, I just thought it was bad data”,

Boyajian said. “Our automated pipelines missed this feature because it

was unlike anything we had seen before,” she added.

So just what is it about Tabby’s Star that is so perplexing? Most stars

exhibit small, periodic, and symmetrical dips in their brightness, if they

exhibit observable periods of dimness at all. These dips are the result of

the regular passage of an orbiting planet in between the star and the telescope,

a planetary eclipse of sorts. But research by Boyajian demonstrated

that Tabby’s Star exhibits frequent and irregular dips in its brightness

too large to be caused by a planet. New research led by postdoctoral researcher

Benjamin Montet of the University of Chicago revealed another

feature not seen in any nearby or similar stars: a dramatic, long-term

dimming over the four-year course of the Kepler study.

The sum of these observations leads to a troubling but fascinating dilemma:

nothing like Tabby’s Star has been seen before, and no single

theory can make sense of all of the star’s unique characteristics. “There is

no good explanation for what’s going on,” Boyajian said. All explanations

must involve an event far larger than anything of its kind seen before,

or a controversial phenomenon that has been theorized but never observed.

One of the favored explanations presented by Boyajian’s team

consists of a comet swarm around the star that causes its fluctuations

in brightness; however, all comet swarms observed so far are hardly a

tenth of the size that would be necessary to produce such a large signal.

The most well-known explanation for the star’s behavior is an energy

harvesting system built by extraterrestrial life (known as a Dyson sphere

or Dyson swarm). That said, any theory of such elaborate proportions,

particularly one based on phenomena that have yet to be observed, must

be regarded with suspicion.

When Kepler refocused in 2013 on a new mission, it appeared that

researchers would have to rely on only four years of data to solve this

astronomical Rubik’s cube. But once again, astronomy enthusiasts came

to the rescue: a Kickstarter project initiated by Boyajian raised over

$100,000—enough to fund a year of constant observation of the star

through Las Cumbres Observatory Global Telescope Network. With

continuous monitoring of Tabby’s Star at multiple wavelengths, Boyajian’s

team will be able to observe long-term trends. They will also be able

to react in real time to short-term changes in the star’s intensity, which



wasn’t possible during the Kepler observations. Sudden changes will set

off a “real-time trigger” that will cue the team to take a burst of higher

resolution images, allowing them to better capture unprecedented rapid

fluctuations in the star’s brightness. Subsequent analyses of these images

have the potential to shed light on the cause of these fluctuations.

While conclusions regarding Tabby’s Star are pending further observation,

one message has already manifested: citizen science is a force

with which to be reckoned. The discovery of Tabby’s Star and its continuing

observation are the result of the massive amount of support that

astronomy enthusiasts can provide; in addition being tracked by the

global network of professional telescopes, Tabby’s Star will be monitored

by the American Association of Variable Star Observers (AAVSO), an

organization comprised primarily of amateurs.

There are, of course, limitations to citizen science in the realm of astronomy.

AAVSO is providing observations of Tabby’s Star to Boyajian’s

team, collected by the home-operated telescopes of astronomy enthusiasts.

Though these observations are useful, they are not as sophisticated

or coordinated as those provided by a professional network. While this

data may prove to be a helpful supplement, AAVSO is unable to provide

a “real-time trigger” in the way that the Las Cumbres Observatory Global

Telescope Network can. The numerous observation stations operated

by AAVSO are not entirely standardized. As a result, observations from

one station are systematically offset from others, precluding the use of

AAVSO to identify short-term fluctuations.

But what citizen science lacks in finesse, it makes up for in both manpower

and willpower. “We were quite surprised by how many people

were interested in supporting this project,” Boyajian said. Unlike many

citizen scientist projects that rely on the human brain’s exceptional

ability to recognize patterns in images— ‘pretty pictures,’” as Boyajian

termed it—signing up for the Kepler project guaranteed hours of staring

at graphs. That didn’t stop over 300,000 citizen scientists from contributing

to the project and from being the first to spot this bizarre star. “Not

a lot of astronomers take advantage of this immense resource,” Boyajian

said. “I can definitely see citizen-science like this growing in the future.”


