YSM Issue 91.2

Yale Scientific
Established in 1894
THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION
APRIL 2018 VOL. 91 NO. 2
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DOUBLE TROUBLE:
INHIBITING AN
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18
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FOR
FOSSIL HUNTERS

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F R O M T H E E D I T O R
Scientific Contributors
Science is the work of many.
We often celebrate scientific researchers—the people who spearhead new
ideas and come to new conclusions. From undergraduates to graduate students
to postdoctoral researchers and principal investigators, the work of many individuals
comes together to reach new scientific and intellectual realms.
With these collaborations, we are able to approach new issues, from the treatment
of colorectal cancers (pg. 20) to the understanding of lung disease (pg.
22). Teams of scientists explore places beyond what we can see, including the
small world of dung beetle navigation (pg. 4) and the even smaller interactions
of proteins that support our cells’ nuclear envelopes (pg. 15). Numerous pairs of
eyes peer into the future, imagining computer chips achieving universal memory
(pg. 8), and look back to the past, uncovering new pathways in the evolution
of siphonophores (pg. 11).
Our cover article this issue redefines our views on fossils and allows us to
more efficiently search for answers—answers that may ultimately give us insight
into extraterrestrial life (pg. 18). What is perhaps so beautiful about this research
is that, not only does it tell a story about our planet’s past, it provides information
that other researchers can use to follow their own paths of discovery.
This translation of research between people is an interaction to be celebrated.
Thus, research and progress is, in reality, the result of much more than just
those who work in the lab. Without the translators of science—the teachers, the
publications, and the journalists—the effects of scientific breakthroughs and the
implications of new ideas are lost.
And so, we hope that, through scientific journalism, we can act as the translators
of discovery. We are excited to work with other publications on Yale’s
campus such as Distilled (pg. 39), a scientific magazine associated with the Yale
Graduate School of Arts & Sciences. Publications such as these are the bridge
between discoveries and understanding, and are thus are key contributors to
the spread of scientific information. We join with publications both at Yale and
beyond to celebrate the contributors of science both in and out of the lab.
Yale Scientific
Established in 1894
THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION
APRIL 2018 VOL. 91 NO. 2
18
MEGA-USEFUL
MICROCAPSULES12
STITCH
IT UP15
DOUBLE TROUBLE:
INHIBITING AN
INHIBITOR20
MODELING LUNGS
FOR A NEW CURE22
MINERAL MAPS
FOR
FOSSIL HUNTERS
A B O U T T H E A R T
Eileen Norris
Editor-in-Chief
The Burgess Shale exhibits a stunning variety of
fossils that have helped us elucidate the evolution
of animals. The deposit, once submerged underwater,
invites us to marvel at the unusual forms
of animals such as the marrella. It is thanks to
advancements in mineral mapping that we are
now able to more effectively locate and unearth
such wonders. In my cover art, I pay an ode to the
beauty of the Burgess Shale, the wonders it holds,
and the amazing new mineral map breakthrough.
Ivory Fu, Arts Editor
Editor-in-Chief
Managing Editors
News Editor
Features Editor
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FRACKING
PATHWAYS
How a high-throughput
reactor can prevent
environmental
damage rather than
merely assess it
BY: KATIE SCHLICK
Although we
are used to cleaning up manmade
messes, a recent publication
from the Plata lab in Yale’s Chemical and
Environmental Engineering Department focused
on generating more precise predictions of potential environmental
damages before they occur. Led by Andrew Sumner, a
fourth-year doctoral candidate, the study investigated the various
chemical processes that occur in shale subsurface during hydraulic
fracturing, commonly known as fracking, a process used to get
fossil fuels out of tough-to-reach reservoirs.
In fracking, water is injected into shale reservoirs to break the rock
apart and release the fossil fuels stored inside. Typically, industry operators
add many chemicals to the injected water to increase efficiency.
Sumner noticed that water emerging from the subsurface contains
chemicals different from those originally injected, implying underground
chemical changes. He built a reactor system that could analyze
15 chemicals under certain conditions. The reactor conditions could be
expanded to more closely emulate the complexity of actual shale.
Sumner and Plata agree that future use of this reactor will impact
both industry operators and environmental regulators. As the chemistry
of fracking is better understood, well operators can more intelligently
design their chemical mixtures and eliminate the ones with
unwanted side reactions or use them more conservatively. Regulators
can also be on the alert for chemicals in wastewater.
The reactor allows researchers to assess the possible reactions occurring
under a set of conditions quickly, a result Plata believes will be transformative
in the field The scientists hope to further the implications of the
reactor with a computer model which synthesizes the information gained
by the system. “Traditionally, environmental engineers have cleaned up
past messes and looked at what was wrong in the first place. Now, we can
learn beforehand, rather than confront it later on,” said Sumner.
Reverse transcriptase is an enzyme that converts an
RNA template molecule to DNA. By conserving sequence
information and enabling easy amplification,
this enzyme allows scientists to investigate RNA. Researchers
from the Pyle lab at Yale have characterized a novel reverse
transcriptase which can be engineered into a powerful
biotechnological tool.
“We found it by accident when trying to solve a crystal
structure of a new type of reverse transcriptase,” said Anna
Pyle, Professor of Molecular, Cellular, and Developmental
Biology at Yale. This reverse transcriptase family interacts
with group II introns, mobile genetic elements that shape
genomes of bacteria, fungi, and plants. After identifying the
most stable member of the enzyme family, her lab not only
revealed its shape on the atomic scale, but also found that it
possessed remarkable enzymatic activity.
When converting an RNA molecule into DNA, conventional
reverse transcriptases cannot produce long DNA fragments,
resulting in piecewise conversion of RNA to DNA and
limiting applications for long RNA sequences. However, the
newly-discovered reverse transcriptase efficiently copies very
long transcripts completely. The researchers named the enzyme
“MarathonRT” in tribute to its impressive endurance.
“Because MarathonRT can handle very long RNAs, it
can be used to monitor multiple changes in the transcript,”
said Pyle. For example, her lab is collaborating to decode
alterations of HIV RNA genome in response to drug therapy.
Using MarathonRT, the whole HIV genome sequence
can be analyzed to reveal relationships between multiple
mutations. MarathonRT has been already distributed
to 60-70 labs around the world, suggesting
its significant implications to
many fields in science
and medicine.
MARATHON
RT
A new reverse trancriptase
copies lengthy transcripts
BY: MINJU HA
6 Yale Scientific Magazine April 2018

While cities grow larger and denser, the forests within
their boundaries become increasingly important.
Urban forests provide benefits such as increased air
quality, heat island reduction, and recreation. However, planting
trees is time-consuming and expensive, thus researchers
are motivated to focus on finding ways to make these urban
forests self-sustaining. A recent Yale study has shed light on
how to best treat and understand these critical forests.
The study analyzed data from research plots in Queens,
New York that test three treatment methods: compost, nurse
shrubs, and tree species composition (two-species versus
six-species). While the nurse shrub and compost treatments
individually did not facilitate the establishment of woody
plants, combining the nurse shrub treatment with compost or
six-species composition treatments increased establishment
by 47 and 156 percent, respectively. “This suggests that there
are interesting interactions between treatments, and that effective
management strategies may require a suite of complementary
treatments rather than relying on independent interventions,”
said Danica Doroski, a doctoral student in the Yale
School of Forestry and Environmental Studies and first author
of the paper. The study demonstrated that a combination of
treatment methods, along with greater preexisting canopy
cover, may hold the key to self-sustaining urban forests.
Doroski emphasized that natural processes occurring in urban
forests make them more comparable to rural forests than
landscaped parks—implying that tools and theories from
classical forestry could be adapted and applied to urban settings
to enhance our understanding. Doroski and her team
intend to continue investigating management methods
that promote self-sustaining urban forests
and realize the multifaceted
benefits they can bring
to cities.
URBAN
FORESTS
Turning over a new leaf
BY: GENEVIEVE SERTIC
GENE
RESISTANCE
Stopping cancer in its tracks
BY: ANDRÉ GARCIA
DE OLIVEIRA
A
major challenge in treating
cancer is that tumors often become
resistant to treatment over time. To understand
the mechanism behind this resistance, researchers
at the Yale School of Public Health conducted a study on
the reoccurence of cancer in patients. By gene-sequencing tumors,
they determined the prevalence of oncogenic mutations that could
lead to treatment resistance.
“Currently, we treat tumors with medication to target and inhibit
the tumor as it is, but not to prevent the future evolution
of tumors into resistant forms,” said Jeffrey Townsend, Associate
Professor of Biostatistics and Ecology and Evolutionary Biology
at Yale. His group hopes that a better understanding of the mechanism
behind tumor resistance will help develop novel techniques
and drugs that not only target mutations present in the tumor, but
also prevent the tumor from evolving further.
The group wanted to investigate the likelihood of a tumor developing
resistance to treatment and what this resistance would look
like. The group chose to study KRAS, a gene frequently implicated
in human cancers and well-characterized in scientific literature.
They sequenced lung tumors with positive KRAS genes to determine
whether other oncogenic mutations within KRAS or within
other commonly mutated downstream genes were prevalent, and
if they could develop resistance during and after the treatment.
The findings suggest that, for therapies targeting specific oncogenes
such as KRAS, resistance is unlikely to be present at the
time of treatment. However, tumors are likely to develop resistance
in these genes through mutations following treatment. The
study demonstrates how to characterize pathways leading to tumor
resistance, a valuable tool that can be used to anticipate cancer
mutations and design new targeted therapies.
www.yalescientific.org
April 2018
Yale Scientific Magazine
7

NEWS
technology
SELF HEALING CHIPS
A push forward for computer memory
BY YULAN ZHANG
As computer applications grow increasingly data-intensive,
many researchers are investigating phase change memory (PCM)
as a more effective form of information storage. PCM is a memory
technology that exploits the material properties of germanium-antimony-tellurium
(GST) to provide fast, non-volatile (no
electricity required) information storage. Current forms of memory
only exhibit one of these characteristics—random access
memory (RAM), the memory used for short-term storage, is fast
but dependent upon electricity, while flash, the memory used for
long-term storage, stores data without electricity, but is slow.
Despite its merits, the high manufacturing cost and short
lifetime of PCM devices have limited the technology’s marketability.
New developments at the Yale School of Engineering,
however, may soon cause this to change. The lab of Yale professor
Judy Cha, in collaboration with IBM’s Watson Research
Center, recently demonstrated how a new design could extend
the lifetime of a PCM device by allowing voids, a major cause
of PCM failure, to self-heal. The research was published January
2018 in Wiley’s Advanced Materials.
Computers store information in binary, a number system that
uses only the digits 0 and 1. In a PCM device, these digits correspond,
respectively, to the crystalline and amorphous phases of
the GST material. Crystalline GST has a regular atomic structure,
similar to a brick wall. Amorphous GST, on the other hand, does
not have a regular atomic structure, similar to a gravel road.
Computers relay binary code to a PCM device by applying
a potential difference, or voltage, across the top and bottom
of each memory cell. Voltage is essentially electric pressure—
it pushes electrons to move in a certain direction; the resulting
electron flow is called a current. As the electrons bump against
the atoms of the GST, they transfer energy to the material in the
form of heat. Larger voltages induce larger currents, which then
generate more heat. By controlling the heating and cooling of
the GST through the applied voltage, the computer can switch
the GST between the crystalline and amorphous states, thus allowing
it to convert information to memory.
Computers use a similar method to retrieve information from
memory. To avoid inducing a phase change, computers apply
a low voltage to the memory cell. Due to structural differences
between the two phases, amorphous GST has greater resistance,
or opposition to current flow, than crystalline GST. Thus,
computers measure smaller currents through amorphous cells
than through crystalline cells. This difference allows computers
to distinguish between the two memory states.
After repeated data writing and retrieval, however, PCM cells
break due to a phenomenon called void accumulation. When
current flows through the GST, the moving electrons push individual
atoms within the GST in a process called electromigration.
The direction and speed of this movement differs between
elements. Images obtained through transmission electron microscopy
revealed, for instance, that antimony moves quickly towards
regions with low potential, while tellurium moves slowly
towards regions with high potential.
In PCM, this results in the net migration of the GST towards
the low-potential end of the cell, leaving a void, or vacuum, in
the high-potential end. “Once a void forms, the path for the current
through the GST becomes disconnected,” explains Yujun
Xie, the graduate student who led the experiment. “The cell becomes
an open circuit—since current can no longer flow, the
device can no longer be read nor switched between states.”
The researchers found, however, that a new cell design allows
voids to self-heal. In contrast to previous designs, the new design
encased the memory cell in a metallic liner, which provided
an alternative path for current to flow in the presence of a
void. This allowed the researchers to reverse the electromigration
of GST by reversing the direction of the applied voltage.
Thus, alternating the direction of the applied voltage would reduce
void accumulation and extend the lifetime of PCM.
These self-healing improvements move PCM one step closer
to the marketplace and bring researchers towards realizing
universal memory, the ultimate goal of the computer memory
industry. Universal memory is fast, non-volatile, and practical,
thus allowing it to function as both short and long-term
computer memory. Eliminating the need for separate forms of
memory would streamline data processing in computer systems,
and would reduce the inconvenience of events like computer
crashes, as short-term computations would be preserved
even if a program suddenly exits. With this new PCM design,
universal memory and PCM data storage devices may soon be
available for widespread use.
IMAGE COURTESY OF YUJUN XIE
In a PCM cell, GST can exist in two states: a crystalline phase
or an amorphous phase.
8 Yale Scientific Magazine April 2018 www.yalescientific.org

applied physics
NEWS
DEMYSTIFYING CONSCIOUSNESS
Understanding electrical circuits in the brain
BY MINDY LE
IMAGE COURTESY OF GRAPHIS
Artistic interpretation of electrodes recording brain activity.
In practice, electrodes are implanted directly into the brain to
measure electrical signals.
When we wake up, our brains shift from being unconscious to
conscious. While we usually think of this transition as the prime
example of the emergence of “consciousness,” consciousness is
also defined as any perception of stimuli that initiates a response
from our brain. For example, when you look at a painting, the
steps your brain takes to register the image constitutes the conscious
perception of the painting. Until now, how this process was
not well understood, prompting Yale researchers to examine what
happens during the few milliseconds of conscious perception.
Led by Hal Blumenfeld, a professor and clinician in the Yale
Department of Neurology, researchers studied this phenomenon
of conscious perception. “[We wondered] what happens
in the split-second that you become consciously aware of
something. How is this different from all the many things that
you are not aware of?” said Blumenfeld, explaining the motivation
for this project.
In the study, participants were given a conscious visual perception
task, and their resulting electrical signal images from
the cerebral cortex, the part of the brain responsible for consciousness,
were obtained. These images allowed researchers to
visualize how the human brain processes stimuli during consciousness.
By studying the brain electrical signals during that
split second, the researchers found that conscious events trigger
a wave of signal processing that passes quickly through most of
the brain, while at the same time some selectively turning off
some brain circuits to control information flow.
The researchers proposed a new model for this type of brain
processing. Their switch-and-wave model represents two steps in
visual processing. The first step is a triggered “switch” that occurs
when electrical signals enter the brain and are consciously perceived.
After entering the primary visual cortex, the part of the
cerebral cortex located at the back of the brain responsible for receiving
and processing visual stimuli, the signals combine with
other electrical signals from areas of the brain associated with
higher brain functions such as action and thought. This starts the
second “wave” step, where a cascade of processing steps through
the neural networks occurs. Ultimately, this model aims to describe
how the human brain receives and processes external stimuli
to produce consciousness.
To test their model, the researchers implanted electrodes into
participants’ brains to record electrical signals during various
tasks. Participants compared identical stimuli, and the corresponding
brain signals were then reported as “perceived” or
“not perceived.” During any perception task, the brain’s electrical
activity changes in specific frequency ranges. By measuring
these changes in electrical frequency, the researchers directly
observed changes in brain activity.
The investigation unveiled new discoveries about how brains
process stimuli and perceive consciousness. Previously, an “ignition”
model of conscious visual perception was hypothesized,
consisting of widespread brain activity after a visual perception.
The switch-and-wave model was proposed in order to account
for new discoveries, including the observation that stimulus
presentation can activate the visual cortex independently
of conscious states, and that both activation and deactivation of
several brain regions occurs only during “perceived” trials.
Previous ignition models did not focus on the importance of
this switch network.. Furthermore, in the first “switch” step, the
wave of brain activity that proceeds through the medial temporal
cortex, a part of the brain associated with memory, had previously
been thought to occur only in processing and memory
encoding. The new finding highlights the complexity of the human
brain, further shown by the fact that the step from stimuli
detection to increased visual cortex and higher association cortex
occurs within just 200 milliseconds.
The investigation revealed that only “perceived” trials initiated
the switch-and-wave process of brain activity although both
“perceived” and “not perceived” trials were subjected to the same
visual events during the task. These results further demonstrate
the need to understand how the brain works when exposed to
environmental stimuli. Often the same event is interpreted differently
by two people, prompting questions as to how exactly
individual brains differ in conscious perception and how this affects
memory recollection and other cognitive processes. While
many questions in neuroscience remain unanswered, this new
model begins to explain the mystery of consciousness.
“Consciousness is sometimes viewed as a topic that is too
challenging to investigate, but I think the progress in consciousness
research in the past few years leading up to our latest
results is very exciting. I hope that others will be encouraged
to enter the field of consciousness research so we can
further deepen our understanding of how we think about, feel
and experience the world,” said Blumenfeld.
www.yalescientific.org
April 2018
Yale Scientific Magazine
9

