YSM Issue 90.4

OCTOBER 2017 VOL. 90 NO. 4 | $6.99

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Yale Scientific Magazine 

VOL. 90 ISSUE NO. 4 

CONTENTS 

OCTOBER 2017 

NEWS 6 

FEATURES 25 

ON THE COVER 

22 

Rsearchers in the Herzon Lab at 

Yale have devised a total synthesis 

of the antibiotic pleuromutilin, 

opening the door to new potential 

antibiotics to help bacterial resistance 

12 

PUTTING THE PATCH 

ON RESISTANCE 

HOT, DENSE, AND 

SPINNING 

Just moments after the big 

bang, all matter existed in a state 

called the quark-gluon plasma. 

Yale professor Helen Caines and 

her group work with the STAR 

collaboration, together aiming 

to discover the properties of our 

universe this early in its history 

15 THE SEARCH 

If cancer cells can’t find the highways 

of the body, they can’t spread and 

become more lethal. A mathematical 

model developed by Andre Levchenko 

and JinSeok Park of the Yale 

Systems Biology Institute provides a 

framework to expalin cell migration 

behavior that can be implemented 

down the line to keep cells searching 

longer. 

18 

IN SEARCH OF LOST 

TIME 

Yale researchers repair memory 

deficits in Alzheimer’s mice using a 

drug that targets abnormal protein 

interactions in the brain 

More articles available online at www.yalescientific.org 

20 NANOPARTICLES 

FOR TRANSPLANTS 

Yale researchers develop a nanoparticle 

delivery system that releases 

siRNA capable of protecting ransplanted 

organs from rejcetion by the 

immune system. the nanoparticles 

have the potential to inhibit immune 

system’s recognition of transplants 

October 2017 


3

q a 

& 

►BY KATHERINE HANDLER 

Wheat is an essential part of diets 

around the globe. In fact, twenty percent 

of the world’s total calorie consumption 

is from wheat alone. Thus, scientists are 

eager to find out how to produce it faster 

and more efficiently, and to do that, 

they’re looking back into the past. 

Wheat was domesticated ten thousand 

years ago in the present-day Middle East, 

when humans rapidly modified the crop’s 

key traits. Nowadays, we continue to produce 

domestic wheat. It differs from wild 

wheat in that it has non-shattering spikes, 

an adaptation that allows the plant to better 

retain its seeds and to be harvested 

more easily. 

Researchers at Tel Aviv University, led 

by Assaf Distelfeld, have been studying 

the genetics responsible for non-shattering 

spikes. Their work analyses the genome 

of wild emmer wheat to better link 

►BY SEVERYN KUSHMELIUK 

Have you ever noticed yourself 

yawning after someone else yawns, 

even if you’re not tired? This past 

August, researchers at the University 

of Nottingham may have figured out 

why this phenomenon occurs, discovering 

that contagious yawning is 

triggered by an area of the brain that 

is responsible for motor function: the 

left primary motor cortex. 

Reflexive yawning is considered 

a form of echopraxia, the automatic 

imitation of another person’s actions. 

While previous studies have 

shown that this form of yawning occurs 

in humans, chimpanzees, and 

dogs, this is one of the first studies 

to link contagious yawning and neural 

activity. 

As part of the study, the researchers 

directed four separate groups of 

How was wheat domesticated? 

IMAGE COURTESY OF PEXELS 

►The spike of a wheat plant, with its seeds still 

intact. 

the grain’s physical traits to the genes responsible 

for them. They found two main 

genes responsible for shattering spikes in 

wild wheat—two genes that are not functional 

in domesticated wheat. 

“The fact that we find the same mutations 

in every domesticated wheat genotype 

is amazing because it exemplifies 

how strong genetic bottleneck or selection 

can be,” Distelfeld said. Human preference 

for the non-shattering spike phenotype 

was a selective force that drove 

the domestication of wheat plant. But 

modifications to wheat may not be over, 

especially with these new genetic discoveries. 

“Now that wheat is in the ‘post-genomic 

era,’ many scientists will feel comfortable 

working on wheat instead of model 

plants, so wheat improvement will be 

faster,” Distelfeld said. 

Why is yawning contagious? 

IMAGE COURTESY OF WIKIMEDIA COMMONS 

►Although yawning has long been known to 

be contagious, researchers have only recently 

discovered the biological basis for why. 

people to watch clips of individuals 

yawning. Different groups were 

instructed to either resist yawning 

or let yawning occur naturally, and 

participants in booth groups were 

hooked up to an electric stimulator—in 

true Frankenstein style— 

that shocked the brain’s left primary 

motor cortex. 

The data revealed that attempts to 

resist yawning actually increase the 

urge to yawn, and that people have 

natural tendancy to yawn that is not 

affected by instructions. Most importantly, 

however, the researchers 

found that electrically stimulating 

the left primary motor cortex increased 

the likelihood of yawning, 

revealing that this area of the brain 

may play an important role in contagious 

yawning.