►A theoretical diagram of Dyson Rings, an extraterrestrial energy

harvesting device that has been proposed as a possible, albeit farfetched,

explanation for the observations of Tabby’s Star.


December 2016

Yale Scientific Magazine





The prevalence of obesity and Type 2 diabetes has been increasing for

at least 50 years. Attempting to explain this trend from an evolutionary

perspective, researchers developed the “thrifty gene hypothesis”: the

idea that evolution selected for genes that promote fat storage as an

evolutionary advantage during famines.

The hypothesis originated in 1962, when James Neel proposed that

modern living conditions had created an evolutionary mismatch,

which occurs when genes that once were advantageous become

deleterious in a new environment. He concluded that this mismatch

had contributed to an increase in Type 2 diabetes, and his hypothesis

was the first widely discussed idea on the subject. However, in 1989,

Neel reviewed his own work and realized that his hypothesis was

probably incorrect, for famines occurred too infrequently to have

generated significant selection pressure. Since then, the theory has

been put aside in favor of other hypotheses, and the new results

discussed below solidify that move.

Guanlin Wang and John Speakman of the Chinese Academy of

Sciences found genetic evidence opposing the thrifty gene hypothesis.

They examined 115 single nucleotide polymorphisms (SNPs), or

common genetic mutations, that had previously been found to be

correlated with obesity. They used genomes from a database compiled

by the 1000 Genomes Project, an international collaboration to

document genetic variability among different ethnicities, to ensure

that effects of specific subpopulations did not influence their results.

When Wang and Speakman analyzed the SNPs associated with a

higher body mass index (BMI) in obese and control populations, they

found no significant selection for these genes, suggesting that evolution

has not selected for obesity. In fact, of the nine genes associated with


►Calorie dense junk food has contributed to the rise of type 2

diabetes and obesity.

BMI, five of them had decreased, rather than increased, fat storage.

Their discovery is not consistent with the genetic basis of the thrifty

gene hypothesis, increasing the plausibility of other theories about

the underlying causes of obesity. Dr. Stephen Stearns, Yale professor

of Ecology and Evolutionary Biology, cites two other hypotheses to

replace the thrifty gene hypothesis: the thrifty phenotype and the

hygiene hypotheses.

Hales and Baker proposed the thrifty phenotype hypothesis in 1992,

suggesting that the body uses information from the environment

early in life to predict its needs for the future environment. These

environmental conditions can induce epigenetic changes, or

nongenetic mechanisms, that affect phenotypic (observable) traits.

They found that babies born during the Dutch Hunger Winter, a

six-month food blockade by the Germans in the Netherlands, were

more prone to insulin resistance due to a nutritional deficit in the

womb. Insulin promotes the absorption of sugar from blood into

tissues, but under starvation conditions, nonessential tissues become

less responsive to insulin so that the brain can receive enough sugar.

When the Germans left, food was abundant, so the environment that

the baby was prepared for did not match the environment it was born

into. As a result, the people born in this period were more prone to

diabetes and other diseases. “This trend can be observed under normal

circumstances, too, as birth weight is a good predictor of the risk of

being affected by diseases later in life,” said Dr. Stearns. The thrifty

phenotype hypothesis addresses a major problem from the thrifty

genotype hypothesis. If there had been continued, strong positive

selection for increased fat storage, all humans would be obese because

these genes would be fixed, or permanently added to the human

genome. In contrast, with “thrifty phenotypes,” epigenetic factors are

affected by the environment and can vary among people.

The hygiene hypothesis relates the gut microbiota to metabolic

diseases. The gut microbiota is composed of bacteria that help to

break down macromolecules and absorb nutrients; it is sensitive

to environmental stimuli. For example, babies born by C-section

rather than vaginal birth have different microbiota because they were

not exposed to the bacteria in their mother’s birth canal, and being

breastfed or taking antibiotics can also affect a baby’s gut microbiota.