NEWS
cell biology
PEERING INTO PORES
DNA origami in nuclear pore complexes
BY LAUREN KIM
Origami is a delicate art that creates elaborate structures
from folding a simple sheet of paper. However, it is more
than just an art; origami is also a technological method for
modern biological research. The most complex parts of a
cell may be recreated and studied from the simple folding
of a single stranded DNA into desired shapes.
The highly compartmentalized organization of the cell allows
for its proper function. Its complex structure dictates the
movements within a cell and requires multiple moving parts
to work correctly. Patrick Lusk, Yale associate professor of cell
biology and ChenXiang Lin, Yale assistant professor of cell biology,
used this DNA origami technology to better understand
nuclear pore complexes and the basis for molecular communication
that occurs between the nucleus and rest of the cell.
Nuclear pore complexes are large protein structures that
are assembled into the nuclear membranes to help form the
selective barrier that separates the nucleus from the rest
of the cell. Acting as a gatekeeper, these proteins regulate
which molecules enter and exit the nucleus. An incredible
amount of material is exchanged at this surface in order for
a cell to function properly, and so it is essential for these protein
complexes to efficiently dictate what is allowed to pass
through the nuclear membrane. Researchers have found
that the selectivity of this barrier is determined by the presence
of certain FG peptides, named such because of the repeating
phenylalanine (F) and glycine (G) amino acids and
also referred to as FG-NUPS. But how the FG-NUPS physically
gate the nuclear pore complex remains unknown as
traditional microscopy methods are unable to visualize the
movement and dynamics of the FG-NUPS in living cells.
IMAGE COURTESY OF BIOLOGYWISE
A significant amount of exchange occurs between the nucleus and
rest of the cell.
Melding nanotechnology and cell biology, Lusk and
Lin engineered scaffolds using DNA origami to mimic
the dimensions of the nuclear pore complex. Using this
technique, the scientists built an artificial nuclear pore
complex to fill with FG-NUPS in order to study their
properties. This test-tube model allowed for them to recreate
the structure of the nuclear pore complex on a nano-scale.
With the help of colleagues at University College
London, the researches visualized the movement of FG-
NUPS for the first time and provided new insight in their
role as molecular gatekeepers.
“If you really want to understand how something works,
you have to build something up yourself,” said Lusk. By recreating
this nuclear pore complex filled with specific FG-
NUPS, the scientists were able to better understand the cell
transport that occurs across the nuclear membrane. Creating
a model and witnessing the movement of FG-NUPS
within this complex showed the researchers how the nuclear
complex simultaneously accepts huge proteins and
blocks smaller ones from entering the nucleus.
DNA origami has not always been used to address biological
questions. Lin hopes that this study of nuclear pore
complexes will demonstrate the utility of DNA origami
in biological research. “DNA nanotechnology is a powerful
solution, but [it is] looking for problems [to solve],”
said Lin. By coupling nanotechnology and cell biology, researchers
can begin to address the unanswered questions of
the complex workings of the cell.
Having built these DNA origami nuclear pore complex
mimics, the team hopes to then incorporate this synthetic
complex into a real membrane to see how the transport
of different sized proteins actually occurs within a cell. Understanding
how FG-NUPS are sorted within the nuclear
pore complex allows for one to establish a set of rules for
its organization and a systematic approach for determining
the selective function of a nuclear pore complex. With this
fundamental understanding, scientists can begin to build a
synthetic cell. Knowing the exact structures and function
of FG-NUPS within nuclear pore complexes can then allow
one to recreate its selectivity in a different setting.
DNA origami is a powerful tool with vast potential within
cell biology. By replicating complex aspects of a cell, scientists
can obtain a better understanding of each individual
function within a cell and incorporate their knowledge into
making a fully functional synthetic cell. As the most basic
unit of a living organism, cells hold incredible importance
in an organism’s existence. With the first successfully synthesized
cell, life at its most basic stage can then be placed
in the hands of modern scientists.
10 Yale Scientific Magazine April 2018 www.yalescientific.org

evolutionary biology
NEWS
A NEW FAMILY TREE
Exploring the unique development of siphonophores
BY ANNIE YANG
PHOTOGRAPHY BY LINDA CHANG
The Portuguese Man of War, a venomous siphonophore that stings
its prey, is found in large groups at the surface of warm water.
As far as gelatinous predators go, the Portuguese Man of War
is well known, particularly to frequent beach-goers. Its long tentacles,
which produce a painful sting upon contact with its prey,
make it a formidable opponent at the ocean’s surface. While often
mistaken for a jellyfish, the Portuguese Man of War is actually
a siphonophore, a unique group of cnidarians, whose evolutionary
history has been elusive until recently.
At Yale’s Dunn Lab, led by ecology and evolutionary biology
professor Casey Dunn, researchers have been working to better
understand the phylogeny or evolutionary history of siphonophores.
Siphonophores are a fascinating order to study because
of their unique characteristic as colonial animals: while a single
siphonophore may appear as one animal, it is, in fact, composed
of many functionally specialized organisms, known as zooids,
that each play an important role in its survival. Some zooids are
responsible for feeding, others for reproducing or swimming.
During the sexual phase of a siphonophore life cycle, a single
fertilized egg develops into the first zooid. One or two growth
zones then sprout, allowing for the asexual budding of subsequent
zooids, which remain attached.
To elucidate the poorly understood phylogeny and explore the
unique development of siphonophores, the team collected various
species from ocean ecosystems across the world. Because siphonophores
are extremely fragile, the researchers relied on multiple
collection methods, including blue water scuba diving and the use
of remotely operated underwater vehicles. Some specimens were
also collected through the process of upwelling, in which deep
water containing the organisms was brought up to shallow levels.
The team then extracted all of the mRNA from the collected specimens,
which represents all of the active genes in the specimens. The
mRNA of the thirty siphonophore species allowed them to use the
genetic data to reconstruct a new phylogeny.
Historically, siphonophores have been categorized into three
groups: Cystonectae, Physonectae, and Calycophorae. In 2005,
Dunn constructed a different phylogeny based on two siphonophore
genes. His proposed family tree suggested the reordering of
siphonophores into two groups: Cystonectae and Codonophora,
which combined the Physonectae and Calycophorae.
The current study, which now involves 1,071 genes, provides
new data corroborating the phylogeny delineated by Dunn
and also proposes new divisions. For instance, the researchers
found strong evidence for Apolemiidae as a sister to all other
codonophorans and Pyrostephidae as a sister to all other
non-Apolemiidae codonophorans.
Furthermore, the results offer a new understanding of the
evolution of certain siphonophore traits. Previous studies suggested
that the common ancestor of siphonophores was dioecious:
the male and female reproductive organs are located in
different colonies. Monoecy, the trait in which the male and
female reproductive organs are located in the same colony, was
hypothesized to have evolved only once within the Codonophora.
However, the current phylogeny provides evidence
that two independent clades of siphonophores, Calycophorae
and Clade A, both exhibit monoecy, suggesting that monoecy
evolved twice. “This is an exciting evolutionary case of something
occurring convergently more than once,” said Cat Munro,
a graduate student on the preprinted paper.
Because zooids are so functionally diverse, scientists have
had difficulty studying the evolution of different types. The reconstructed
family tree, however, provides new data for scientists
to explain the long-standing mystery of their origins.
For example, bracts, zooids present only in Codonophora, are
responsible for protection and buoyancy. The new phylogeny
suggests that when bracts were lost in certain clades; other zooids
evolved to make up for lost functions.
This research is momentous for understanding siphonophore
phylogeny and trait evolution. “With this latest paper,
we are able to tease apart some deeper relationships between
the species more easily because of improvements of technology
and the amount of data that we have to work with. We were
able to identify a new group that we weren’t able to identify before,
and it has shifted how we think about how siphonophores
have evolved,” said Munro.
However, a number of siphonophore traits have yet to be completely
understood. Alex Damián Serrano, another graduate student
in the Dunn Lab, is investigating the evolution of specialized
parts of siphonophore tentacles and their relationship to siphonophore
habitat and diet preferences, while Munro is currently looking
at a large set of gene expression data from different species to
better understand siphonophore functional specialization. With
the reconstruction of this new phylogeny, scientists can explore
siphonophores in pioneering ways that will allow them to further
unravel the enigmas of this interesting evolutionary tale.
www.yalescientific.org
April 2018
Yale Scientific Magazine
11

modern
microcapsules
Exploring the
potential control
of drug delivery
with light and
magnetism
by
Eileen
Norris

materials science
FOCUS
Chances are, at some point in your
life, you’ve taken some form of medicine
in capsule form. In fact, many
antibiotics are delivered via ingested
capsules. In comparison to tablets—in which
the drug forms the tablet itself rather than being
contained in a small “shell”—capsules have
many advantages, the primary being more efficient
drug delivery. Once the capsule is broken
or dissolved, the drug it contains is in a form
that is faster absorbed into the body.
We are familiar with capsules that are taken
orally and dissolve in our stomach, allowing
for drug release, but what if these capsules
were small enough to be transported
in blood vessels to deliver drugs to specific,
targeted locations throughout the body?
A team at Yale, led by Chinedum Osuji, Associate
Professor of Chemical and Environmental
Engineering, is designing such capsules.
The team has developed a new method
of creating tiny capsules, called microcapsules,
that respond to light and magnetic
cues. Their work may have implications in
the ultimate development of controlled, localized
drug delivery using microcapsules.
A novel approach to fabrication
A significant component of Osuji’s research
is the design of more efficient and simple processes
for generating microcapsules. A common
microcapsule fabrication method involves
a layer-by-layer approach, entailing
sequential steps in which different shell materials
are deposited as individual layers onto
a template particle. “It’s similar to 3D printing—you
just add material layer by layer,” said
Gilad Kaufman, a key member of Osuji’s team
of researchers. The process, however, is time
consuming, and the efficiency with which
drugs or other agents are thereafter encapsulated
is generally low. These drawbacks have
hindered broad adoption of the process.
The new microcapsule formation process,
designed by Kaufman, Osuji, and Karla Montejo,
a summer undergraduate researcher from
Florida International University, involves microfluidics—the
manipulation of fluid flow on
the micro level. There are two key advantages
to this process. “One key advantage to microfluidics
is that you can very reliably control
the size of the droplets and ensure that
they are all the same size. You want to have
uniform size so that there is little variation in
the microcapsule properties—for example,
the bioavailability of objects in circulation
changes with their size, as does the amount
of encapsulated drugs and their release behavior,”
Kaufman said. A second important
advantage is that the microfluidic approach
that they have developed eliminates the need
to fabricate multiple layers: the microcapsule
shell is formed by creating one relatively thick
layer in a single-step rather than many thin
ones. This is beneficial in certain scenarios as
a thicker shell will result in improved microcapsule
mechanical properties, which allows
the microcapsules to remain intact and stable
until the time of desired release.
Microfluidic capsule “droplets”
Generally, microfluidics can be compared
to water flowing through pipes in a house, but
with very small pipes. Osuji’s new method of
creating microcapsules uses a configuration
of “pipes” that facilitates coaxial flow, in which
one fluid is surrounded by another fluid. The
inside fluid, which contains the drug or substance
being encapsulated, is separated into
individual droplets as it meets with the outer
fluid. Each droplet can be transformed into a
microcapsule by interfacial complexation.
Interfacial complexation is not a novel idea.
Interfaces are everywhere—they are nothing
more than the meeting of two materials. In
some cases, interfaces offer you the ability to
control reactions. A popular high school experiment
looks at the formation of nylon at
the interface between two liquids; this nylon
can actually be wound up and collected on
a spool. More generally, interfacial complexation
is when a reaction occurs at the interface
of two immiscible liquids, and the solid
product of this reaction cannot be dissolved
in either of the two liquid reactants. Osuji
and his team were the first to use this idea in
microfluidic devices to create thick shell microcapsules.
In their current research, they
performed interfacial complexation using
graphene oxide and silicon oil, thus forming
the microcapsule at the interface. The microcapsules
that are created in this process can
then be used in the desired context.
Finding unique materials
The use of graphene oxide is perhaps one
of the key advantages identified in Osuji’s research.
An understanding of material interactions
is necessary for successful creation
of microcapsules via microfluidics. “One of
the principle challenges that we had was ensuring
the stability of the microcapsule and,
of course, the stability of the graphene oxide
in the microfluidic device that we used to
make the microcapsule,” Osuji said. In other
words, a large factor of microcapsule design
and formation is making sure that the
capsules remain as discrete well-defined objects
without spontaneously rupturing, and
preventing the capsules from aggregating, or
sticking together. Graphene oxide has a high
Young’s modulus, which means it is a relatively
stiff material, giving the microcapsules
a strong shell. Finally, and perhaps most importantly,
graphene oxide has photothermal
properties, which is key for the photothermal
release aspect of the microcapsules.
Photothermal properties have been examined
in the context of drug delivery such as
cancer therapies for many years now. The concept
is simple: upon exposure to light at certain
wavelengths, particles can generate cancer-killing
heat, or dissociate to release the anti-cancer
You can envision a system in which
you have a capsule carrying some
drug and in which the release of the
drug can be controlled with light. You
can imagine one scenario in which the
capsules could be distributed homogenously
throughout the body, and another
scenario in which you only release
the drug where you want—the
tumor location, for example.
drug or other therapeutic substance contained
inside. Osuji’s new microcapsules have additional
benefits. Graphene oxide responds to
near-infrared (NIR) and infrared light (IR), a
wavelength at which human tissue is almost
transparent, meaning that the light can reach
the capsule directly without much interference
from the human body. “You can envision
a system in which you have a capsule carrying
some drug and in which the release of
the drug can be controlled with light. You can
imagine one scenario in which the capsules
could be distributed homogenously throughout
the body, and another scenario in which
you only release the drug where you want—
the tumor location, for example,” Osuji said.
www.yalescientific.org
April 2018
Yale Scientific Magazine
13