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

Reaching Out 

Millions of Americans traveled this summer to catch a glimpse of our sun turning 

black. The Great American Eclipse united the nation in an awe-inspiring display of 

nature’s power; at one eclipse viewing, even after organizers ran out of solar glasses, 

people simply shared the glasses that were already passed out. They traded eclipse facts 

and celebrated the simple joy of witnessing a historic scientific event, one that they 

could tell their grandchildren about. 

But what if that same excitement carried to all fields of science? 

After all, the eclipse is simply the moon passing in front of the sun, and a total eclipse 

can be seen somewhere on the Earth every two years or so. How much more amazing 

is it when scientists are able to create materials eight hundred million times hotter than 

the sun (pg. 12), or when nanoparticles can be used to prevent organ rejection (pg. 20)? 

Science is a fundamentally human endeavor, driven by our curiosity and passion to 

understand the world. It is why finding diverse, long-dead microbes in ancient rocks 

can excite our imagination(pg. 27), and why tiny molecular motors that punch through 

diseases in our body can be so surprising (pg. 32). Understanding everything from auditory 

hallucinations (pg. 9) to distant galaxy formation (pg. 28) can send tingles down 

your spine and set your mind on fire. We are innately drawn to the story of science, 

because it is the story of humanity. 

Yet we tend to bury these jewels of knowledge beneath a mountain of jargon and 

technical language. Research to discover sterile neutrinos (pg. 34) can get bogged 

down in dense statistical analyses, while discoveries as elegant as the causes of twisting 

flowers (pg. 7) can become lost in abbreviations of genetic markers. The mission of the 

Yale Scientific Magazine is to make these beautiful ideas clear and accessible to everyone, 

because you shouldn’t need a Ph.D to appreciate the sublime beauty of massive 

methane craters in the Arctic sea (pg. 26). 

Simultaneously, we seek to train the next generation of science communicators. This 

issue, we are especially excited to welcome the writers, artists, photographers, and 

designers of the Class of 2021. Already, they have been reporting on diverse topics, 

ranging from reclassifying diseases (pg. 25) to biodegradable plastics (pg. 35). We are 

eagerly looking forwards to see their continued contributions in the next four years. 

As you read this issue, I hope that you will catch our infectious enthusiasm and share 

your own wealth of knowledge with the world as well. If we all become better science 

communicators, telling the world about the science that excites us, we can truly change 

the world. 

A B O U T T H E A R T 

Chunyang Ding 

Editor-in-Chief 

What better way to portray the potential of mushrooms in 

antibiotics research than to tap into the mushrooms themselves? 

The inspiration for this piece came from the unique 

shape of the mushrooms described in the cover article — the 

Clitopilus passeckerianus. Their pale bodies are fan-like and 

upward reaching, furled, and maybe even a little spooky. 

While tracing the details of their winding gills was laborious, 

it is my hope that the final illustrated product puts these 

notable figures of modern antibiotic research on full display. 

Editor-in-Chief 

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NEWS 

in brief 

Hardware Security “Fingerprints” 

By Ayah Elmansy 

PHOTOGRAPHY BY XANDER DE VRIES 

►DRAM provides each device its 

unique “fingerprint,” which can be 

used for electronic security. 

We all strive to keep our prized possessions 

safe. Sometimes those possessions include not 

just physical items, but also our digital information. 

Inspired to help us keep our data secure, Yale 

professor Jakub Szefer is researching security applications 

of the tiny differences between devices. 

Szefer is an assistant professor of electrical engineering 

at the Yale School of Engineering and 

Applied Science. Recently, he received the 2017 

Faculty Early Career Development Award from 

the National Science Foundation, which will provide 

funding for his research. Szefer is collaborating 

with his research group on this work, which 

includes graduate student Wenjie Xiong, as well 

as researchers in Germany at Technische Universität 

Darmstadt and Ruhr University Bochum. 

Szefer’s project focuses on the use of electronic 

devices’ unique “fingerprints” to improve computer 

security. At the electronic level, every computing 

device has distinctive hardware features, 

even between identical models. These differences 

in the devices’ digital circuits, processors, and 

data storage systems are known as dynamic random-access 

(DRAM) memory. Small variations 

occur when these devices are manufactured, 

causing slight deviations in factors such as the 

length of the wires of circuits or the capacitors’ 

thicknesses. These minor deviations accumulate 

to give each device its unique “fingerprint,” 

which can be used to authenticate and identify 

the device. 

Szefer wants to explore how these fingerprints 

can be applied to the security of our everyday devices 

like smartphones, phones, computers, and 

embedded devices. “We hope to show that cryptographic 

protocols can be designed, which derive 

their security from not just difficult mathematical 

problems but also from the intrinsic 

properties of the hardware,” Szefer said. Through 

their continued efforts, Szefer and his collaborators 

hope to benefit both the hardware security 

community and consumers who use computing 

devices every day. 