These changes have been shown to affect their risk of obesity, insulin

resistance, and Type 2 diabetes.

With a lack of genetic evidence to support the claim that humans

evolved to better store fat, the thrifty phenotype and hygiene hypotheses

are now favored to replace the thrifty genotype hypothesis. Wang and

Speakman’s paper provides more concrete evidence to refute the thrifty

gene hypothesis, supporting what many scientists already believed.

Because the thrifty phenotype and hygiene hypotheses explain why

metabolic diseases can be inherited but are also heavily influenced by

the environment, they provide a more robust explanation for the rise

in obesity and Type 2 diabetes.

34 Yale Scientific Magazine December 2016 www.yalescientific.org





Malaria: Finding the Missing Pieces of Malaria’s Migratory Patterns


In 1925, Spain’s Catalan Government set up a humble

hospital in the Ebro Delta region. The hospital treated

patients suffering from malaria. Ildefonso Canicio, a

doctor at the hospital, spent decades diagnosing and

treating patients. By drawing blood from patients,

and placing a drop on a microscope slide, he could

determine whether the blood contained Plasmodium,

the parasite that causes malaria.

Canicio threw away most of his slides, but he kept

a few slides from the 1940s. Little did he know that

seventy years later, these slides would provide insight

into the global migratory patterns of the malaria


To fight malaria in the present day, researchers are

looking to the past to understand how the parasite

evolved over time, specifically exploring how human

movements transmitted the parasite across the globe.

Malaria was successfully eradicated from Europe after

World War II. Thus, researchers have had to search

for old, badly preserved slides from Europe’s preeradication

era, hoping to find clues about the nowextinct


Carles Lalueza-Fox, a paleo-genomics researcher

at the Institute of Evolutionary Biology in Barcelona,

reached out to Canicio’s family who gave him three

slides to analyze. Back at the lab, he quickly realized

that analyzing the slides would be difficult. “There

were just a few drops of blood in the samples. Once

they were extracted and sequenced, they were gone.

The slides were fragile and covered with stains and

oils,” said Lalueza-Fox.

Despite the fragility and small size of the samples,

Lalueza-Fox and his team successfully obtained

a huge amount of genetic data from Plasmodium

mitochondrial DNA (mtDNA). Unlike nuclear DNA,

mtDNA is inherited only from the mother, so it is

better suited for determining the maternal lineage

and genealogy of a species. “As far as I know, this is

the first study where such old slides were used and

such an amount of genetic data from the pathogens

was retrieved,” Lalueza-Fox added.

Using the reconstructed European Plasmodium

mtDNA genomes, Lalueza-Fox and his team shed light

on certain controversies surrounding the parasite’s

evolutionary history. “It was not clearly understood

how the pathogen spread along different continents,

because Europe was central to some of these dispersals

but no data from Europe was available,” noted Lalueza-


His team found surprising genetic similarities

between European Plasmodium mtDNA and Indian

Plasmodium mtDNA. Lalueza-Fox believes that

malaria was transmitted from India to Europe when

the Persian Empire expanded into India in the sixth

century BCE.

The team also found evidence that European,

Central American, and South American parasites

are genetically similar–indicating that, the exchange

of food, plants, culture, and technology between the

Old World and the Americas in the 15th and 16th may

have helped spread malaria.

Lalueza-Fox is now attempting to construct the

nuclear genome of the European Plasmodium

parasite. “So far, we have about 40 percent of the

nuclear genome of the P. falciparum. I reckon we need

four or five more slides,” Lalueza-Fox said.

In Lalueza-Fox’s opinion, understanding the

nature of parasites from 100 years ago is critical for

understanding the resistance of modern parasites to

treatment. “Plasmodium is a very dynamic organism

and very difficult to tackle because of these mutations,”

Lalueza-Fox added.