FOCUS
materials science
IMAGE COURTESY OF GILAD KAUFMAN
Release of a model compound (Methyl Orange dye) under NIR laser irradiation of the microcapsules. The dye released is evident form the strong
orange background color in the image on the far right. Biomedically, these microapsules could be made to contain drugs for release at specific areas
of the body, such as a tumor, using targeted NIR laser irradiation.
Directing the microcapsules
Furthermore, another goal is to not only
control the localized release of the drug, but
also to direct the capsule to a particular site
in the body. To achieve this goal, the team of
researchers incorporated ferrite—a form of
iron—nanoparticles into the shells of microcapsules
by dissolving the ferrite nanoparticles
in the liquid of the microfluidic device.
With these magnetic ferrite nanoparticles,
they were able to direct the microcapsules
to specific locations within a vial, and then
trigger localized release of the encapsulated
substance using NIR light. These experiments
confirmed the magnetic response and
the NIR-controlled drug release of the microcapsules.
That being said, there are limitations
to the magnetoresponsive characteristics
of the microcapsules.
While the researchers can control capsule
movement within a vial in the lab, it is another
task entirely to direct the capsules to a certain
area of the human body, such as a tumor.
In the human body, limitations would likely
arise in the ability to direct the magnetic microcapsules
due to a complicated blood vessel
system and the necessary magnetic field
strength—a much stronger magnet would be
required to control these microcapsules in the
human body. It does show, however, that it’s
possible to influence the localization of these
capsules on some level. For example, using
strong magnets, one can increase the concentration
of the capsules in a certain general
area of the body, and then control release using
light directed at a more concentrated location.
In other words, the microcapsules could
potentially be magnetically drawn to a given
area surrounding a tumor, and the NIR-signaled
drug release could be limited to only
the specific location of the tumor.
There are further limitations to the biomedical
use of these microcapsules. Predominantly,
to be used in the body, the capsules
must be much smaller than the capsules that
Osuji, Kaufman, and their team have been
able to create. Currently, Osuji’s capsules are
approximately 80 microns in diameter, or
about the diameter of a single human hair.
“The size of the microcapsule is controlled
by various parameters, one of which being
the size of the nozzle in the microfluidic device.
To be used in blood vessels, the microcapsules
should have a diameter of about one
micron or smaller. It is much harder to make
a nozzle that is sufficiently small to produce
microcapsules of that size,” Kaufman said.
Furthermore, the size of the droplets is controlled
by the intrinsic properties of the fluids
themselves, such as surface tension. If
you imagine a faucet with dripping water,
ABOUT THE AUTHOR
the sizes of those water droplets are correlated
to the rate of water flow, the diameter of
the pipe, and the properties of the water.
Looking forward, the new one-step method
to create these new photoresponsive and
magnetoresponsive microcapsules has many
possible biomedical implications. The challenge
now is to find a way to shrink these microcapsules,
while maintaining their functional
and structural integrity, for a direct
medical use. “The main difficulty was finding
a way to make microcapsules in a simple
process that has the potential to be scalable,
and also has potential applications by using
building blocks that are responsive to specific
environmental stimulants,” Kaufman said.
Perhaps equally important, the research
shows the scientific and medical implications
that arise from a combination of very
simple ideas. “The idea came and the expertise
was there to enact it. It is inherently a
simple and versatile process. It is a very accessible
technology,” Osuji concluded.
EILEEN NORRIS
EILEEN NORRIS is a pre-med student and a sophomore in Ezra Stiles College majoring in
Biomedical Engineering and History of Science and Medicine. She is the current Editor-in-Chief
and previous Production Manager of the Yale Scientific. She currently works in the Niklason lab
on lung engineering.
THE AUTHOR WOULD LIKE TO THANK Professor Chinedum Osuji and Gilad Kaufman for dedicating
their time and enthusiasm to sharing their research.
FURTHER READING
Kaufman, Gilad, Karla A. Montejo, Arthur Michaut, Paweł W. Majewski, and Chinedum O. Osuji.
“Photoresponsive and Magnetoresponsive Graphene Oxide Microcapsules Fabricated by Droplet
Microfluidics.” ACS Applied Materials & Interfaces 9, no. 50 (2017): 44192-4198.
14 Yale Scientific Magazine April 2018 www.yalescientific.org

STITCH
ITUP
How A Little-Known Nuclear
Envelope Protein Maintains
the Integrity of our Genome
by Lukas Corey || art by Elissa Martin
Despite countless bruises, burns, blisters,
cuts, and bug bites, our skin remains resilient.
This is largely due to a number of
bodily repair mechanisms in place that
address the damage. Professor Shirin Bahmanyar
and graduate student Lauren Penfield
GRD ’20 of Yale University have been
working to understand an analogous system
on the subcellular level—that of nuclear
envelope repair that protects DNA
from harmful substances in the cell.
They learned more about the repair process
in which a protein called lamin, a
known structural support protein of the
nuclear envelope, also acts to prevent holes
from forming in the membrane and aids
the repair process when disruptions of the
membrane do occur. They further developed
a timeline for the cellular repair process
and opened the door to a new realm of
nuclear envelope dynamics studies.
The security guard of the cell
The nuclear envelope is a two-sided
membrane that encloses and protects genetic
information from potential harmful
substances inside cells. Much like the security
guards surrounding a government official
in a crowd, the envelope forms a barrier
and keeps away threats. The nuclear
envelope is reinforced by lamins on the inner
side of the membrane, forming a meshlike
framework that supports the envelope’s
shape and structure.
By revealing more about its dynamic
structure and functions, Bahmanyar and
her colleagues have challenged the misconception
that the nuclear envelope is a
static structure prior to cell division. Two
of its most fundamental roles are inherent
in the way it encloses DNA. First, it must
be able to allow RNA, a message carrier
that is used to convert DNA into proteins,
into the cell. This is accomplished
via structured holes in the membrane
known as nuclear pore complexes (NPCs).
Secondly, it must be able to disintegrate
during cell division, so that pairs of chromosomes
can separate to opposite sides of
the parent cell, and subsequently reform in
each of the daughter cells.
In addition, recent research has led to
better understanding of the specific roles
played by the nuclear membrane in nuclear
compartmentalization and tethering
DNA to specific regions of the nucleus.
The consequences of its massive
importance in many cellular functions
are dire for those with laminopathies,
mutations or alterations in the genes encoding
lamins. Muscular dystrophy, cardiomyopathy,
and dermopathy are common
examples of laminopathies in which,
in the absence of lamins, the tissues are
easily damaged and destroyed.
Sleeping on the job
Unfortunately, the study of these conditions
is limited by poor overall understanding
of how two important functions
of lamin, supporting the structure of the
nuclear envelope and managing the organization
of the nucleus, work together. It
is often difficult for researchers to identify
which specific roles are responsible for
certain defects. To isolate the structural
role of lamin, a model system was developed
in the embryos of Caenorhabditis elegans
(C. elegans), a type of roundworm.
Because these embryos, in their early
stages, make little to no RNA out of DNA,
this model can be used to isolate the effects
of mutations affecting the structural
role of lamins.
In studying the structural role of lamins
in C. elegans embryos, Bahmanyar and
Penfield found that a certain mutation
would lead to the disappearance of the
nuclear envelope prior to the embryo’s
first cell division. Curiously, the nuclear
envelope in the roundworms with
this mutation appeared to act normally
during the earliest stages of single-celled
development when the two parental nuclei
are separate.
However, when the two parental nuclei
of the embryo are pulled together during
pronuclear migration, a later high-stress
www.yalescientific.org
April 2018
Yale Scientific Magazine
15

“
THE NUCLEAR ENVELOPE
IS NEVERTHELESS A
FUNDAMENTAL
CELLULAR COMPONENT,
AND FUTURE BIOMEDICAL
TECHNOLOGIES WILL
REQUIRE AN
UNDERSTANDING OF
THIS COMPLICATED AND
FASCINATING ORGANELLE,
A CHALLENGE
BAHMANYAR’S GROUP
SHOWS NO SIGNS
OF SHYING
AWAY
FROM.
stage of development, the membrane disintegrated.
In other words, the security
guards of the nuclear envelope appeared
to be doing their job, but, when a threat
appeared, they didn’t do anything.
Holes everywhere
To tease out the effect of this lamin mutation
on the permeability of the nuclear envelope,
the researchers expressed a fluorescent
tubulin molecule, a structural protein that
luminesces when exposed to certain wavelength
light, in the cell and used fluorescent
microscopy to track whether the tubulin was
being excluded and removed from the nucleus
as it normally should be. They found
that in mutant-lamin roundworm embryos,
the fluorescent tubulin protein permeated
into the nucleus.
They further recognized that the fluorescent
tubulin molecule could penetrate
the nucleus of roundworms with the mutant
lamin even during the early stages of
embryonic development. This suggests
some disturbance of the mutant-lamin
membrane even during times of low stress
when the nuclear membrane appeared
normal. Furthermore, they found
that 82 percent of the mutant
nuclei were able to remove
the fluorescent protein
following the initial
penetration.

molecular biology
FOCUS
“The lamin mutant nuclear membrane
must have had transient gaps opening and
closing,” Penfield said. However, never before
had it been shown that live organisms
could reestablish the nuclear membrane barrier
following disruption. “We were the first
to show evidence of repair after sudden and
complete loss of nuclear compartmentalization
in an intact organism,” Bahmanyar said.
Laser attacks
To better understand these holes and
learn more about the mechanism by which
normal lamin proteins and a healthy nuclear
envelope respond to them, the researchers
artificially punctured the nuclear
envelope using laser light. Again, the permeability
of the nuclear membrane to the
fluorescently-tagged tubulin molecule was
used as a marker. The punctures caused an
initial equilibration of tubulin between the
cytosol and nucleus followed by a decrease
in nuclear tubulin, indicating the recovery
of the nuclear envelope barrier.
This demonstrates that there must be a
mechanism of repair and restructuring of
the nuclear envelope. In the lamin mutants,
this mechanism is sufficient to maintain the
envelope’s integrity following the initial transient
disturbances before pronuclear migration.
“As long as they can repair these ruptures,
they can still survive,” Bahmanyar
said. However, when the forces pulling the
nuclei together create too much strain on the
nuclear envelope, the mutant-lamins tear,
leading to chromosome scattering and loss
of the nuclear membrane barrier.
Calling the police
To understand the interactions between
lamin and other proteins involved in repairing
holes in the membrane, Bahmanyar and
her team investigated various proteins on
the nuclear membrane in the same embryo
system. First, nuclear pore complex proteins
were visualized during early embryonic development.
In most of the lamin mutants,
a distinct section of the nuclear membrane
lacking nuclear pore complexes developed.
Near this gap of nuclear pore complexes,
which was verified to be where the envelope
ruptures occur, chromatin, the regular state
of DNA in the nucleus, was seen to condense
rapidly, potentially leading to DNA damage
and later issues with nuclear organization.
This strongly suggested that lamin plays a
critical role in organization and distribution
of nuclear membrane proteins, which is in
turn related to membrane stability.
To test this idea, a protein called Endosomal
Sorting Complexes Required for Transport-III
(ESCRT-III), which is known to be
involved in nuclear repair, was fluorescently
labeled so that its movement in the cells
could be tracked. As expected, ESCRT-III
accumulated near the damaged areas that
lacked nuclear pore complexes. A nuclear
envelope protein known to bring ESCRT-III
to seal holes during regular cell division,
called LEM-2, amassed at the same location.
Although lamin was not required for this repair
process, it was also found in the same
region, and likely is involved in stabilizing
the rupture while repair occurs. However, in
these lamin-depleted mutants, these attacks
occur more frequently and do more damage
to the precious cargo within.
Hiring the Secret Service?
This research has promising potential
for people with laminopathies, which are
often life-threatening or fatal. It may be
possible to synthetically engineer normal
lamin and transport it to the nuclear
membrane of cells. Alternatively, with
developing genetic engineering technologies,
researchers might be able to manipulate
cells to produce fully functional
lamin instead of the mutated version. It is
not unreasonable to predict that, soon, we
may understand the nuclear envelope system
well enough to synthetically engineer
improved lamin to increase the security it
provides for our DNA—essentially, hiring
the secret service to stand guard.
Furthermore, it is hypothesized that migrating
cancer cells would overuse this
nuclear rupture-and-repair process to fit
through small blood vessels when traveling
ABOUT THE AUTHOR
through the bloodstream. These migrating
cancer cells are critical for metastasis formation—the
main cause of cancer deaths. “If
we have molecular markers for nuclear envelope
rupture and repair, we might be able
to better detect migrating cancer cells,” Penfield
said. Then, the immune system might
be programmed to attack and kill these cells
before they turn into new tumors or they
could be removed via other methods.
Finally, knowing that the membrane
plays an important role in accepting viral
DNA and reforming after incorporating it,
understanding lamins and the nuclear envelope
could be helpful in the field of genetic
engineering. A better knowledge of
IMAGE COURTESY OF BAHMANYAR LAB
Fluorescent microscopy image of a wildtype
embryo with LEM-2 in green and VPS-32,
a component of the ESCRT machinery that
resides in the cytoplasm, in red.
lamin proteins, how the nuclear envelope
works to repair itself, and what treatments
might increase the efficiency of DNA incorporation
would take us one step closer to a
genome editing therapy. While a challenge
to study due to its rare activity, the nuclear
envelope is nevertheless a fundamental cellular
component. Future biomedical technologies
will require an understanding of
this complicated and fascinating organelle,
a challenge Bahmanyar’s group shows no
signs of shying away from.
LUKAS COREY
LUKAS COREY is a first-year student in Pauli Murray College studying Molecular, Cellular, and
Developmental Biology and Computer Science. He is currently researching transposable DNA
elements in Professor Ronald Breaker’s lab.
THE AUTHOR WOULD LIKE TO THANK Professor Shirin Bahmanyar and Lauren Penfield for
staunchly pursuing an understanding of this elusive organelle and for their time.
FURTHER READING
Lammerding, J., and K. Wolf. “Nuclear Envelope Rupture: Actin Fibers Are Putting the Squeeze on the
Nucleus.” J Cell Biol 215, no. 1 (2016): 5-8.
www.yalescientific.org
April 2018
Yale Scientific Magazine
17