IMAGE CREDIT BY ZUREKS 

►The researchers found notothenioids 

to be in jeopardy from climate change 

and species invasion. 

Something’s Fishy 

By Namoi D’Arbell Bobadilla 

It’s cold in the Antarctic Ocean, but 

things are heating up. Yale ecology and 

evolutionary biology professor Thomas 

Near worked with a research group to study 

an ancient Antarctic fish lineage called 

notothenioids. These fish are essential 

links in Antarctic food webs and are the 

basis for several fisheries all over the world. 

The researchers used DNA sequences from 

89 notothenioid species to reconstruct the 

process of how they evolved and to study 

their changes in habitat over the years. Their 

study, published in June in Nature Ecology 

& Evolution, showed that notothenioids are 

in danger from climate change and species 

invasion. 

Historically, notothenioids have survived 

natural warming cycles through migration, 

such as between the Antarctic continent 

and its islands. “Continents tend to produce 

biodiversity that emigrates to islands, but 

the Antarctic islands are behaving like 

a continent,” Near said. In other words, 

studies have shown that around Antarctica, 

the islands generate a diversity of marine 

life. Unfortunately, these island waters are 

now warming. This temperature rise allows 

fish that usually live in warmer water to 

invade and compete with native species 

like notothenioids. Notothenioids must 

now face both rising temperatures—which 

can alarmingly alter Antarctic marine 

ecosystems—and increased competition 

from invading species. 

“This polar ecosystem has probably been 

fairly stable for 25 to 30 million years,” Near 

said. However, now the climate change 

has brought unprecedented instability to 

Antarctic ecosystems and has placed its 

most dominant lineage, notothenioids, in 

jeopardy from habitat change and invasive 

species. Near reminds us of our duty to 

address such problems: “With our dramatic 

utilization of natural resources comes 

responsibility for stewardship of the planet 

that we’ve perturbed.” 

6 Yale Scientific Magazine October 2017 www.yalescientific.org

in brief 

NEWS 

The Twists and Turns of Flowers 

By Ashwin Chetty 

Have you ever taken time to enjoy the 

beauty of flowers? Professor Vivian Irish and 

postdoctoral associate Adam Saffer of Yale’s 

Molecular, Cellular and Developmental 

Biology department have done so for years, 

especially from a scientific perspective. 

They study what affects a flower’s shape 

and appearance. Recently, they discovered 

a molecule that affects the twist of flowers, 

which refers to the way flowers turn. In 

their Current Biology paper published in 

August, they revealed that in a specific type 

of flower, Arabidopsis thaliana, a substance 

called pectin influences the twisting of plant 

cells. Pectin is a common substance in the 

kitchen and gives jam its gelatinous quality. 

Saffer first looked at a mutation that caused 

plant cells to be short and twisted. The 

researchers then identified a mutated gene 

underlying the helical shape of these cells. 

This gene plays a role in the biosynthesis 

of a certain kind of pectin called RG- 

I. The researchers believe that RG-I may 

normally counteract a component of cell 

walls that causes cells to twist. However, 

when the mutation is present in a cell, less 

RG-I is is produced. RG-I inhibits twisting, 

so when RG-I levels are low, the unknown 

component is free to make cells twist. Thus, 

the mutation causes the beautiful helical 

shape of plant cells. 

The Irish Lab is working to better 

understand the role of pectin in providing 

cell structure, and Irish is partnering 

with researchers at Yale’s department of 

mechanical engineering and materials 

science to develop models to explain this 

left-handed twisting. By identifying a novel 

characteristic of pectin, Irish and Saffer 

have opened doors for the development of 

new biomaterials. While they are excited 

for these applications, at the end of the 

day, both still like to enjoy the aesthetically 

pleasing nature of flowers. 

PHOTO BY TANVI MEHTA 

►Pectin, the substance that gives jam 

its gelatinous quality, can influence the 

way that flowers twist. 

Raising a child is no easy task—what 

would you do if you were put in charge of 

raising someone else’s child? In a recent 

study, researchers from the Yale Department 

of Ecology and Evolutionary Biology 

explored whether males of different animal 

species would care for offspring that aren’t 

their own. The researchers studied how the 

energy needed to raise a child could affect 

males’ decisions to care for offspring. 

Previous theories state that males are most 

likely to care for children that are certain to 

be their own. Yet in many species, a male 

may take care of offspring that were not 

conceived by him but rather by a competing 

male. Postdoctoral research fellow Gustavo 

Requena explained the difference between 

his model and those of earlier theories. “In 

our study, we used mathematical models 

to emulate males’ decisions in different 

scenarios and ultimately address the same 

question but took into account a more 

general biological reality,” he said. This 

Game of Sperms 

By Lauren Kim 

model involves sperm competition games, 

which show how males allocate energetic 

resources to increase their chances 

for success within male-male mating 

competition. 