His team will continue to search for the missing

pieces of the Plasmodium “puzzle,” researching the

extinct parasite to enhance our understanding of



December 2016

Yale Scientific Magazine






Ten. Ten Yalies begin the countdown, holding their breath,

praying. Nine. A lone rocket sits in an endless expanse of canyonfilled

wilderness. Eight. They smile, their eyes never straying from

Chronos, awaiting the culmination of their year of work. Seven. Six.

The numbers fly, tumbling out of their mouths. Five. Four. Three.

The exhilaration builds. Two. All they can do now is watch. One.

Devin Cody, now a senior double majoring in Electrical

Engineering and Applied Physics, remembers that day in June

of 2014 clearly. The competition rocket team, a subset of the Yale

Undergraduate Aerospace Association (YUAA), launched Chronos,

a rocket which they had been developing for months, seven thousand

feet into the air, earning second place at the Intercollegiate Rocket

Engineering Competition. The objective of their launch was to test

general relativity using two atomic clocks. They hoped that the clock

in the rocket would tick slower (on the scale of ten trillionths of a

second) relative to the clock on the ground due to time dilatation,

a physics framework that dictates how time passes differently in

different reference frames. Although the data from the clocks was

ultimately inconclusive, the launch itself was successful.

For Cody, launching Chronos was a thrilling experience. “It was

exhilarating to see our rocket fly into the air at close to the speed of

sound, just praying that the parachutes would deploy,” said Cody.

Since the launch, he has become an active member of the YUAA. He

served as one of the group’s co-presidents during his junior year, and

he continues to serve as a senior advisor on their executive board

this year.


►Devin Cody serves as a senior advisor on the Yale Undergraduate

Aerospace Association’s executive board.

During his sophomore year, Cody was selected to lead a YUAA

project to build a radio telescope. He drew on his experiences from

the previous summer at the National Radio Astronomy Observatory

in West Virginia, where he helped improve the accuracy of

telescopes by developing code to both detect and correct errors and

malfunctions. At Yale, Cody’s 16 person team designed and built an

8 foot telescope, complete with a mount, receiver, and control code.

“That was a really cool project for me because I got to work with

some incredible engineers at Yale and with people who became some

of my closest friends,” said Cody. The telescope currently sits on the

roof of the Yale Leitner Observatory and Planetarium.

Cody’s favorite research, however, was the work he did this summer

with the Avionics and Hardware Engineering group of SpaceX,

a private company currently pushing the boundaries of aerospace

technology. SpaceX aims to bring down the cost of access to space by

developing technology that will enable rocket reusability. At SpaceX,

Cody developed an Electromagnetic Compatability (EMC) testing

apparatus to test whether a coaxial cable provided adequate shielding.

While he was there, Cody tested which shielding mechanisms were

the most effective, research that was in great demand by members

in other groups within SpaceX. “It was incredible seeing the impact

that my work had almost immediately,” said Cody. “I think you

realize your work matters when you have people from the other side

of the company pushing you to get your work done fast because they

need your results to make informed decisions about their work.”

Well into his senior year at Yale, Cody is now exploring another

passion, quantum computing. Together with Professor Michel

Devoret, he is studying quantum bits (qubits) in order to determine

their properties. Qubits are similar to regular computer bits—

both are small units of data used to store information and execute

instructions. However, qubits are used in quantum computers and

are potentially capable of more efficient calculations. To investigate,

Cody and a graduate student from Devoret’s lab are designing a

computationally efficient method of optimizing qubit design.

Devin Cody will graduate from Yale this spring with a double

major in Applied Physics and Electrical Engineering and copious

work experience at the National Radio Astronomy Observatory,

SpaceX, NASA, and the Yale Quantum Institute. When asked about

his plans for after Yale, Cody laughed. “It’s a valid question, I don’t

have many answers just yet. I’m not entirely sure what I want to

do… definitely electrical engineering.” But even within electrical

engineering, Cody is certainly not tied to any one area, and it will be

fascinating to see in which direction he chooses to launch.