Think of a fossil.
What do you see?
Perhaps dinosaur
bones, teeth, or
mollusk shells?
Mineral Maps
for
Fossil Hunters
Improving the
localization of rare
soft-tissue fossils
by || Christine Xu
art by || Zihao Lin
When we think of fossils, we traditionally
picture hard tissue parts. However, rarer
soft tissue fossils are also extremely valuable
in piecing together the story of early
life on Earth.
Not every part of every organism makes
it into the fossil record. The fossil record
is biased towards hard tissues like shells,
teeth, and bones; soft tissues are usually left
out of the fossil record because they tend
to decay rather than fossilize. But many
types of early organisms, like worms and
shrimps, were made of soft tissues. Soft
tissue fossils provide valuable information
on early life—that is, when fossil-hunting
researchers are able to find them.
A team of researchers at Yale, led by Professor
Derek Briggs of the Geology and Geophysics
Department, investigated where soft
tissue fossils are likely to be found. In a recent
study published in Geology, the researchers
characterized the mineral signatures of rocks
that tend to preserve soft tissue parts, in order
to help scientists pinpoint places to find
soft tissue fossils. This research accelerates the
search for rare soft tissue fossils not only on
Earth, but possibly even on other planets.
Treasures at the Burgess Shale
Most early organisms did not have shells
or bones; it took until the Cambrian Explosion,
around 500 million years ago, for
organisms to develop hard body parts that
were preserved in the fossil record. Studying
soft tissue fossils thus provides insights
into some of the earliest life forms on our
planet, such as what they looked like and
how they might have survived.
While soft tissue fossils are generally rarely
found in the fossil record, there is an exception:
the Burgess Shale, a geologic rock
formation in the Canadian Rocky Mountains,
containing fossilized creatures from
around the Cambrian Explosion. The Burgess
Shale preserves a remarkable diversity
of organisms, including an unusually high
18 Yale Scientific Magazine April 2018 www.yalescientific.org

geology
FOCUS
number of soft tissue fossils. For this reason,
a major category of soft tissue fossils
is referred to as Burgess Shale-type fossils.
Briggs wondered what conditions are conducive
to the formation of soft tissue fossils
like those in the Burgess Shale. “I was interested
in the preservation of fossils: the processes
that account for the transfer of an organism
into the fossil record, and the biases
that that results in,” Briggs said. Pursuing
this line of thinking, Briggs and his team began
to study some of the mineralogical differences
between rocks that do and do not
contain soft tissue fossils.
Clues from minerals
Ross Anderson, currently a fellow at All
Souls College, Oxford and previously a graduate
student in Briggs’ group at Yale, pioneered
this study on the mineralogical conditions
that lead to soft tissue preservation.
While hunting for fossils around the world,
he saw that different regions would preserve
more soft tissue or hard tissue fossils and
wondered why this was the case.
“If you go far back enough, before organisms
made shells or bones, the fossils become
much harder to find,” said Anderson.
“I investigated the conditions conducive to
those early fossils being preserved, so we
can more easily find them.”
Anderson and Briggs collected about 200
rock samples from sites around the world,
including the Burgess Shale. About half of
these preserved fossils with soft tissues, like
parts of primordial worms and shrimps. The
others included more common hard tissues
fossils, like shells and bones and trilobites.
The researchers ground up the rocks surrounding
the fossils and analyzed them
using a technique called X-ray diffraction,
which provides a mineral signature for
each rock. They compared the mineral signatures
of those rocks containing soft tissue
fossils with those that had only hard tissue
fossils. Anderson noticed that the rocks
with soft tissue fossils had high levels of a
distinct mineral called berthierine, which
tends to form in tropical and iron-rich areas
such as the Burgess Shale.
In a previous study on the impact of bacteria
on fossil formation, Briggs, Anderson,
and colleagues had postulated that certain
clay minerals are toxic to bacteria, promoting
soft tissue fossil formation by protecting
the fossils from bacterial decay. One such
toxic clay mineral was berthierine. Thus, this
mineral may prove to be the explanation for
the preservation of soft tissues in fossils.
From the Burgess Shale to Mars
PHOTOGRAPHY BY CHRISTINE XU
A soft-tissue fossil, which is less-commonly
found in the fossil record due to their tendency
to decay rather than fossilize.
ABOUT THE AUTHOR
Briggs’ and Anderson’s findings will help
other fossil researchers in their hunt for soft
tissue fossils. Now, this knowledge can allow
them to target specific areas and types
of rocks in their search, saving time and resources.
This information could also aid in
the discovery of more Burgess Shale-type
soft tissue fossils, leading to a larger number
of clues about the different types of organisms
existing on early Earth.
Additionally, microfossils of small organisms
like bacteria are valuable to understanding
early microbial life, but extremely hard
to find. Typically, the process for identifying
rocks likely to contain microfossils is arduous,
requiring countless hours observing sections
of rocks and looking for bacterial fossils.
“Imagine you go out and break up the rock
with a hammer and find fossils—if you do
this for the pre-Cambrian, you can’t see the
fossils. So you collect large amounts of sedimentary
rock and you process them in various
ways,” Briggs explained. Now, Briggs
hopes that their research will lead to expedited
identification of rocks that are likely to
contain these microfossils.
Another impact of their research lies in
the search for life on other planets, such as
Mars. “The rover on Mars—the Curiosity
Rover—has the ability to make mineralogical
measurements,” Anderson said. “It has
an X-ray diffractometer on it, and it has the
ability to see if those rocks it looks at on a
daily basis are conducive to finding soft tissue
fossils or not.”
Briggs and Anderson’s research was partly
funded by NASA, and they are hopeful that
their mineral maps can help with the search
for fossils, especially microfossils, at locations
from the Burgess Shale to Mars. “The
long term application would be to look for
fossils on other planets,” Briggs said.
Their research helps scientists not only
look for possible records of life on other
planets, but also understand the factors
that led to such intricate life forms on our
own planet. “Understanding how complex
life first evolved on Earth is one of the fundamental
questions in the natural sciences,”
Anderson said. “How did we go from
a world with just microbes, to one where
when you look out the window there are all
sorts of plants and animals? We can make
simple observations in rocks and learn a lot
about how life evolved on Earth.”
CHRISTINE XU
CHRISTINE XU is a senior MCDB major in Saybrook College. She has been writing for Yale Scientific
Magazine since her freshman year and was the previous News Editor. She plans to pursue a career
in research, medicine, and writing. On a typical day, you can find her taking pictures of brains in
her lab, singing with her a cappella group Pitches & Tones, or watching cat videos.
THE AUTHOR WOULD LIKE TO THANK Derek Briggs and Ross Anderson for their time and
enthusiasm in sharing this fascinating work.
FURTHER READING
Anderson, R. P. et al., 2018. “A mineralogical signature for Burgess Shale-type fossilization.”
Geology 46(4):347-350.
www.yalescientific.org
April 2018
Yale Scientific Magazine
19

FOCUS
medicine
D O U
Imagine two twins who, though identical
in every respect from height to facial features,
differ in a single gene. One twin has
it, the other does not. Yet, the cascade effect
is staggering—just one missing gene results
in a viciously unregulated cell growth. Left
uncontrolled, the cell cycle repeats on loop.
Cells accumulate in the body, eventually becoming
devastating, cancerous tumors. How
could things have gone so wrong?
Researchers at Yale University, overseen
by Professor of Pharmacology Dianqing Wu,
discovered a new role of the protein called
Dickkopf-related protein 2 (DKK2) that is
overexpressed when cells lack a certain regulatory
gene called adenomatosis polyposis
coli (APC). Without the APC gene, DKK2
levels increase, promoting growth of cancerous
cells, eventually forming tumors. Suppression
of DKK2 using a novel antibody
shows promising results in promoting activity
of tumor-killing immune cells. Moreover,
their research, published in Nature
Medicine, demonstrates how blocking the
function of DKK2 encourages the host’s own
immune system to fight against cancer cells.
Taken together, their results present promising
implications for improving the efficacy
of immunotherapy treatments for those with
colorectal cancer.
A background on colorectal cancers
Over 80 percent of colorectal cancers are
caused by a mutation in APC, a gene which
is responsible for regulating a cell-signaling
and growth pathway called the Wnt/β-catenin
pathway. In past research, this pathway
has been shown to affect blood glucose levels
and bone mass as well as play a role in embryonic
development and gene expression.
Without the APC gene, the Wnt/β-catenin
cell signaling pathway is hyperactive, resulting
in overproduction of cells and eventual
tumor formation.
Previous research has shown that in
normal cells, DKK2 interferes with the
Wnt/β-catenin pathway, preventing cell signals
from being passed along to continue
cell division. Therefore, it seems intuitive
that a decrease in DKK2 would increase
the activity of the Wnt/β-catenin pathway,
which would subsequently increase cell
proliferation and increase the number of
tumors, right? Not quite—the story is much
more complicated.
A blockade to the study
By analyzing gene expression databases,
the researchers noticed that DKK2 expression
is significantly higher in colon cancer
samples, particularly in those likely harboring
the APC mutations, than in normal
ones. The researchers went on to determine
whether DKK2 expression differed between
hosts with the APC gene and those without.
In order to study this, researchers used a
cancerous mouse model with the APC gene
suppressed through genetic engineering
techniques, which models the human condition.
The researchers found a significantly
higher expression of DKK2 in mice lacking
the APC gene. Even more, samples of human
colon cancer cells indicated a correlation between
increased expression of DKK2 with
higher rates of normal cell death. This left the
researchers wondering about the role of this
protein—as well as whether they could regulate
overexpressed DKK2.
One way to determine the role of DKK2
is to block the function of the protein and
observe the resulting effect. The researchers
used two means to create the DKK2 blockade:
a genetic approach by which the DKK2
gene is disrupted in mice and the pharmacological
approach by which an antibody,
termed 5F8, was generated to neutralize
DKK2 activity. Following DKK2 blockade via
either the genetic approach or treatment with
5F8 antibody, they found lower occurrences
of tumor formation in the intestines of mice
and increased survival of these tumor-bearing
mice. This means suppression of DKK2
is attributed to better health outcomes. Furthermore,
these conclusions support DKK2’s
role in tumor progression, where a larger
amount of the protein significantly increased
the severity of tumors formed.
Getting to the bottom of it
IMAGE COURTESY OF DAN WU
Immunostaining images showing DKK2 protein,
colored in red.
I N H I B I T I N G A N I N H I
Having deduced the role of DKK2 on increasing
tumor formation, the researchers’
next goal was to uncover the exact mechanism
of their protein’s function. Specifically,
the researchers were interested in exploring
the relationship between the DKK2 blockade
with natural killing (NK) and CD8 +
cells. These immune cells are crucial for
targeting and killing cancerous cells. What
would happen if these immune cells were
not present in APC-lacking cells treated
with the DKK2 blockade? To test this, the
researchers treated the mice with antibodies
specific to both NK and CD8 + cells, deplet-
T R O
20 Yale Scientific Magazine April 2018 www.yalescientific.org

medicine
FOCUS
B L E
ing these cells. They found that DKK2 antibody
treatment was no longer effective—
the blockade could not suppress tumors
without these immune cells.
From these results, the researchers concluded
DKK2 plays a role in controlling
the immune system’s ability to monitor the
tumor environment. Of interest to Wu and
his team was investigating the mechanism in
which DKK2 influenced these immune cells.
To determine whether the mechanism could
be attributed to cell signals sent through
the Wnt/β-catenin pathway, the researchers
then treated cancer cells with a protein
known to activate the pathway. However,
they found no effect on suppression of NK
cells, suggesting that DKK2 was not inhibiting
immune cells through Wnt/β-catenin.
Moreover, they arrived at a surprising conclusion:
DKK2 is acting independently of
the Wnt/β-catenin pathway and suppresses
the activity of interleukin-15, an important
BITOR TO TREAT TUMORS
cytokine for NK and CD8 T cell functions
via a previously unknown mechanism. Taken
together, the researchers’ discovery has
implications for future treatment methods
for colorectal cancer.
A promising potential for cancer treatment
Current immunotherapy treatments are
effective for a subset of colorectal cancers,
termed microsatellite instable (MSI), but not
for the subset largely caused by mutations
in the APC gene, termed microsatellite stable
(MSS). Using treatment of 5F8 in mouse
models, the researchers found the antibody
was effective not only in MSI, but also MSS,
leaving the researchers to ponder the effect
of combination treatment of antibody with
current immunotherapy treatments.
To determine how treatment with the 5F8
antibody affects health outcomes when used
in conjunction with a current immunotherapy
treatment for both MSI and MSS colorectal
cancers, the researchers then treated
a mouse model with both drugs. The current
immunotherapy treatment inhibits tumor
cells from evading the immune system in
MSI colorectal cancers, but not MSS. “We
wanted to see whether our mouse models
would show higher survival rates with combination
treatment,” Wu said. The results
were promising—treatment of the current
immunotherapy drug together with 5F8
antibody promoted greater MSS tumor suppression
than the antibody alone.
Yet, these results do more than overturn
what was originally thought to be the role of
DDK2. For starters, the team’s antibody successfully
blocks the function of DKK2, thereby
suggesting the efficacy of this antibody in
reducing tumor formation. The second significant
finding from their study is that this
antibody serves as a potential therapeutic
treatment for those with colorectal cancers.
While current immunotherapy treatments
help immune cells called T cells identify and
attack cancerous cells, they are often less
ABOUT THE AUTHOR
successful in colorectal cancers. Therefore,
the 5F8 antibody may be used in conjunction
with current immunotherapy drugs to
further suppress tumors. “The combination
of the two [drugs] will show a better, synergistic
outcome,” Wu said.
There are still unanswered questions and
drawbacks to address. For instance, DKK2
is not the only protein that causes tumor
immune evasion. Other proteins and their
mechanisms of action remain to be discovered.
In addition, the team’s research was
done on mouse models, and their results may
not be aligned with that of human models.
However, the researchers’ discoveries contextualize
DKK2’s malignant role in tumor
formation. Pushing forward, Wu states the
necessity of further tests in human models
before the antibody can be considered for
cancer treatment. The research team has
licensed this intellectual property to a biotechnology
company that will test the antibody
further. If all goes well, there could be
another drug on the market to treat colorectal
cancer and related melanomas. “Our next
step is to see if DKK2 blockade can really
show efficacy in treating human colorectal
cancers. We are very hopeful,” Wu said.
JESSICA TRINH
JESSICA TRINH is a sophomore Neuroscience major in Branford College. She is the President of
Synapse , the outreach branch of Yale Scientific. She also teaches health education in New Haven
middle schools, nutrition counseling at HAVEN Free Clinic, and is currently leading a research
project on nutrition.
THE AUTHOR WOULD LIKE TO THANK Dr. Dianqing Wu for graciously sharing his research.
FURTHER READING
Marçais, A. & Walzer, T. 2018. "An immunosuppressive pathway for tumor progression." Nature
Medicine 24, 260-261.
A R T B Y L A U R E N G A T T A
www.yalescientific.org
April 2018
U B L E
Yale Scientific Magazine
21