Factors that affect the males’ decisions 

include female promiscuity, maternal 

effort, and the difficulty of providing 

care to offspring. Based on these factors, 

researchers found that when there is more 

energy required, males will provide care 

based on relatedness to his offspring. For 

example, a male Arowana fish will carry 

eggs in his mouth to protect his offspring. 

However, in low-cost situations, males will 

provide care regardless of relation. 

In this way, scientists hope to provide 

an answer as to why males continue to 

provide energetically-costly care towards 

offspring that may not be their own. From 

these results, they can develop a greater 

understanding of different parenting 

patterns in nature. 

IMAGE COURTESY OF NATIONAL GEOGRAPHIC 

►Male Arowana fish carry the eggs in 

their mouths, protecting the offspring 

until they are ready to leave permanently. 

www.yalescientific.org 

October 2017 


7

NEWS 

materials science 

HARNESSING THE SUN FOR CLEAN WATER 

Nanotechnology improves water purification 

►BY ALLIE FORMAN 

For you and me, obtaining safe drinking water may be as 

simple as walking to the nearest sink and getting a cup of tap 

water. But 29 percent of people worldwide do not have ready 

access to safe drinking water, instead getting their water from 

sources contaminated by feces. This leads to over half a million 

deaths annually. Climate change and population growth 

are expected to exacerbate the issue, making access to potable 

water even more challenging. 

One solution to this problem is by making salt water drinkable 

through desalination. But the most commonly used technique 

for desalination, reverse osmosis, requires large inputs 

of energy to boil water, making it unsuitable for places without 

reliable electricity. 

With this in mind, Yale researchers in the School of Engineering 

and Applied Science, in collaboration with scientists 

at Rice University, Arizona State University, and the University 

of Texas-El Paso, are working to improve an alternative 

solar-powered desalination method known as membrane distillation. 

This process has the potential to be less energy-intensive 

than reverse osmosis, making it suitable for underdeveloped 

areas and environmentally friendly. 

In membrane distillation, salt water and pure water are 

placed on opposite sides of a membrane that only allows gases 

to pass through. The salty side is heated, while the pure water 

is cooled. The difference in partial pressure causes the water on 

the salty side to travel through the membrane as a gas, leaving 

the salt and other contaminants as solids on the “dirty” side of 

the membrane. 

Membrane distillation has not been widely used for a number 

of reasons. Energy is required to generate and maintain 

the temperature difference between the impure salt water and 

clean freshwater reservoirs, and the process uses more energy 

to produce the same amount of pure water when compared to 

reverse osmosis. Along with their collaborators, Yale researchers 

Menachem Elimelech and Akshay Deshmukh have optimized 

a low-energy membrane distillation technique that uses 

solar power coupled with nanoparticle technology. 

Their design uses a carbon black-coated membrane that 

maximizes uptake of solar energy. This sets up a temperature 

gradient in which the salt water closest to the nanoparticle-covered 

membrane heats up. The process does not require 

an additional power source besides solar energy, and the materials 

are widely available. 

While the nanoparticle-enabled solar membrane distillation 

system is still in development, the scientists have demonstrated 

its viability with a paper recently published in the Proceedings 

of the National Academy of Sciences. The project is attracting 

attention because of its potential applications around the 

world, especially in areas lacking access to electricity. 

The improved membrane distillation design is ideal for 

smaller, decentralized applications, such as a rural village not 

connected to the grid. Unlike reverse osmosis—which necessitates 

a proper electrical connection for the high-pressure 

pumps, the new solar membrane distillation model requires 

very little infrastructure. “We wouldn’t use a process like this to 

compete with reverse osmosis in a big community,” Deshmukh 

said. “But for smaller stuff, which is off-grid, it could be useful 

because it’s using sunlight and it’s not a high-pressure process.” 

Membrane distillation technology can also be used to remove 

other contaminants besides salt from water. “This could 

be used in situations where the water is very dirty. For example, 

for waste water from industrial sites where the osmotic 

pressure is very high, reverse osmosis can’t be used to treat 

it, because the membranes can’t deal with the pressure,” said 

Deshmukh. He also thinks their design could be implemented 

in natural disaster situations, where normal water treatment 

infrastructure has been disrupted. 

Though the researchers have produced a model of the design, 

the technology is not yet ready to hit store shelves. The 

scientists now need to refine their design and market approach. 

While there is still work to be done, they believe that 

the new technology will improve many lives around the globe 

by providing much needed access to clean water. 