36 Yale Scientific Magazine December 2016 www.yalescientific.org





Dr. Ralph Greco, a talented physician at Stanford Medical School,

conducts research, but his biggest contribution to the field of medicine

does not involve a pipette. Greco’s biggest contributions have

been his improvements to the surgical residency program at Stanford.

When asked about his motivation for researching resident wellbeing,

Ralph Greco recites the chilling story of a promising student’s

suicide. This incredibly talented man had graduated from the Stanford

program and was completing further training in Chicago when

he died. Greco recalls the memorial service he held in his house as

particularly somber since the resident had left notes for his parents,

recounting the verbal abuse he experienced daily from a surgeon in

the program.

The history of resident abuse can be charted back to a specific doctor

from the 1800s. Greco cites surgeon William Stewart Halsted as

the father of both the modern residency program and the cruelty

associated with it. Greco’s theory is that Halsted’s implementation

of the residency program at Johns Hopkins University had a basis in

verbal abuse and authoritarian behavior, likely the result of his cocaine

addiction. Because Halsted formally trained the first chairs of

many medical schools, the cycle of abusive role models continued.

After his resident died, Greco wanted to create a change and prevent

further resident abuse.

Greco, along with other esteemed academics interested in resident

wellbeing at Stanford, began to break the cycle. Stanford was among

the first institutions to implement a mandatory 80-hour workweek

for residents: a precedent that other medical schools soon followed.

He also created the Balance in Life program at Stanford—a program

focused on promoting physical, psychological, professional, and social

balance among residents through events, mentorships, healthy

food and mental health initiatives. Since then, Greco has devoted

the latter part of his career to improving the residency system, and

he hopes to stop mentors from participating in abusive behavior targeted

at residents.

Not all medical professionals support Greco’s intentions, however.

Greco recognizes that hospitals are reluctant to pour money into resident

wellbeing—and into medical schools in general—because they

want to maintain their efficiency. He has also had difficulty changing

the mindset of doctors who once dealt with abusive behavior themselves.

“Just as people who are abused sometimes become abusive

parents, and learn to do that, this mindset becomes part of the upbringing,”

Greco explains. The cycle is difficult to break.

Greco has not limited himself to the pursuit of scientific endeavors.

He is also an avid sculptor, and has been since he picked up the


►Dr. Ralph Greco is a physician at the Stanford School of Medicine,

where he has started the Balance in Life program to improve resident


hobby at Princeton when an art teacher “took him under her

wing.” Greco now considers stone his favorite medium. Art is extremely

important to Greco, and he connects the activity to his focus

on resident wellbeing. By pursuing his passion for art, he hopes to

model a healthy work-life balance and show residents and doctors

that they can make time for the hobbies that they love. He admits

that finding this balance is difficult during residency, but creating a

foundation for students to have a healthy mindset is critical.

Greco cites Yale as an important place that opened doors for him

as a physician scientist. He still talks with friends from medical

school, and he continues to attend reunions. Greco plans to formally

retire from Stanford next year, but he does not anticipate problems

with his program after his retirement. He has already recruited the

next leader of the program, and Greco is confident that she will continue

working to educate residents and improve their lives at work.

In retirement, Greco hopes to advance his artistic prowess and continue

creating stone sculptures, although he does point out that stone

is not the lightest material to work with.