MODELING LUNGS
for a NEW CURE
Researchers are demystifying complex lung
diseases using new engineered models
by SONIA WANG || art by ANUSHA BISHOP
It’s a diagnosis that stumps even the best of doctors. Idiopathic pulmonary fibrosis
begins with a small cough and progresses over time to stop lung function—so
much so, that patients cannot receive enough oxygen by inhaling. Scarred lung tissue—fibrosis—hardens
the lung and makes it difficult to breathe and receive oxygen.
On average, patients can only expect to live
two to five years after a diagnosis of idiopathic
pulmonary fibrosis (IPF). What’s worse is
that doctors come to diagnose IPF only after
patients do not respond to any other known
treatments for fibrosis. “Idiopathic” means of
an unknown cause. Doctors can only scratch
their heads in vain, as there is no cure, and no
known cause for IPF.
“It really is a disease where we don’t understand
why or how it occurs,” said Professor of
Biomedical Engineering Anjelica Gonzalez.
“The result is either they die after diagnosis
or have a transplant.” But transplants also can
result in problems if transplant organs are not
compatible with the patient, causing a strong
immune response in the patient.
In a collaboration between the Anjelica
Gonzalez lab in the Department of Biomedical
Engineering and the Erica Herzog lab at
the Yale School of Medicine, researchers have
been able to engineer human lung tissue and
model the process of fibrosis in human lungs.
This advancement will make it much easier for
researchers to further investigate fibrosis and
the effect potential drugs.
Pericytes: the link in the system
Your blood vessels are like the irrigation
system of the body, bringing nutrients and
oxygen to the brain, heart, and other specialized
cells. Blood vessels vary in size and function;
the body’s smallest blood vessels, for example,
allow for direct cell-to-blood exchange
of nutrients and wastes.
Pericytes are small cells that wrap around the
lining of the blood vessels, thereby regulating
both blood vessel development and blood flow.
Gonzalez has always been interested in the engineering
principles behind how blood vessels
deliver oxygen to tissues on such a small scale,
and began studying the role of pericytes in supporting
the circulatory system.
The researchers found a novel role for pericytes
in IPF progression. During IPF, tissues
die because of limited nutrient and oxygen
delivery. Blood vessels in the lungs become
disrupted and stop functioning. Pericytes
were previously thought to die along with
normal tissue cells. But Gonzalez’s lab found
that pericytes were not only alive in IPF patients,
but they also made up part of origin
sites of fibrosis. In other words, the pericytes
themselves had become dysfunctional.
Modeling the lung
With this newfound knowledge of the role
of pericytes in fibrosis, Gonzalez’s lab began
to engineer human lung tissue that could
model the transformation from healthy tissue
into stiff fibrotic tissue.
“[The engineered lung] is the size of a
thumbnail, a little glass slide that mimics the
lung environment,” said Parid Sava, a previous
graduate
student in the
Gonzalez lab and
first author on the paper.
“We take the scaffolding
and match it to the mechanical
properties of fibrotic or healthy tissue.”
The scaffolding serves as the base “membrane”
upon which cells are anchored. This
membrane can be made either stiffer or
softer using hydrogels—stiffer scaffolding
imitates hardened, scarred fibrotic tissue,
while softer scaffolding imitates healthy tissue.
Then, the researchers added cells to the
scaffolding and observed the outcomes.
Fibrosis is a vicious cycle; the stiffer the original
lung tissue, the more fibrosis will occur. Researchers
identified a compound, transforming
growth factor-beta 1 (TGF-β1), that drives
pericytes to leave the blood vessels and increase
their secretion of proteins that form supporting
extracellular matrix, which increases the
stiffness of the surrounding tissue. An increase
in model tissue stiffness was seen to cause increased
fibrosis induction by the pericytes,
22 Yale Scientific Magazine April 2018 www.yalescientific.org

iomedical engineering
FOCUS
liver fibrotic diseases can have—but the
lung cannot do the same.
Using human tissue instead of mouse models
or organs with the ability to regenerate paints a
more accurate picture of the disease. “It gives
clinical researchers a better idea of what happens
in the human system,” Gonzalez said.
Bringing hope to patients
showing
that tissue
stiffness can have
effects on the severity of fibrosis and the progression
of IPF.
This modeling technique represents an
advancement in research methods, making
it easier for researchers to study in human
lung fibrosis. Prior to Gonzalez’s research,
animal models such as mice were
primarily used to study tissue fibrosis. The
problem was that animal models repair
themselves over time, so animal models
cannot be used reliably to model human
pulmonary fibrosis progression.
“Lung fibrosis is so extreme because
lungs cannot regenerate,” Gonzalez said.
For instance, the liver can heal scarred tissue
and therefore reduce the damage that
Now that the researchers have a model for
how fibrosis progresses, they hope to investigate
how to reverse the process of fibrosis. “IPF
is a pretty terrible disease…we wanted to figure
out why this is happening and find drugs
to prolong their lives,” Sava said. “What we’re
really excited about is how to re-treat it.”
In the future, researchers will test potential
drug candidates on fibrotic models to see if
scarred, fibrotic tissue can be converted back
into healthy tissue. Treatment with nintedanib,
a currently used antifibrotic agent, reduced
the progression of lung remodeling by the
pericytes. “We’ve looked at three [drugs] and
are on the way to a few more,” Gonzalez said.
The lab’s lung models not only provide a more
accurate depiction of fibrosis, but they also cut
down on costs of clinical trials, as drugs can be
proved in the tissue models before being tested
on mouse models and in human trials.
The new fibrotic models can also be applied
to investigate other diseases. Diseases
that share a similar progression from soft
tissue to scarred fibrotic tissue can also be
modeled by using different types of cells to
fill in the scaffolding. “We can take tissues
from liver fibrosis, kidney fibrosis, and skin
fibrosis, for example, and use the same model
as before where we figure out what is driving
the condition,” Sava said.
Researchers can also model other diseases
that involve changes in the tissue of the lung.
“In IPF [lung tissue] gets stiff, but in other
ABOUT THE AUTHOR
IMAGE COURTESY OF ANJELICA GONZALEZ
A lung tissue sample being subjected to tensile
testing to measure tissue stiffness.
lung diseases, the tissue degenerates or becomes
soft,” Gonzalez said. Now, researchers
can begin to understand the role of mechanics
on disease and investigate potential new
treatments further.
Researchers in the Gonzalez and Herzog labs
are taking an interdisciplinary approach not
only to investigate potential new therapies, but
also to make it easier for researchers to investigate
therapies in the future. The new model of
tissue fibrosis that the Gonzalez lab has created
will facilitate new investigations into the causes
of and potential treatments for IPF, similar fibrotic
diseases in other tissues, and other lung
diseases that involve mechanical tissue changes.
In the future, perhaps a drug candidate able
to reverse IPF will emerge, providing hope to
the patients affected with a once incurable, little-understood
disease.
SONIA WANG
SONIA WANG is a current senior in Jonathan Edwards College majoring in Biochemistry and
Economics. She used to be managing editor and news editor for the Yale Scientific, and loves
scientific writing. She currently works in the Joan Steitz lab on microRNA degradation.
THE AUTHOR WOULD LIKE TO THANK Dr. Sousa and Dr. Zhu for sharing their time and enthusiasm
about their research.
FURTHER READING
Sava, P., Ramanathan, A., Dobronyi, A., Peng, X., Sun, H., Ledesma-Mendoza, A., Herzog, E.L., &
Gonzalez, A. L. (2017). Human pericytes adopt myofibroblast properties in the microenvironment
of the IPF lung. JCI insight, 2(24).
www.yalescientific.org
April 2018
Yale Scientific Magazine
23

HIGH SCHOOL ESSAY CONTEST
BIOMIMICRY:
BY JOHN LIN || FROM WILLIAM P. CLEMENTS HIGH SCHOOL
USING CACTI TO IMPROVE
WATER STORAGE METHODS
Water covers about 71 percent of Earth’s surface, but throughout
the world, this natural resource appears to be drying up. Due
to global warming, desertification is rapidly spreading across the
world. The world is finding that critical freshwater reserves are
disappearing in the face of increasing population growth. Just as
more water is needed, less water is available. However, cacti have
dealt with this problem for millennia and have adapted to arid
climates. We can learn from these prickly plants to solve one of
the world’s most pressing problems.
Our current stopgap measures are failing. Most modern water
storage methods use jerry cans, lidded buckets, and clay pots
but require backbreaking labor that is predominantly done by females.
UNICEF estimates that across the world, women and girls
spend 200 million hours collecting water each day, forcing them
to abandon their education and employment and enter a cycle of
poverty and dependence. Additionally, this water is often dirty, resulting
in major waterborne disease outbreaks that devastate developing
nations. Finally, these buckets require a tradeoff between
water supplies, temperature, and sanitation. For example, clay
pots lose water to evaporation but are cooler. On the other hand,
buckets create a warm environment ripe for bacteria growth.
Instead of using costly chemical reactions to synthesize hydrogen
and oxygen, scientists can find a cheap solution in biomimicry.
Succulent plants are uniquely adapted to absorb and retain
water from their arid surroundings. Learning from them will help
us efficiently deal with desertification and minimize water conflicts.
Cacti are among the most effective succulents, surviving in
habitats from the Atacama Desert to the Patagonian steppe. Semiarid
and arid areas experience varying levels of rainfall, demanding
different tissue thicknesses and structural designs. We should
study cacti to produce location-specific containers that can absorb
and store safe water at optimal temperatures.
Scientists should explore water retrieval methods including
cacti’s water absorption. Cacti build shallow roots that can branch
out, allowing them to react quickly to rainfall. We can utilize capillary
action, much like plant roots, to gather water at a heap energy
cost. Researchers at the Chinese Academy of the Sciences are
studying artificial root systems that could store rainwater. Some
cacti also store fog water, thanks to spines that collect water molecules.
Scientists from Beihang University are already developing
similar structures by electrospinning polyimide and polystyrene.
Moreover, this could help improve filtration systems. Dr. Norma
Alcantar from the University of South Florida found that prickly
pear cactus gum effectively removes sediment and bacteria from
water. We could eliminate common diseases, free women to pursue
studies, leisure, or careers, and save millions of lives.
Researchers can also improve water storage by focusing on cacti
because of their high water retention. Because of their fleshy tissue,
many cacti can hold large amounts of water. In fact, Charles
Gritzner, Distinguished Professor Emeritus of Geography at
South Dakota State University, notes that some can store up to
two tons of water, or 1,800 liters. We can learn from their thick
structures to maximize the quantity of water stored. Cacti also
have unique structural designs including protective hair to deflect
sunlight, which defends against dangerous heat levels. Cacti have
additionally developed waxy skin to prevent water loss. We can
combine this with biodegradable material to promote environmental
sustainability by avoiding plastic. These innovations fix
the current temperature-water loss tradeoff and maximize utility.
This large, bulky bucket would be incredibly adaptable. In foggier
areas like the Atacama Desert, artificial spines would help collect
water, while mechanical roots would work better in drier places.
The layer of gum-like lining on the inner walls of the pail would improve
sanitation. The water would be protected from heat through
intricate designs of folds and hair. The outer waxy coating would
help preserve water while maintaining cooler temperatures. Humanitarian
organizations could distribute this in developing nations,
ensuring that each family has a stable, safe source of water.
The consequences of ignoring water shortages are dire because
water is the most precious resource of life. Not only is approximately
60 percent of the adult human body made of water, each American
uses around 80-100 gallons of water every day. This has promoted
hygiene and eliminated disease outbreaks, with handwashing alone
reducing diarrheal disease-related deaths by almost 50%. With antibiotic-resistant
bacteria developing rapidly, hygiene is critical for
public health. Water is also heavily used in food production, irrigating
62.4 million acres of American cropland in 2010. Agriculture
accounts for 70% of freshwater withdrawals each year. As global
warming intensifies regional climates, more water is needed. Otherwise,
the world would be torn apart by hunger and thirst.
Losing water will also have major geopolitical implications.
The World Economic Forum has ranked water crises among
the five most impactful global issues for the past four years. As
countries compete for an ever-shrinking supply of water, wars
are bound to break out. The Global Policy Forum predicts that
more than 50 countries across five continents will likely be
forced into water conflicts. Already, nuclear armed states such
as India and Pakistan engage in water fights. The resulting wars
could claim billions of innocent human lives.
Although more advanced technology is being developed, biomimicry
provides a cheap, clean, and quick answer to the billions
of people surviving on inadequate and unsafe water. Unless
we take action, water wars, food shortages, and disease
outbreaks will tear the world apart. For the sake of humanity’s
survival, we must turn to cacti to guide our water foraging efforts
in the developing world.
www.yalescientific.org

FEATURE psychology
BY ALICE TAO
AN ELEPHANTINE TEST OF CHARACTER
Elephant personality tests reveal unique traits
IMAGE COURTESY OF FLICKR
Sociability, how the elephant socializes with other elephants and with
humans, was one of the three personality factors discovered in the study.
Elephants are people, too! Or, at least, their personalities
have a similar structure to those of humans. Different people
have different personalities; some people are more social,
while others are braver, or more aggressive. Personality
is made of these consistent differences in individuals’ behaviors.
Over the past few decades, behavioral scientists have corroborated
this concept through personality studies. However,
most existing studies have focused on humans, primates, or
zoo populations. Personality data for long-lived, highly-social
wild mammals with complex cognitive abilities are still rare.
To close this gap, researchers at the University of Turku in Finland
have begun conducting personality research on a semi-captive
population of elephants in Myanmar, Burma since 2014. Elephants
are long-lived and usually give birth to only one calf at
a time, which allows a mother to care for a calf for a long time
after birth. Furthermore, they have high cognitive abilities and
live in a complex social environment. The traits their lives share
with those of humans and some non-human primates make elephants
unique subjects for complex personality research.
Burma is home to the second largest total population of Asian
elephants remaining worldwide. The university’s research was
conducted on a population of over 250 timber elephants who
live and work in government-owned timber camps in Myanmar.
These elephants work by pulling logs from one place to
another but still live comfortably in their natural habitat. Their
unique living conditions allowed researchers to study hundreds
of individual elephants at once. Furthermore, the elephants
work closely alongside a single mahout, a human elephant rider
who works with and tends the elephant. Mahouts generally
work with their focal elephant for many years, often for their
whole life. “Mahouts gain profound knowledge about their elephant’s
behavior, and likely nobody else could assess these elephants
better than their mahouts,” said Martin Seltmann, a
postdoctoral researcher from the Department of Biology at the
University of Turku and lead author on the study.
The researchers collected data for the study using questionnaires
about the elephants’ personalities. These questionnaires were given
to the elephants’ mahouts in order to evaluate aspects of their
elephants’ behavior based on 28 different behavioral traits and the
frequency of each behavior. The study found that this population
of Asian elephants had three distinct personality traits: attentiveness,
sociability, and aggressiveness. Attentiveness is related
to how the elephant responds to commands from mahouts and
how the elephant acts in and perceives its environment in general.
Sociability refers to how the elephant seeks close relationships
with both other elephants and humans. Aggressiveness is how
combatively the elephant acts towards others and to what extent
that behavior impacts their social interactions. They found no
significant differences in the structures of these three personality
factors between male and female elephants.
Of the three personality traits discovered in the study, Seltmann
found the attentiveness trait most intriguing. This study
was the first to suggest a personality factor like attentiveness in
elephants, but Seltmann believes this observed trait may not be
unique to them. “It would be exciting to investigate if a similar
personality factor would manifest in other working animals, like
domestic horses or search dogs,” Seltmann said. He also pointed
out the lack of a neuroticism factor in the population, which
was surprising to him because of how frequently the factor is
observed in other studies conducted on elephants in zoos. Neuroticism
is most likely found in the zoo populations because
they are living in a fully-confined captive state. In this study,
Seltmann attributes the lack of the neuroticism factor to the elephants’
semi-captive natural environment, which allowed the
elephants to live in their natural environments under normal
living conditions of wild elephants.
As one of the first of its kind, this study sheds more light on
how personality develops and helps provide the basis for future
research linking personality to reproductive success. “We want to
look at the relationship between an elephant’s early environment,
its stress physiology, and its personality. We may also investigate
potential maternal effects on an elephant’s personality,” Seltmann
said. Furthermore, this research may also help facilitate the protection
of the Asian elephant species and improve the subjective
well-being of individuals in this population. As the endangered
species continues to decline in population, a better understanding
of the factors which structure the elephant’s personality can
help inform their management and healthcare. Only then, armed
with the knowledge that elephants are in fact just like us, can mahouts
perfect their methods of working with their animal counterparts—as
equals.
25 Yale Scientific Magazine April 2018 www.yalescientific.org