IMAGE COURTESY OF AKSHAY DESHMUKH 

►The new design utilizes a nanoparticle layer to heat salt water 

with solar energy. 


neuroscience 

NEWS 

NOW YOU HEAR ME, NOW YOU DON’T 

Testing susceptibility of people to hearing voices 

►BY SUNNIE LU 

PHOTOGRAPHY BY YASMIN ALAMDEEN 

►Dr. Powers and Dr. Corlett took MRI scans of people 

performing auditory tasks to understand auditory hallucinations. 

You hear footsteps coming down the hallway and voices chanting, 

“We’re coming.” A shadowy figure suddenly appears in the 

corner of your room, while a girl dressed up as a rat looms over 

your bed. Although these scenarios sound like they come from 

horror movies, they actually are real examples of hypnagogic hallucinations, 

which occur during the onset of sleep. Both having 

these experiences, Yale psychiatrist and neuroscientist Albert 

Powers and Yale neuroscientist Philip Corlett fascinated with 

auditory hallucinations. Their research, featured in Science, suggests 

that people who hear voices are more likely to experience 

induced hallucinations in a lab. 

It may seem concerning that both Powers and Corlett have 

experienced hallucinations while falling asleep, but these hallucinations 

are usually symptomatic of a neurological condition, 

not a psychiatric illness. However, people without a psychiatric 

condition can hear voices too. The two scientists wanted to figure 

out what produces auditory hallucinations and why some 

voice-hearing experiences are benign and others require medical 

attention. 

To explore these questions, they sought out four groups of 

test subjects: both psychotic and nonpsychotic voice-hearers 

and non-voice-hearers. After identifying potential subjects, the 

researchers separated the psychotic and nonpsychotic people 

using a questionnaire developed by forensic psychologists to 

distinguish between people who were actually experiencing hallucinations 

and those who only claimed to do so. 

After screening their subjects for hallucinations, Powers and 

Corlett induced auditory hallucinations in their subjects to identify 

whether psychotic people were more likely than non-psychotic 

people to hear conditioned sounds. Using a technique 

originally developed at Yale during the 1890s, the subjects were 

stimulated with a checkerboard image and a one-second long 

sound simultaneously and repeatedly, while getting their brains 

imaged by MRIs. This conditioned the subjects to associate the 

image with the tone. As the scientists changed the intensity of 

tone, sometimes turning it off, the subjects pressed a button when 

they thought they heard the tone, while changing the length of 

time they pressed the button to show their level of confidence. 

Many reported hearing a tone when only the checkerboard 

image appeared but no tone played. This inconsistency occurred 

more often with the two voice-hearing groups—the people with 

schizophrenia and self-identified clairaudient psychics. Both 

groups were almost five times more likely to report that they 

heard a nonexistent tone than the non-voice-hearing groups. 

Furthermore, the two non-voice-hearing groups were 28 percent 

more confident that they had heard the tone when no tone 

played. These results support a possible explanation for hallucinations. 

“The brain makes models for what the outside world is 

like,” said Corlett, noting that these models sometimes don’t always 

match reality. This study suggests that people hallucinate 

when their expectations overweigh what their senses tell them. 

Powers and Corlett further understood auditory hallucinations 

through analyzing the MRI scans collected: the parts of the 

brain that were responsive to the tone were active when people 

reported conditioned hallucinations, producing MRI scans of 

brains that looked like those of people actually hearing the tone. 

The images also revealed that both hallucinating and non-hallucinating 

people with psychosis exhibit abnormal brain activity in 

regions that monitor internal representations of reality. These results 

contribute to the idea that hallucinations stem from internal 

representations overruling actual sensory data. 

This study was able to distinguish not only between those who 

hallucinate and those who don’t, but also between psychotic and 

non-psychotic people. “The sooner you catch psychosis and the 

sooner you intervene, the better the general outcomes are,” said 

Powers. According to Powers, most people with the symptoms 

associated with increased chances of psychosis don’t even develop 

psychosis. The question then is, who should receive treatment? 

This new research may help to answer that key question 

by providing the basis for tests to diagnose patients who require 

psychiatric treatment early. 

“There is no one-size-fits-all anti-psychotic, so there should be 

different treatments for different people,” Corlett said. Although 

this sort of precision medicine has not existed in psychiatry so 

far, Corlett hopes that this study, along with future research, will 

lead to more personalized psychiatric treatments, which he believes 

would be more effective in helping people suffering with 

mental health issues. 


October 2017 


9

NEWS 

genetics 

MAKING CANCER CELLS NERVOUS 

Targeting the genes involved in nerve cells in the brain 

►BY DIYU PEARCE-FISHER 

Cancer is the second most common cause of death in the 

world. Almost one out of every six deaths can be traced back to 

this deadly disease. Science has made huge strides towards treating 

and curing cancer, but there are many different types of cancer, 

and no single cure that works for every case. Understanding 

the cause of each type of cancer is crucial to treating each patient, 

so much recent cancer research focuses on the genetic factors that 

cause normal cells to become cancerous. 