December 2016

Yale Scientific Magazine



book review




Until recently, microbes were primarily seen as carriers of sickness

and disease. However, with technological advances and a few key

discoveries that have highlighted their potential for medicine, microbes

are now in the research spotlight. Ed Yong explores the nature of the

close relationship between bacteria and animals in his new book I

Contain Multitudes: The Microbes Within Us and a Grander View of


Yong begins by discussing the sheer ubiquity of microbes, thousands

of which exist in the air, food, water, and even on this page. Then, he

weaves a narrative that follows how microbes affect our bodies: how

we maintain and manipulate our relationship with them, the benefits

we reap from this relationship, and what happens when it fails. His

chapter on horizontal gene transfer, the movement of genes from

one organism to another without a parental-offspring relationship,

was particularly interesting. He included an example of Bacteroides

plebeius, a bacterium common throughout the world, and Zobellia

galactanivorans, a bacterium found on seaweed. In the Japanese

population, which consumes seaweed more regularly than the rest of

the world, Zobellia has transfered the genes responsible for seaweed

digestion to Bacteroides, which resides in the gut of the Japanese


Yong also weaves an interesting narrative about the Wolbachia

bacterium into the book. “Wolbachia is so fascinating because

of how widespread it is and how it plays important roles in human



disease,” said Yong. It is heralded as

one of the most successful microbes

on the planet because of its presence

in 40 percent of insect and arthropod

species. It originally did not have a

practical medical application when it

was first discovered but has recently

been found to be able to potentially

treat tropical diseases like the Dengue

fever. “The whole story is a testament

to science that does not have to have an

immediate and practical application,”

said Yong.

In I Contain Multitudes, Yong


nods to past, notable discoveries in

microbiology research, while incorporating examples of current

research that connect to his themes. He also introduces a refreshing

feeling of wonder—a feeling that is often ignored in books on

similar topics—by highlighting the beauty of these microbial-animal

interactions. “I wanted to get people to appreciate how interesting

microbes are, rather than viewing them as sources of disease or dirt,

to actually realize that they are important parts of the world around

us. We should embrace that they are the dominant form of life on the

planet with profound influences on the way life works,” said Yong.

In popular science, few things are as romanticized as space exploration.

It is the classic science fiction plot: the fearless captain and his loyal crew,

journeying where no man has gone before. Yet to the average American,

space exploration appears to be beyond our grasp, a distant, fanciful

possibility in the drudgery of day-to-day life.

A new podcast is hoping to change that perception. “Are We There

Yet,” hosted by Brendan Byrne, follows the multifaceted efforts of

interplanetary space travel, ranging from NASA’s New Horizons Probe

to Elon Musk’s mission to Mars. Through informative discussion and

interviews with the men and women at the forefront of space exploration,

Byrne hopes to answer to question: “Are we there yet?”

Byrne was inspired to start his podcast after researching NASA’s and

other organizations’ plans to go to Mars. Byrne chose the podcast format

over a traditional news segment so that he could explore his topics in

greater detail. “I get the chance to really dig into these topics and not

be constrained by time,” he explained. “I hope each episode inspires the

listener to do some more exploring on their own.”

Each week, Byrne introduces a topic, briefly shares his own perspective

on the state and significance of the issue, and introduces his guest,

whom he then interviews for the remainder of the podcast. His guests

are typically scientists, researchers, and engineers from institutions such

as NASA and Caltech’s Jet Propulsion Laboratory—all at the forefront of

their field. They are courteous, intelligent, and highly informed.

They are not, however, entertaining. While excellent sources of

information, Byrne’s interviews are often dry and at times descend into

jargon. While expert sources are an invaluable part of the show, the

podcast would benefit from more speaking time for the host. When

Byrne speaks, he immediately makes the subject more accessible. “I hope

to take these insanely complicated technologies or plans and make them

understandable,” he explained. He also understands the importance of

public interest in the future of space exploration. “To succeed at space

exploration, we need public support.” As a host, Byrne is excellent at

exposing his listeners to these complicated technologies. He simply

needs to put greater emphasis on making them accessible.

While “Are We There Yet?” presents scientifically accurate and

relevant information, it does not capture the audience’s imagination.

There is promise, though. “We’re hoping to expand the show into a

more produced and immersive experience,” he stated. If Byrne can

execute his vision, “Are We There Yet” will be a compelling, entertaining,

and informative program. Right now, however, it is more like a weekly

fireside chat. For those captivated by the subject alone, however, this

podcast is still worth a listen.

38 Yale Scientific Magazine December 2016 www.yalescientific.org





The Economy Doesn’t

Affect Our Quality.

10% discount for all yale faculty and students

call (203) 787-0400 or (203) 376-0356

visit 50 Whitney Ave, New Haven, CT 06510

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