FEATURE biochemistry
PULLING MOLCULES OUT OF THIN AIR
The first artificial protein that can act as a life-sustaining enzyme
BY SUNNIE LIU
How did life emerge? What does it mean for something to be
alive? These questions may be well suited for a philosophy seminar,
but they have also been asked in science labs throughout
history. In 1859, Charles Darwin published his book On the Origin
of Species, explaining how life came to be with the theory of
evolution. In 1953, the famous Miller-Urey experiment studied
how life started in the first place under the conditions of Earth’s
early atmosphere. Likewise, in 2018, Princeton chemistry professor
Michael Hecht’s lab is examining these philosophical
questions through the lens of science. According to Hecht, the
central question his lab is investigating is: “What are the minimal
requirements for life?”
To explore this inquiry, Hecht and his lab are making artificial
proteins that can facilitate life-sustaining chemical processes. Former
Princeton graduate students Ann Donnelly and Katie Digianantonio,
postdoctoral fellow Grant Murphy, and Hecht recently
created the first artificial protein that can catalyze the reactions
necessary for life both in the lab and in living cells: Syn-F4.
The artificial Syn-F4 protein sustains life by functioning as an
enzyme. Life is sustained by myriad chemical reactions, each of
which requires an enzyme to catalyze it. Without enzymes, biological
reactions would not occur quickly enough for life to exist.
To make proteins from scratch, the researchers synthesized
DNA sequences to code for countless random variations of
amino acid sequences, which are the building blocks of proteins.
From this massive collection of different artificial DNA
sequences, they screened for DNA sequences that could potentially
replace previously known genes that E. coli need to survive.
“Finding that random DNA sequences can do something productive
goes against the prevailing thought that DNA sequences
have to be optimized over millions of years to do something
productive,” said Digianantonio.
In this study, the Hecht team tested a synthesized DNA sequence
that encoded the artificial protein Syn-F. First, they created
a strain of E. coli that was missing the essential gene that encodes
the Fes enzyme, which is involved with iron uptake. While
iron, a nutrient E. coli requires to survive, is abundant naturally,
it exists in a form that is not easily accessible. Organisms have
special molecules that they use to access and collect iron, one of
which is called enterobactin, but they need an additional tool like
Fes to extract the iron from these molecules. When the scientists
offered iron to modified E. coli, all the colonies remained red, indicating
that the iron was still held by the enterobactin. Without
Fes, this modified E. coli strain could not liberate the iron from
the enterobactin on its own. However, when the researchers replaced
the missing essential gene that encodes Fes with a synthetic
DNA gene that encodes Syn-F4, the E. coli colonies changed color
from red to white, indicating that the cells successfully accessed
the iron, and suggesting that Syn-14 acted as an enyzme in place
of Fes to catalyze the release of iron from enterobactin.
While Donnelly was the first to describe Syn-F4’s enzymatic
mechanism, her astonishment in the wake of the discovery
motivated her to repeat the experiment herself and further ask
both Digianantonio and Murphy to repeat it. All of the results
confirmed that Syn-F4 did indeed function enzymatically. Since
2011, the Hecht lab has been able to delete four essential E. coli
genes and replace them with synthesized DNA sequences that encode
artificial proteins. While the previous three artificial proteins
did not function as enzymes and instead worked indirectly to sustain
E. coli survival, Syn-F4 made a huge breakthrough as the first
artificial protein to act as an enzyme.
Artificial proteins like Syn-F4 open doors that researchers did
not previously know existed. “Nature is merely building with what
it already has. If we in the lab can give organisms totally new sequences
to work with, what could happen?” Digianantonio said.
For instance, enzymes help speed up the industrial production of
food, fuel, and medicine, but these industries often repackage preexisting,
natural enzymes that have evolved over billions of years.
“We can do much more if we do not limit ourselves to proteins
that already exist in nature,” said Hecht.
In addition, the Hecht team is taking the first step towards
creating an artificial proteome—the complete set of all the proteins
expressed by an organism—that can sustain life. Thinking
ahead, Hecht said, “Can you replace an entire genome with novel
sequences? That would be creating new cells.” While artificially
making new cells in a lab may sound like science fiction,
Hecht believes that chemistry involves exploring the boundary
between the possible and the impossible. “Molecular biologists
are studying life that exists, evolutionary biologists are studying
life that was, and chemists are studying that which might be possible”
Hecht concluded.
IMAGE COURTESY OF FLICKR
This photo shows E. coli, whose essential genes the Hecht team
removed and replaced with artificial DNA sequences.
26 Yale Scientific Magazine April 2018 www.yalescientific.org

iomedical engineering
FEATURE
SENSATION REGENERATION
Self-healable and recyclable electronic skin
BY GENEVIEVE SERTIC
IMAGE COURTESY OF JIANLIANG XIAO
The new e-skin offers sensitivity to environmental stimuli, malleability,
and an ability to self-heal in addition to full recyclability.
Skin provides us with an incredible range of sensory input.
We feel the softness of a pillow as we drift off to sleep or feel
a jolt of pain when we touch a hot stove. But skin isn’t just a
highly evolved sensor; it bends and stretches with our movements
and heals itself when we get a scratch. Creating a material
that mimics these properties has the potential to give prosthetics
a sense of touch or robots an understanding of their
sensory environment. Electronic skin, or e-skin, is a developing
technology that sets out to do just that.
E-skin is a thin electronic material designed to imitate properties
of human skin—an ability to receive sensory input and,
ideally, an ability to self-heal. Researchers all over the world are
developing e-skin for one application or another, whether it is
for shirts that monitor body condition or for magnetic sensors
with potential applications in virtual reality. But one issue that
all electronic skin faces is what to do with it if it becomes too
damaged or worn to be used. The usual answer is that the electronic
material has to be discarded along with the 50 million metric
tons of electronic waste generated every year. The materials in
electronic waste are valuable and potentially hazardous to environmental
and human health—dual deterrents to their disposal.
A group of researchers at the University of Colorado Boulder,
led by professor of mechanical engineering Jianliang Xiao and
professor of chemistry and biochemistry Wei Zhang, recognized
this issue and set out to develop an e-skin that offered
the best of both worlds: full recyclability, complex sensory recognition,
sufficient flexibility, and the ability to self-heal. Made
from a polymer known as polyimine that is laced with silver
nanoparticles, the material has implications for products that
respond to environmental stimuli, like prosthetics, robotics,
smart textiles and even space suits.
The e-skin’s self-healing and recycling properties make it
straightforward to use. When the e-skin is torn, the addition of
a healing agent, pressure, and heat allows the chemical bonds
on either side of the skin to reform. Irrevocably damaged or unwanted
e-skin can be fully recycled via soaking in a recycling
solution that breaks the e-skin down to its chemical components,
which can then be used to create a new patch of e-skin.
The key to the recyclable and self-healing properties of this
new type of artificial skin lies in its use of a dynamic covalent
thermoset, a type of crosslinked polymer that can break and
reform its covalent bonds reversibly under certain conditions.
Polyimine, the dynamic covalent thermoset used in the e-skin,
has an advantage over other materials traditionally used in
e-skin thanks to its dynamic covalent bonding, which allows
for the e-skin’s recyclability, malleability, and self-healing properties.
The polymer also exhibits higher chemical and thermal
stability as compared to other self-healable e-skin, which helps
it work in a range of external conditions.
However, polyimine by itself is an insulator; it blocks electrons
from moving through the material. The sensing devices require
an exchange of electrical information through the e-skin, but
these electrical signals cannot pass through pure polyimine.
This is where the silver nanoparticles come into play: they introduce
conductivity to the e-skin material and, therefore, enable
the sensors that allow the e-skin to demonstrate sensitivity to
pressure, temperature, flow, and humidity. When used together,
the polymer and silver nanoparticles give the skin its diverse
properties: self-healing, recyclability, and malleability from the
polyimine, and conductivity that enables sensor functionality
from the silver nanoparticles.
The diverse capabilities of this e-skin are impressive, but there
is still more work to be done. “A few things need to be improved:
better self-healing and recycling capability, improved mechanical
flexibility, enhanced sensitivity, and spatial resolution,” Xiao said.
His team plans on looking into achieving these improvements.
The e-skin’s multifaceted functionality has applications
across a wide array of industries—from robots to aerospace—
and its recyclability reduces waste and material costs, both
huge benefits in commercial applications. But beyond its potential
role in making sophisticated sci-fi robots a reality, the
e-skin may find its earliest roles in more practical applications.
“Among [the applications of e-skin], we think the most significant
impact in the near future would be in the healthcare
industry—for example, enabling sensation of prosthetics and
health monitoring of human bodies,” Xiao said. With its high
reusability and ability to feel and bend like real skin, this e-skin
has the potential to have a small impact on the environment,
but a large impact on the technology and people within.
www.yalescientific.org
April 2018
Yale Scientific Magazine
27

FEATURE biomedical engineering
P L A C
B Y L E S L I E S I M
Over one in ten babies are born prematurely,
before they are 37 weeks old. Although preterm
birth may seem like a pretty common occurrence,
its causes are in fact under-examined, and
its symptoms can be extremely dangerous. Of
the 15 million premature babies each year, about
one million die from problems associated with
preterm birth. Some face lifelong visual, auditory,
or learning disabilities. In many countries,
preterm birth rates are increasing, and preterm
birth is already the leading cause worldwide for
the death of children under five years old.
Premature babies can often be saved with the
right medical and financial resources, but in
many countries, these resources are not readily
available. Preventing complications and
preterm deaths primarily comes from having a
THE RESEARCHERS BUILT
THE FIRST PLACENTA-ON-A
CHIP, WHICH MODELS THE
MOTHER-FETUS PLACENTAL
BARRIER AND THE TRANSPORT
OF NUTRIENTS ACROSS IT.
healthy pregnancy that allows the fetus to grow
properly and the mother to carry and provide
sufficiently. Thus, research on possible causes
and underlying mechanisms of premature
birth may be necessary in order to better understand
how to lower its frequency.
One of the important organs involved in fetal
development is the placenta. The placenta
key mechanisms and mediators of molecular
transfer across the placental barrier. Our
lack of understanding on placental transport
function becomes particularly problematic in
drug development. While some medications
can enter the fetal bloodstream, others cannot,
and researchers are still unsure how the
placenta selectively allows certain molecules
to pass between the mother and the fetus.
Part of this is because traditional placenta
research has many limitations, and using
whole organs in isolation may not be ideal for
such studies. Previous experiments conducted
on donated human placental tissue required
hooking the live organ up to the testing apparatus,
which necessitated a high level of expertise
and a complicated, often messy setup. Its
STUDYING PRETERM BIRTH & DR
The Huh lab at University of Pennsylvania created this placenta-on-a-chip.
IMAGE COURTESY OF THE HUH LAB
develops in the mother’s uterus during pregnancy
and controls the exchange of nutrients,
oxygen, and wastes between the maternal
and fetal blood. Despite decades of research,
however, much remains to be learned about
high likelihood of failure also meant that pharmaceutical
companies were reluctant to become
involved. In addition, donated placental
tissue is only usable for a few hours after birth.
Amidst these limitations, it seemed that performing
research on placental tissue may not
be feasible, but the Huh Lab at the University of
Pennsylvania has paved its own way.
The Huh Lab has tackled these issues by
engineering a chip that acts like a human placenta.
The first placenta-on-a-chip models the
mother-fetus placental barrier and the transport
of nutrients across it. They hope to use
this chip to study drug delivery to the placenta
and preterm birth.
The placenta-on-a-chip has a simple design
with great potential. The chip is a small block
of silicone the size of a flash drive. It contains
O N - A -
28 Yale Scientific Magazine April 2018 www.yalescientific.org

iomedical engineering
FEATURE
E N T A
A R T B Y E L I S S A M A R T I N
two overlapping layers of microchannels that
are lined with human cells and separated by
a porous membrane. In this three-dimensional
design, trophoblast cells isolated
from the outer surface of the placental
barrier are cultured on the upper side
of the membrane, while endothelial
cells derived from fetal blood vessels
are grown on the lower surface of
the membrane. These cells are fed
fresh nutrients so that they proliferate
and form a multicellular structure
that resembles the maternal-fetal
barrier in the human placenta. Just like
in the real placenta,
growing fetus, thus proving
that the chip functions like
the placental barrier. Huh and
his team believe that their chip
will be a good substitute for the
current donated tissues used in
placenta research. “The placenta is
arguably the least understood organ
in the human body. Much remains to
be learned about how transport between
mother and fetus works at the tissue, cellular
and molecular levels,” Huh said. But their research
has given them confidence that the placenta-on-a-chip
can serve as a platform to test
drug transport before use in actual the human
placenta in the future.
Huh and his team look forward to using the
UG TRANSFER DURING PREGANCY
the two
layers of cells act like a gate
keeper that controls the flow
and exchange of nutrients and
blocks pathogens from going between the circulatory
systems of the mother and fetus. The
chip system also allows the trophoblast layer to
form microvilli, small projections on the cell
surfaces which express proteins that are essential
for the barrier function of the placenta.
“One of the most important functions of the
placental barrier is transport, so it’s essential
for us to mimic that functionality,” Huh said. In
their model, the Huh Lab was able to reproduce
a process called syncytialization, in which
the two layers of cells in the chip continue to
grow within the chip, just like placental cells
would develop during a pregnancy. During a
pregnancy, the trophoblast
cells fuse to form syncytium
tissue, which thins over the
course of the pregnancy and becomes
the outermost cell layer of the placenta that
is in direct contact with the mother’s blood.
This process is critical in pregnancy because it
affects placental transport. The placenta-on-achip
was an improvement on previous models
that were not able to reproduce this change.
Not only does the chip replicate the natural
growth and development of the placenta
during a pregnancy, but it also has a similar
glucose transfer rate across the placental barrier
to that of experimental perfusion studies
on donated human placenta. This consistency
in glucose transfer rate is important because
it shows that the chip can mimic the process
of nutrient transfer through the placenta to a
chip system to innovate research on reproductive
medicine. One of their next steps is to
work with pharmacologists to simulate realistic
drug transport situations. To demonstrate
the feasibility of this idea, the Huh group has
recently published an article in which they
used the placenta-on-a-chip to simulate active
placental transport of glyburide, a common
medication used for gestational diabetes.
Apart from drug transfer, the Huh team also
wants to better understand the health impacts
of taking vitamins and herbal supplements,
both of which may be transferred through the
bloodstream to the fetus during a pregnancy.
The placenta-on-a-chip puts medicine on the
path to a better understanding of mother-fetus
placental transport and ultimately to improving
reproductive health.
C H I P
www.yalescientific.org
April 2018
Yale Scientific Magazine
29