Researchers at the Yale Systems Biology Institute led a team of 

scientists studying the genes involved in glioblastoma, a type of 

brain cancer. This cancer targets star-shaped support cells in the 

brain called astrocytes, which serve many purposes in the nervous 

system. Glioblastoma is one of the deadliest types of cancer. 

While over two-thirds of the people diagnosed with any type of 

cancer make it to the five-year survival mark and beyond, the median 

survival time for patients diagnosed with glioblastoma is between 

1 and 1.5 years. The Yale-led team of researchers developed 

a technique enabling them to identify specific gene combinations 

that cause glioblastoma. They believe their approach could be applied 

to other types of cancer as well, which would revolutionize 

how we approach cancer treatment. 

Cancer is caused by genetic mutations. However, even if two 

patients have the same type of cancer, the patients may or may 

not have the same mutations. Prior to the Yale-led study, genome 

sequencing identified 223 genes with links to glioblastoma. But 

that also means that there are hundreds of thousands of possible 

combinations of genes, with certain combinations responding 

slightly differently to treatment. Thus, the Yale researchers wanted 

to clarify how these different combinations affect glioblastoma 

treatment. 

To do this, the Yale team employed the use of a technique called 

CRISPR. First pioneered in 2012, CRISPR is a gene editing technique 

that has revolutionized the biomedical sciences by enabling 

researchers to create cells with mutations and test the effects of the 

mutations. However, CRISPR does have its limitations. To use this 

type of CRISPR, each combination would have to be tested one 

by one, which would be hard to compare since the time-intensive 

tests would give results two to three years apart. 

To address this, the Yale-led team developed a novel CRIS- 

PR technique that is less biased, more time-efficient, and more 

cost-efficient. Rather than testing each individual mutation and 

waiting for the results of each experiment, which would exhaust 

both time and resources, the new technique employs a pool of viruses, 

each of which targets a specific gene. Infected from a pool 

of viruses, each mouse brain cell has the potential to have multiple 

mutations. Thus, the team could test for multiple combinations 

simultaneously. The researchers found specific combinations of 

mutations that could cause glioblastoma, as well as two combinations 

that could make the glioblastoma tumor resistant to chemotherapy. 

By understanding the results of different combinations of mutations, 

doctors will be able to screen for these mutations and decide 

the appropriate treatments. For instance, if they find that a patient 

has the combination of mutations that cause a tumor to be resistant 

to chemotherapy, the doctors will know not to waste time and 

resources on an unsuccessful chemotherapy, which could further 

harm or discourage the patient. Information like this is especially 

important when the average survival time for cancers like glioblastoma 

is under two years. 

The researchers believe that their approach can be applied to 

other types of cancer, which would allow doctors to give treatments 

specific to each case, hopefully leading to a higher chance 

of success. “In order to find better therapy or treatment, we need 

to find the therapeutic responder, or the genes that regulate or 

change some response. Now we have the tools—we have the experiment 

setting—we can simply do the same experiments but 

with gene therapy,” said Sidi Chen, one of the investigators on the 

team. By using CRISPR to create the different glioblastoma-causing 

gene combinations and applying specific types of therapies to 

see how each combination responds, the scientists may be able to 

figure out exactly which treatment will work for each case of cancer. 

In other words, targeted “cures” for cancer may soon become 

an applicable reality. 

IMAGE COURTESY OF CHEN LAB 

►A gioblastoma induced by new gene-editing and screening 

technology. 

10 

Yale Scientific Magazine October 2017 www.yalescientific.org

public health 

NEWS 

NOT SO SWEET 

Metabolic problems caused by artificial sweeteners 

►BY SERENA CHO 

PHOTOGRAPHY BY KELLY ZHOU 

►Diet drinks contain artificial sweetners that trick our brains 

into thinking we are getting a sweet calorie reward. 

Diet Coke, Vitamin Water Zero, Minute Maid Light: with 

the hype over healthy living and weight loss, the food industry 

has introduced many low-calorie drinks to the market. 

Most of these beverages use artificial sweeteners, which 

provide the same sweet taste with fewer or no calories. But 

what effects do the artificial sweeteners have on our body? 

Are they safe, after all? The hidden effects of artificial sweeteners 

on our body have been long disputed. 

According to research conducted by Yale School of Medicine 

scientists, the mismatch between the sweet taste and 

caloric value in diet beverages could explain the link between 

artificial sweetener use and cases of metabolic failure, 

such as in diabetes. Because the brain cannot register 

how much sugar was consumed, our body cannot properly 

digest and process the diet beverages. 

A sweet taste helps indicate the amount of energy present 

in a food source. “Our bodies evolved to efficiently use 

the energy sources available in nature,” said senior author 

and Yale psychiatry professor Dana Small. She continued, 

“Our modern food environment is characterized by energy 

sources our bodies have never seen before.” When a beverage 

tastes too sweet or not sweet enough for the number of 

calories it contains, the signal communicating its nutritional 

value can be disrupted. Our metabolism is confused, and 

the beverage cannot be digested properly. 

Small and her colleagues discovered the problems of 

“diet” beverages when performing an experiment on brain 

responses to sugar ingestion. The team observed the brain 

activity of fifteen healthy participants after drinking tasteless 

sugary drinks. Normally, when sugar is introduced to 

the body, the brain releases dopamine, a chemical compound 

that induces reward and pleasure. However, when 

the participants drank tasteless but sugary drinks, the 

amount of dopamine released was not proportional to the 

calories in the beverage. “In other words, the assumption 

that more calories trigger greater metabolic and brain response 

is wrong,” Small said. She was interested in pursuing 

this further, commenting, “A strange finding that makes no 

sense means that you’re going to learn something new.” 

Further research revealed that a sweet taste also determines 

how sugar is metabolized and signaled to the brain. 

“Calories are only half of the equation; sweet taste perception 

is the other half,” Small said. In fact, sweet low-calorie 

drinks could produce greater metabolic response and higher 

dopamine levels than less sugary higher-calorie drinks. 

In nature, when sweetness reflects the number of calories 

in the food, the body properly metabolizes the calories and 

activates the corresponding brain reward signals. However, 

the modern food industry introduces beverages with the 

kind of sweetness that our body hasn’t been exposed to before. 

“A calorie is not a calorie,” said Small, commenting on 

how the impact of these drinks on our bodies goes beyond 

just the number of calories. When sweetness and calories 

don’t align, like in artificially sweetened drinks, the beverage 

fails to trigger metabolism and the brain reward circuits 

can’t register the number of calories consumed. The metabolic 

failure observed here could help explain the link between 

artificial sweeteners and problems like diabetes. 


►Artificial sweetners confuse our metabolic systems, possibly 

creating mixed signals that lead to health issues like diabetes. 


October 2017 


11

WHAT IS HOT, DENSE, 

& spins like crazy? 

art by Emma Wilson 

by Sophia Sánchez-Maes 

It all started with a big bang...but then what? 

Our universe is 13.8 billion years old— 

the most remarkable detail about this fact 

is what it implies about its beginning. Space 

itself is continuously expanding, and winding 

back the clock shows it getting smaller 

and smaller, eventually shrinking down to 

a single point from whence it all came: life, 

the universe, and time itself. Squeezing the 

contents of the entire universe into a single 

point may seem unimaginably difficult, but 

compress matter enough, and that inward 

pressure is enough to break molecular bonds 

into atoms. Compress further and atoms 

themselves break into their components: 

protons, neutrons, and electrons. Next, the 

stress would break even the bonds that tie 

those subatomic particles together, releasing 

even smaller particles called quarks and gluons—two 

of the 13 elementary particles that 

constitute the most basic building blocks of 

matter. As carriers of the strong force, gluons 

are the glue that acts to bind quarks together 

into protons and neutrons. The strong force 

governs interactions between all particles 

with a color charge, like quarks and gluons, 

and is also responsible for binding together 

the atomic nucleus. 

In order to overcome intermolecular and 

interatomic forces and explore the properties 

of this primordial cosmic soup, scientists 

must replicate the conditions of the early 

universe just milliseconds after the Big Bang, 

which involved blistering temperatures and 

tightly packed matter. 

This August, the STAR collaboration, a 

group of scientists aiming to deduce the 

properties of the quark gluon plasma and 

the physics that underlay them, published 

their measurement of the vorticity of the 

quark-gluon plasma in Nature: a experiment 

which elucidates the unexpected fluid properties 

of this matter that dominated early in 

the universe, and is an important step to bettering 

our theory of the strong force. 

IMAGE COURTESY OF BROOKHAVEN NATIONAL LABORATORY 

►The tracks in this image depict the particles 

produced by the collision of gold ions at RHIC, 

as captured by the STAR detector’s Time 

Projection Chamber. 

Exploring the universe, before it was cool 

Researchers like Yale’s Helen Caines don’t 

need to journey through time to discover 

properties of early universe. They have only 

to cross the Long Island Sound to Brookhaven 

National Laboratory, where the Relativistic 

Heavy Ion Collider is cooking up the 

same conditions. At Brookhaven, STAR researchers 

focus narrow beams of gold ions 

(atoms which have lost their outer electrons) 

at one another, each traveling close to the 

speed of light. Such incredible speeds also 

give the ions incredible energy, so any headon 

collision between gold ions is able to 

dissolve the 79 protons and 118 neutrons in 

each gold ion into quarks and gluons, forming, 

for a brief instant, the quark gluon plasma, 

a soup of quarks and gluons which exists 

at extreme temperatures and densities. The 

Relativistic Heavy Ion Collider, along with 

CERN’s Large Hadron Collider in Geneva 

are the only facilities in the world with machines 

powerful enough to produce quark 

gluon plasma. 