FIGHTING
ADDICTION
ONE PILL
AT A TIME
A new compound that effectively blocks
dopamine can help tackle addiction
BY FANGCHEN ZHU | ART BY SUNNIE LIU
In America today, almost one in two
adults knows a relative or close friend
who has suffered from drug addiction.
Whether a brother, daughter, uncle or
colleague, 46 percent of Americans have
a personal story to tell about someone
battling addiction.
The American Psychiatric Association
defines addiction as a brain disease in
which people develop dependency on substances
such as drugs or alcohol. Those
afflicted with addiction are unable to stop
using the addictive substances even if they
want to, and suffer from withdrawal symptoms
if and when they do stop. An estimated
21.5 million American adults suffer
from some kind of substance addiction,
making it one of the most severe health
crises in the nation. While there are many
forms of addiction, the neurobiology is
generally similar across the board: an intake
of addictive substances triggers a rapid
release of a neurotransmitter, or neural
signaling molecule, called dopamine. One
feels a temporary high because dopamine
floods the ventral striatum—the reward
control center of our brains—and then
dissipates, which leaves the addict craving
more. At normal levels, dopamine is
essential in learning and motivating behavior,
as well as regulating motor control.
At elevated dopamine levels, however,
such as after ingesting an addictive
drug, our brain learns to associate the
drug with greater neurochemical reward.
This results in a more intense desire for
the next hit of the drug and withdrawal
symptoms when dopamine levels ultimately
dip back to normal.
Researchers have investigated the possibility
of treating addiction by regulating
dopamine level in the brain using γ-aminobutyric
acid (GABA), a neurotransmitter
that can directly inhibit the binding of
dopamine receptors. GABA is naturally
synthesized in the brain but is actively
degraded by enzymes called GABA aminotransferases
(GABA-AT). Vigabatrin
is currently the only FDA-approved drug
that takes advantage of this pathway and
inhibits the degradation of GABA by inactivating
GABA-TA. This medication
has been found to be an effective treatment
for epilepsy and cocaine addiction
30 Yale Scientific Magazine April 2018 www.yalescientific.org

medicine
FEATURE
in humans, but there is a 25-40% risk of
vision loss due to off-target binding. This
significant risk makes vigabatrin an unappealing
choice. Recently, however, the
Silverman Group at Northwestern University
synthesized a drug that regulates
dopamine levels as effectively as vigabatrin
at 1/1000th the dosage. This finding
has the potential to pave the way for much
more efficient treatment for addiction.
This yet-to-be-named GABA-inhibitor
is an improved version of the
(1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic
acid (CPP-115)
GABA-AT inactivator, which was designed
by the same group in 2013 and
found to be 186 times more efficient than
vigabatrin. “We were not satisfied with
just finding CPP-115—we want to understand
the mechanism and improve on it,”
said Professor Richard Silverman, who
conducted the study. Hence, they developed
the new compound, which is ten
times more effective than CPP-115. This
new GABA inhibitor and CPP-115 both
work in the same way as vigabatrin in
regulating dopamine levels. They react
irreversibly with GABA-TA to form an
AN ESTIMATED 21.5
MILLION AMERICAN ADULTS
SUFFER FROM SOME KIND
OF SUBSTANCE ADDICTION,
MAKING IT ONE OF THE
MOVE SEVERE HEALTH
CRISES IN THE NATION.
inhibitor-enzyme complex that prevents
GABA-TA from binding to and degrading
GABA. This in turn allows GABA to
block sharp increase in dopamine levels.
The Silverman group also found that
the compound does not inactivate or inhibit
off-target enzymes, which makes it
a much safer option than vigabatrin. The
new compound does not react with other
aminotransferases or enzymes commonly
involved in drug-drug interactions. A pharmaceutical
screen revealed that the compound
has no significant reactivity with 176
common pharmacological targets. “Vigabatrin
has known side effects, such as serious
retina damage,” Silverman said. “CPP-115
and the new compound are much more effective
and can be taken at smaller dosage.
Hence, there is a good probability that there
will be no side effects.”
Having obtained good results in cells,
the next step was to show the compound
was effective in living organisms. The Silverman
group administered the GABA
inhibitor to rats that were also given cocaine
or nicotine, and the drug was found
to regulate the drug-induced elevation
in dopamine levels in the rats’ striatum.
“Current methods of treating addiction
involve giving addicts another addictive
substance, but it is not sustainable to fight
addiction with addiction,” Silverman said.
“In our model, we can provide a drug that
blocks dopamine release directly.”
Another problem that addicts face in
fighting addiction is conditioned place
preference. The hippocampus, which is
associated with spatial learning, shows a
sharp increase in activity after each hit of
dopamine. It has been suggested that this
increase in activation is responsible for the
brain learning to associate the specific environment
in which the drug was ingested
with the rush of dopamine. Hence, the
next time the addict encounters the environment,
they will release dopamine even
before the addictive substance is present.
The researchers also showed that the compound
can block hippocampus activation
after intake of addictive substances. Taken
together, these results suggest that the
new GABA inhibitor compound can not
only block the elevation in dopamine after
taking addictive substances, but it can also
help prevent the addictive behavior from
forming in the first place.
Robert Malison, Professor of Psychiatry
at Yale University, agrees that this
method of treating addiction by moderating
GABA levels has a lot of potential.
“To date, most, but not all, treatments for
addictive disorders are based on so-called
‘agonist replacement,’” Malison said.
“Targeting GABA-AT to treat addiction
represents a novel strategy that shows
clear promise. If further clinical trials can
ascertain that there are no adverse effects,
then this could be a breakthrough insofar
as it resurrects a previously promising
strategic approach.”
The bigger concern of drug development
has always been how well it can be applied
to tackling disease in humans. This
problem is especially relevant today as the
United States is in the midst of the worst
drug overdose epidemic in history. In
October 2017, President Trump declared
the nation’s opioid crisis a public health
IMAGE COURTESY OF PXHERE
Current treatments for addiction replaces one
addictive substance for another.
emergency. Over the past few decades,
there has been a precipitous increase in
opioid-related overdose death; each year,
billions of dollars go towards costs associated
with treating addiction. Like other
forms of addictive substances, opioids
create dependency through affecting the
dopaminergic pathway, and this GA-
BA-inhibitor could potentially help us
fight such addiction. “Dopamine function
has been implicated as potentially
important in the addictive properties of
several addictive drug classes, including
opiates. While this study does not present
the efficacy of this strategy for opiates
specifically, it is possible that its efficacy
of the new compound might extend to
other drugs of abuse,” Malison said.
Silverman revealed that the new compound
is currently undergoing studies
for FDA approval. “This compound needs
to be tested in humans,” he said. “If it is
successful, then this method should be a
gold standard for future treatment of addiction.”
However, there no such thing as a
miracle pill. Silverman warned that it will
take more than developing an effective
drug to solve the problem; the success of
the treatment also depends on the mindset
of the addict. “If an addict does not want
to be free, it will be very hard to help,” he
said. Therefore, while it is important to
look for solutions in science and medicine,
this approach must be done in tandem
with other types of interventions to
achieve the best outcome and help addicts
overcome their addictions.
www.yalescientific.org
April 2018
Yale Scientific Magazine
31

FEATURE particle physics
R E A L -
B Y C O N O R J O H N S O N
As you read this
sentence, infinitesimally
small particles
of light are bouncing
around at infinitely
fast speeds,
transferring these
words you see on
the magazine page
or mobile screen directly
to your eyes.
These particles are called photons, and
they are responsible for the most beautiful
sunsets, the most fantastic paintings,
and the most gorgeous snippets of nature.
There is one property, however, that unites
photons from all these diverse settings: the
particles do not interact with each other.
Unlike particles with mass, which come
together to form atoms and a whole host
of other structures, photons at their most
elementary level do not seem to interact
at all. This property explains the following
phenomenon: you shine two flashlights in
a dark room so that their beams cross, and
you see nothing special in the area where
the photons intersect. The streams of light
are two ships in the night, passing by without
even knowing the other exists.
Vladan Vuletic and Mikhail Lukin beg
to differ. Vuletic, Professor of Physics at
the Massachusetts Institute of Technology,
and Lukin, Professor of Physics at Harvard
University, have been studying how to
make these particles interact with astounding
success. A 2013 paper by the two professors
detailed the first weak interactions
created between two photon molecules—a
dimer—but their more recent paper, published
in Science, proves the existence of
three photons strongly bound together: a
trimer. This refinement reflects improvements
in their experimental system and
brings us closer to futuristic quantum inventions
most scientists never thought
would be possible.
The reason for Vuletic and Lukin’s
groundbreaking success lies in their elegant
experimental design and the properties
photons acquire when interacting with
matter. “When photons travel in space
they are just photons,” Vuletic said. “But
when photons travel in a medium, they
can be absorbed by atoms and reemitted
by atoms.” Lukin, Vuletic, and the rest of
their team at the MIT-Harvard Center for
Ultracold Atoms took advantage of this
unique property. When photons are in this
absorbed state, they are able to weakly interact,
but the presence and power of this
attraction is dependent upon what matter
they are passing through. To facilitate
long-range interaction between photons,
Vuletic and Lukin used a cloud of supercooled
rubidium atoms as the medium.
Once a photon is reemitted from the atom,
having passed through the rubidium cloud,
it becomes a “quasi-particle”, having gained
certain properties of attraction and repulsion
from the atom.
Vuletic described this process as akin to
INTERACTING PHOTONS COULD MAKE
IMAGE COURTESY OF WIKIMEDIA
An artist’s rendition of the traveling paths of
two photons. The difference in oscillations
between the pink and yellow photons are
indicative of a difference in phase (ie. how long
it takes one oscillation to occur).
two boats on a lake. On the metaphorical
lake of the rubidium cloud, the interaction
between the photon boats and the rubidium
water creates waves that ripple out and
interact with the other photon boat, creating
an attraction between the two even
though they never directly interact. If the
rubidium lake is not present—if these boats
are grounded on a dry lake bed—there is
no way for the photon boats to affect each
other and they never interact.
Imagine the journey of a single photon
through Lukin and Vuletic’s experimental
setup. The massless particle is first emitted
from a weak laser beam, racing at
near-light speed towards the ultracooled
cloud of rubidium atoms, which is chilled
to a temperature just above absolute zero
to prevent confounding collisions. Once
it hits the cloud, it is absorbed by one of
L I G H T S
32 Yale Scientific Magazine April 2018 www.yalescientific.org

particle physics
FEATURE
- L I F E
A R T B Y E L I S S A M A R T I N
THIS STAR WARS FANTASY A REALITY
the near-immobile rubidium atoms, now
living as part of the atom. Then, within
millionths of a second of absorption,
the photon quasi-particle is reemitted by
the atom, having gained a small fraction
of an electron’s mass from its time inside
the atom. The quasi-particle continues its
journey through the cloud, now traveling
about 100,000 times slower. At some point
during this journey, the quasi-particle will
happen upon another quasi-particle and
attract, potentially even picking up a third
quasi-particle before exiting the cloud and
being measured by researchers.
The researchers looked at the formation
of these dimer and trimer photons using
a measurement called phase shift, which
records the changes in the frequency of
photon oscillation before and after exiting
the rubidium cloud. This phase shift measurement
is an indicator of how strongly
the photons are bound: the larger the phase
shift, the stronger the interaction. According
to the math, the phase shift of a trimer
photon structure should be about four
times greater than that of a dimer photon
structure, because there are more avenues
of interaction in a trimer structure. The
researchers observed, however, that the
trimer’s phase shift was only three times
larger than that of the dimer. Vuletic found
that this lack of efficiency was actually due
to repulsion, despite the trimer structure’s
strong attractions. “There’s a weaker, but
still there, three photon repulsion at the
same time, and so that makes the binding
a little bit weaker and the phase a little bit
weaker,” he said.
The findings of this paper raise the question
of whether larger photon structures
do actually exist in nature, contrary to current
scientific consensus. Although Vuletic
and Lukin had to set up extremely specific
conditions for photons to interact, the fact
that it is possible and that there are different
types of photon interaction suggests
that this might not be a solely artificial
phenomenon after all. Vuletic suggested
that his research has changed light’s fundamental
properties, but maybe these properties
aren’t so fundamental after all.
There are also more tangible uses of this
work. Although this newly-discovered
ability of strong photon interaction might
initially seem unexciting to non-physicists,
it could lead to groundbreaking applications
in the field of quantum technology.
It might be a little while before lightsabers
are a reality, but many scientists are
excited about the prospect of applying this
discovery to quantum computing. Quantum
computers, which theoretically would
be able to instantly perform calculations
a modern supercomputer could not even
dream of, rely on the entanglement of bits
of information. Entanglement, a connection
between two quantum particles that
instantaneously links them regardless of
distance, is often fickle; one of the main
challenges facing the development of a
quantum computer today is how to set up
entangled systems consistently and accurately.
The strong, structured attraction of
photons this research supports is a potential
way to reliably achieve this entanglement.
Vuletic, however, is most excited about
the potential of his discovery to revolutionize
quantum communication. “Quantum
communication is the idea that you
can send messages absolutely securely
protected by quantum mechanics if you
use individual photons,” Vuletic said. Because
photons are fundamental particles,
meaning they cannot be split into anything
smaller, it would be practically impossible
to interfere with or to steal a signal sent using
a photon. The distance and strength of
this signal, however, depends on the ability
of the sending and receiving centers of the
single photon—so called quantum gates—
to induce binding and phase shifts. With
no phase shift, Vuletic says, a signal cannot
be sent more than 50 miles. With the phase
shift achieved in this research, you would
be able to have light speed communication
between Boston and L.A, provided there
are intermediate amplification stations for
the signal. Achieving phase shift twice to
three times as large would allow a photon
signal to be theoretically sent across the
entire universe using intermediate stations.
It follows, then, that Lukin and Vuletic
are constantly trying to increase the phase
shift of these photon interactions. While
this research only found direct evidence of
trimer structures, the researcher’s lab also
has indirect evidence of larger-scale photon
interactions that could lead to greater
phase shifts—a lake with four, five, or even
more photon boats. Vuletic thinks that
these larger interactions could be repulsive
as well as attractive—rather than sticking
together as trimers do, larger photon states
could repel like ping pong balls bouncing
off one another. If their team succeeds in
finding photon states that create even larger
phase shifts, the implications for quantum
technology are literally and figuratively
limitless.
A B E R S
www.yalescientific.org
April 2018
Yale Scientific Magazine
33

FEATURE earth science
Although we walk on it every day, very few people consider
what exactly our planet is. Earth’s composition can be
reduced to four main layers. Working from the outside in,
these layers are the crust, the mantle, the outer core, and
the inner core. This last layer, the inner core, is a superhot
solid sphere of iron that sits at the center of Earth. The
mechanism of the inner core’s formation has recently come
under scrutiny, and a newly posited explanation provides
insight into Earth’s genesis.
The conventional theory about the formation of the
Earth’s inner core, also known as the nucleation or accretion
event, suggests that a massive pool of molten iron
spontaneously crystallized into a giant, solid, spherical core
surrounded by a layer of liquid metal. This idea has been
generally accepted for approximately 80 years. It is based
on the assumption that, at some point in time, the temperature
of the molten iron dropped to a point lower than
its melting point, allowing the molten metal to undergo a
spontaneous phase transition from liquid to solid.
C O U N T E R
PEERING INTO THE HISTORY OF EARTH’S FORMATION
BY ISAAC WENDLER
P O I N T
However, researchers at Case Western Reserve University
recently published a new study that questions this traditional
explanation. They attempted to answer the so-called
“inner core nucleation paradox,” which asserts that the energetic
barrier to the nucleation of the molten iron—the
amount of energy necessary for this phase transition—is
too high for spontaneous crystallization to have occurred
in the way that the conventional theory suggests.
The new study agrees with convention in that nucleation
requires the molten iron to have been supercooled well below
its melting point. (Supercooling is a chemical process
in which a compound can exist in a liquid state even at a
temperature below its freezing point.) It argues, however,
that in order for spontaneous accretion to occur, the molten
core must have been supercooled by nearly 1000 Kelvin,
a temperature that is not possible for a body as massive
as the Earth’s core. Thus, the researchers reasoned that
there must be another mechanism at play.
The study posits that the introduction of a low-energy substrate,
such as a piece of solid iron, into the supercooled molten
metal is a plausible event that could have occurred simultaneously
with supercooling. This substrate could adequately
lower the energetic barrier to nucleation and initiate crystallization
without supercooling the core by 1000 Kelvin.
“The nucleation event could be similar to the introduction of
an ice cube into supercooled water,” said Dr. Ludovic Huguet,
principal investigator in this new study. In this scenario, the ice
cube serves as the substrate that initiates the phase transition of
the supercooled water to solid ice.
The study hypothesizes that this substrate could have been an
iron nugget that broke off from the Earth’s mantle and made its
way into the molten iron at the center of the planet. However,
the researchers admit that this event it is extremely rare. The iron
nugget must have been large enough to withstand disintegration
over the course of its trajectory towards the center of the Earth
and enter the molten core intact. More specifically, it must have
had a minimum radius of about 9 kilometers, or 5.6 miles.
With this study completed, Dr. Huguet intends to broaden
the scope of his research and look past planet Earth, into the
extensive universe. He is now doing research on energy barriers
and nucleation events on other planets in his quest to understand
how exactly planets’ cores are formed. “Presently, I am investigating
the consequences of the nucleation barrier for other
planets where their cores have a regime of crystallization different
than that of the Earth,” he added.
Although this new nucleation theory comes with its probabilistic
limitations, it marks a next step forward in understanding
the true geologic history of the Earth. “The formation
of the inner core is only one piece of the puzzle of the
thermal history of the Earth,” said Dr. Huguet. In other words,
a solid understanding of this event could allow geologists to
unlock more secrets about our planet’s rich past.
IMAGE COURTESY OF BIOLOGYWISE
The nucleation event is akin to an ice cube dropped in
supercooled water.
34 Yale Scientific Magazine April 2018 www.yalescientific.org

FOCUS
technology
repurposed by
Mary Chukwu
From Farm to Fuel Cell
What if the future of renewable energy lies in a good
breakfast? While the thought of the most important
meal of the day, or one of its components, powering
anything other than a human body may be novel, the
race for renewable energy has been going for decades.
Though most everyday people can imagine a world
filled with more solar panels or wind farms, perhaps
fewer think of another contender: hydrogen power.
Researchers led by Professor Yusuke Yamada at Osaka
City University in Japan have found a new way to
produce hydrogen using egg white protein and light—
an innovation that could make hydrogen energy
production emission free in the future.
Although hydrogen itself, when used for energy,
only leaves water as a byproduct, its positive impact on
the environment is diminished if it is produced from
non-renewable sources. Currently, most hydrogen
power is produced from fossil fuels, primarily natural
gas, through a chemical process known as reforming.
Researchers have overcome this problem by creating a
process that avoids the need for fossil fuels entirely: a
photocatalytic hydrogen evolution system. As the name
suggests, the system uses light to catalyze, or speed
up, a reaction that produces hydrogen. The transfer
of electrons between molecules provides the energy
needed for the hydrogen evolution to occur.
In the new process, lysozyme, the principal protein in
egg white, provides a porous, cross-linked framework
that immobilizes rose bengal molecules in very close
proximity to platinum nanoparticles at the molecular
level. Rose bengal, a red dye used to detect damage to eye
tissue, is photosensitive and becomes negatively charged
in the presence of light, and platinum nanoparticles are
hydrogen production catalysts. When light hits a rose
bengal molecule, it becomes highly reactive, gains an
electron from a nearby electron-rich molecule, and
passes that electron, along with the energy stored in it, to
the platinum nanoparticles, which then use this energy
to catalyze the creation of hydrogen molecules.
While photocatalytic systems like the one described
above have been created before using other substrates,
egg white provides unique advantages for such a
system. “Lysozyme is a very well-known protein that
can be [cheaply] produced in bulk,” said Hiroyasu
Tabe, first author on the paper. “We can easily make
lysozyme crystals and manipulate their structure.”
What’s more, lysozyme is amenable to containing
entire systems of molecules. “We can complex two or
more compounds [within the cross-linked lysozyme
framework] and visualize their chemical structure
using crystal structure analysis,” said Tabe.
Naturally filled with large pores, cross-linked lysozyme
crystals can house within their solvent channels charged
molecules like rose bengal, as well as metal nanoparticles
within small molecular compartments. These combined
structures were visualized using X-ray crystallography, a
technique that uses the diffraction of X-rays to map the
three-dimensional structure of crystals.
Anchoring molecules in a substrate framework is
critical to the success of the photocatalytic system
because the random movement of particles in solution
impedes the precise accumulation of hydrogen for
useful purposes. The researchers tested this scenario
against systems where the rose bengal and platinum
nanoparticles were immobilized in cross-linked
lysozyme crystals, which were found to improve the
efficiency of the reaction. Three times as much hydrogen
was produced when the photocatalytic system was
embedded within a crystal framework.
The experiments were completed at the two- and
three-liter scale, but now that the method has been
shown to have potential, industrial applications are
possible in the future. Scaling up will be important to
areas such as automotive fuel and residential electricity.
Although fuel cell cars such as the Hyundai Tucson
already exist, one of the most important limits to their
expanded adoption is the scarcity of hydrogen fueling
stations in existing infrastructure. Increasing the
supply of cleanly produced hydrogen for such vehicles
could have an important role in lessening our carbon
footprint, as transportation accounts for about thirty
percent of US greenhouse gas emissions.
The researchers are hopeful that their method will
help to reverse this trend. The proof of concept—
that a photocatalytic hydrogen evolution system is
feasible—paves the way for further exploration of
different substrates.
Although the lab’s current work deals with the
production of hydrogen itself, future work will focus on
the creation of hydrogen fuel cells, which convert stored
hydrogen and oxygen into water, releasing electricity in
the process. Ultimately, the researchers hope to expand
the green production of energy through sunlight. In a
world with an increasingly uncertain environmental
future, creative solutions like egg white will become key
drivers of positive change.
35 Yale Scientific Magazine April 2018

UNDERGRADUATE PROFILE
ISAAC ROBINSON (SM ‘21)
LUCKY YONA (MY ‘18)
IMPROVING HEALTHCARE ONE HACKATHON AT A TIME
BY ANNA SUN
PHOTOGRAPHY BY ANNA SUN
The creators of Bené were awarded $1,500 by the Tsai Center for
Innovative Thinking during the 2018 Yale Healthcare Hackathon.
Meet Bené. Bené casually asks, “How was your day?” You might
pause to collect your thoughts before responding, or perhaps an exciting
event comes to mind immediately. Bené carefully observes you,
taking note of your voice, facial expressions, and even how long it took
for you to respond. With tools like Bené, artificial intelligence-based
technology is rapidly becoming the new face of medicine.
Now, meet Lucky Yona (MY ’18) and Isaac Robinson (SM ’21), the
two Yale undergraduates who helped develop Bené at the 2018 Yale
Healthcare Hackathon. The hackathon is a three-day event where people
with diverse backgrounds, including healthcare professionals, software
developers, entrepreneurs, and even patients, work together to
tackle current issues with healthcare. This year’s theme was artificial
intelligence-enabling medicine. Yona, a senior majoring in economics,
is pursuing a future in technology entrepreneurship, while Robinson
is a first-year prospective computer science and music double major
interested in healthcare and biotechnology. The two combined forces
with eight other team members—four MD/MBA candidates, one PhD
student, and three MD candidates, all at Yale—at the hackathon to develop
an application that could help improve disease diagnosis, specifically
for depression. “Our app started with the idea that people take
selfies all the time. We thought we could take a look at whether or not
there are indications in people’s faces that they might be developing a
disease,” Robinson said.
As other participants pitched their ideas during the event, Robinson
and Yona met the MD/MBA group who were interested in depression
stratification, a method of determining people’s risks of depression onset.
“While there are many confounding variables for analysis of physical
illnesses, there are fewer for depression,” Yona said. People are afflicted
by mental illnesses in unique ways, but research has shown that
speech and facial analysis over a long period of time can be useful for
differential diagnosis of depression. Bené analyzes data from responses
to a series of engaging trivia questions in order to make these preliminary
diagnoses. Its simplicity and convenience make a user feel more
comfortable and inclined to continue interacting with the app by responding
to more questions. With more data collected, the app uses
machine learning to get better and better at detecting changes in emotions
over time by analyzing voice and facial expressions.
The team’s innovative idea and hard work paid off when they were
awarded $1,500 by the Tsai Center for Innovative Thinking for creating
a practical application for medicine that also enhances the patient
experience. Although the app is still under development and not
available for public use, Robinson has taken a lead role in modifying
the program for more robust analysis. The team plans to apply for the
summer accelerator sponsored by Tsai Center for Innovating Thinking
to polish the product and move closer to placing Bené on the market.
In the meantime, Yona and Robinson have also taken on a new project
called Pearl. “It’s the first attempt at a universal biometric authentication
platform,” Yona said. This time, imagine using Apple’s Touch ID
everywhere, except after your thumbprint registers with the program
once, you only need your thumb to pay in stores or identify yourself in
the future. Never again would you fear about losing your keys or wallet!
The details of the project are still under wraps, but a prototype of
Pearl is anticipated to come out this spring. Yona and Robinson hope
that their inventive ideas with technology can bring about positive and
smooth lifestyle changes for everyone.
Robinson and Yona have both acknowledged that computer science
has made these entrepreneurial technology projects possible for
them. Even while working together with eight other people during
the hackathon to create Bené, they were constantly learning new
things. Both Robinson and Yona often find themselves surprised that
they are able to readily use their knowledge in order to create useful
products and solutions to problems in the real world. “It’s important
to take advantage of opportunities presented to you. Now, I am
trying to learn how to prioritize all of them,” Robinson said. What
might make the top of their list of project priorities? Both agreed,
“There are problems in the world that we need to fix, and there are so
many tools out there we can use to make things better and to make
these changes happen.” Certainly with Bené, they are one step closer
to improving healthcare for everyone.
36 Yale Scientific Magazine April 2018 www.yalescientific.org

ALUMNI PROFILE
NATHAN HALL
(MEM/MBA ‘17)
REBUILDING A SUSTAINABLE APPALACHIA
BY DIANE RAFIZADEH
Coal country has always been home for Nathan Hall (MEM/MBA
’17), a ninth-generation native of Central Appalachia who recently
completed a Master of Environmental Management degree at the Yale
School of Forestry & Environmental Studies (FES), alongside an MBA
from the Yale School of Management (SOM). Born and raised in rural
Kentucky, Hall followed an unconventional path and is now working to
solve the environmental and financial crises of his homeland. He runs
Reclaim Appalachia, a non-profit that aims to rehabilitate the region,
where coal mining and mountaintop removal have had a strong impact.
In his youth, Hall wanted to escape his hometown as soon as possible.
“I had to move away from the region to gain an appreciation. I realized
that the green hills and hollers all around me represented a very unique
topography and important biosphere, and the people themselves had
many good qualities and were largely misunderstood,” Hall said.
After high school, Hall didn’t start college immediately. Instead, he
moved to the city of Louisville, which was culturally a world away. He
had never really considered environmental consciousness before, but he
learned about a protest movement against mountaintop removal in Appalachia.
Mountaintop removal is a form of coal mining that requires
explosives to remove hundreds of feet of rock above the underlying coal,
wreaking havoc on the topography of the landscape. While in Louisville,
Hall worked a variety of manual labor jobs and became involved
in activism, such as helping open a community center and advocating
for low-income minorities affected by chemical industry contamination.
After a brief experience with the anti-mountaintop removal movement,
he moved back home to eastern Kentucky to reconnect with his
home region, eventually finding his way into underground coal mining.
For six months, he worked underground as a belt shoveler and brattice
builder, and began to think about alternatives to the “status quo.”
Hall eventually decided to continue his education and enroll at Berea
College, a small liberal arts school in Kentucky that operates on a tuition-free,
work-study basis. There, he created an independent major and
learned about everything from biodiesel—fuels generated from living
matter—to business management. He even worked on Berea’s farm for
a few years and got his hands dirty with all aspects of agriculture. “That
was the most impactful thing—the work-study experience, being on the
farm and building the biodiesel systems,” Hall said.
Post-grad, Hall was awarded the Watson Fellowship, which funds a
$25,000 travel grant for independent exploration abroad. Hall went to
ten different countries, from Wales to Romania, India, Thailand and beyond.
He explored places environmentally similar to Appalachia, hoping
to learn from the parallels and gain experience with projects that
could be relevant to the region.
IMAGE COURTESY OF NATHAN HALL
Nathan Hall is President of Reclaim Appalachia, a non-profit working to fix
the environmental and economic effects of mountaintop removal coal mining.
After taking a job with Green Forests Work reforesting strip-mined
mountains throughout Appalachia, Hall felt like he needed a broader
understanding of how to operate in a for-profit world. He made his
way to Yale to complete his master’s degree, double-dipping in both FES
and SOM. “I thought the Yale program offered the most flexibility and
opportunity to combine areas that might not seem directly related, but
where someone who has enough independent motivation can craft their
own mix of classes,” Hall said. He reminisces about his time at Yale, having
made great memories—even walking his dog in East Rock park. “At
FES especially, there’s a tight-knit community of great folks with similar
goals and interests,” he said.
Hall is now president of Reclaim Appalachia, a social enterprise within
the non-profit umbrella of Coalfield Development in West Virginia
that focuses on both the people and the environment of the Central
Appalachian region.. The economy has historically been heavily dependent
on coal mining. “The coal industry has always been boom and bust
and left the region with an unstable and undiversified economy,” Hall
explained. Now that coal is on a long-term downward trend in global
energy infrastructure, Hall is focusing on sustainable economic development
on the large swaths of land left after surface mining. “On the one
hand, there’s a need to bring back the native vegetation for a host of reasons,
including water quality improvements and carbon sequestration,”
he said. “However, reforestation alone cannot provide the near-term financial
returns needed to create a new economic base.” The group wants
to take advantage of the region’s plentiful water resources, semi-predictable
weather, and unique characteristics of post-mining soils. Though it’s
not possible to fully restore the ancient geology of the land, Hall and his
team are working hard to rebuild a sustainable and economically-sound
landscape in Central Appalachia.
www.yalescientific.org
April 2018
Yale Scientific Magazine
37

Science in the Spotlight
A Crack in Creation
By Andrea Ouyang
COURTESY OF WIKIMEDIA
5/5
Genetics courses at universities across the
country would do well to add Jennifer Doudna’s
and Samuel H. Sternberg’s A Crack in Creation:
Gene Editing and the Unthinkable Power
to Control Evolution to their syllabi. This
account of the rise of CRISPR editing, written from Doudna’s
perspective as the head of the lab that first put the technology
to use, covers the history of genetic manipulation with a thoroughness
and accessibility that most textbooks on genetics can
only dream of achieving.
This quality of work is appropriate, considering the breadth and
depth of the topics the coauthors cover, from growing human
organs in pigs to the possibility of eradicating mosquitoes forever.
In the end, it all circles back to CRISPR, a technology derived
from bacteria that allows scientists to edit genes in almost any
organism with unprecedented precision and accuracy. The book
is at once a love letter to the process of scientific discovery and
an homage to the succession of biochemists and biologists who
advanced the knowledge needed to understand the mechanisms
of different gene-altering technologies. Names, dates, and contributions
are elegantly, meticulously recounted and explained
in a way that neither loses the reader to jargon nor insults the
reader’s intelligence by dumbing down the essence of important
scientific principles that led to the discovery, such as nonhomologous
recombination or zinc-finger nucleases.
According to Doudna, what is unprecedented about this new
gene-editing technology is not the scope or precision of its
power, but rather the timing of its discovery. Both the scientific
community and society at large remain ill-equipped to make
ethical and moral decisions delineating its use. Towards the end
of the book, there is a call for scientists to practice greater transparency
and more open communication and for the public to
be willing to engage in scientific dialogue. Unlike the discovery
of the CRISPR system, this prerogative is nothing new or radical,
but it does come at a time when the need for collaboration
among the public, the government and the scientific community
is greater than ever, a sentiment alluded to in a section discussing
controversy over the ethics of editing genes in everything
from food crops to human embryos.
This thoughtfully written book is suited for anyone with an
interest in the history of scientific discovery, and its focus on
opening a broader discussion on the ethical and moral use of
technology make it an engaging read for layreaders and career
biologists alike.
38 Yale Scientific Magazine April 2018 www.yalescientific.org

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