Having proven that the produced plasma is 

indeed comparable to that of the primordial 

cosmos, scientists in the STAR collaboration 

moved on to also show that this material is 

full of unexpected surprises. For example, 

researchers anticipated that such a hot, energetic 

state of matter would behave like some 

sort of super gas, without the strong collectivity 

properties that characterize liquids, 

unlike gasses, which diffuse evenly. 

In actuality, the quark gluon plasma 

(QGP) behaves like a liquid, since its constituents 

interact more strongly than those of a 

gas. “We know that the gluons themselves 

interact, and the quarks interact via gluons, 

so it makes sense if they can interact very 

strongly with each other,” Caines said. 

In this series of experiments, scientists are 

aiming to determine the properties of the 

quark gluon plasma’s fluid properties. Not 

only is the QGP a liquid, but it has the lowest 

viscosity of any liquid ever encountered, 

meaning that unlike viscous substances like 

honey, it has nearly no resistance to flow. 

This unique property has prompted scientists 

to call it nearly “perfect.” 

Since this medium formed under such 

extreme temperatures and pressures, it’s 


particle physics 

FOCUS 

distance, it gets increasingly strong, like a 

spring that wishes to retract. Eventually, so 

much energy is expended in pulling apart 

this particle that another particle antiparticle 

pair is pulled from the vacuum to preserve 

net colorlessness. This means that it’s 

impossible to detect free quarks. This might 

be puzzling, since quarks in the QGP aren’t 

bound in mesons or nucleons, but zooming 

in anywhere in this soup, conditions are “locally” 

colorless. Since scientists can’t detect 

the quarks individually, the STAR collaboration 

scientists instead detect the particles 

created from the QGP as it cools, whose motion 

is inherited from this fluid that formed 

them. 

It’s not “just a phase” 

not surprising that the medium breaks other 

records. These record-setting properties 

include a low viscosity, a high temperature, 

and a now legendary vorticity, or swirling 

properties. These measurements not only 

help us understand this unexpected liquid 

phase, but also assist in our understanding of 

quantum chromodynamics (QCD), a theory 

which governs the interactions of the colored 

charged particles (quarks and gluons) 

which make up the QGP. 

The force is strong with this one 

Quarks are never observed in alone, but 

are always bundled in pairs or groups of 

three by gluons, which carry the strong 

force. There are six types of quark, with 

up and down quarks combining in groups 

of three to create protons and neutrons 

– the heaviest components of atoms. The 

theory governing their interactions is 

called quantum chromodynamics (QCD). 

Quarks come in three states called ‘colors.’ 

The strong force, which governs the behavior 

of quarks, is incredibly unusual. 

Gravity, the force with which we’re most 

familiar, only attracts objects toward each 


IMAGE COURTESY OF WIKIPEDIA` 

►The color charge acts such all matter must be locally white, binding quarks into combinations 

that preserve this colorlessness and preventing the sustained existence of free quarks. 

other. Electromagnetism has positive and 

negative (anti-positive) charges – but like 

gravity, their effect fades with the inverse 

square of the distance. Quarks and gluons 

have color-charge, which has nothing 

to do with color but for convenient 

metaphor. There are three colors (red, 

green, and blue) and three anti-colors 

(anti-red, anti-green, anti-blue) Any stable 

state must be colorless – which can 

only be achieved by mixing all the colors, 

like in protons and neutrons (made up of 

three quarks) – or by combining a color 

and anti-color, like in particles called mesons 

(which consist of a quark and an anti-quark). 

Furthermore, mass and charge 

are fundamental properties of particles, 

whereas color charge can change via gluon 

interactions. It is the strong force, and 

the color charge that mediates it, that is 

responsible for the interactions between 

quarks and gluons. By understanding 

the behavior of the QGP, scientists are 

probing these fundamental forces and 

properties. 

Try pulling a meson apart and you’ll see 

that the strong force operates differently 

in another important way: with increasing 

The QGP is a fluid, and is defined by superlatives. 

At four trillion degrees Celsius, 

tens of thousands of degrees hotter than a 

supernova, it’s the hottest thing we know 

in the universe. It also has the lowest viscosity, 

or resistance to flow, of any known 

fluid. Now, the STAR collaboration has also 

made the first measurement of its vorticity, 

or rotation. 

When gold ions collide head-on, their 

constituent particles combine to create the 

QGP; but typically the collision between 

ions is more glancing. In that case, region 

of contact, like the center of a Venn diagram, 

will combine to become QGP, while 

the outside regions will continue speeding 

away from each other. These glancing collisions 

give the resulting soup a net angular 

momentum, setting the QGP spinning. 

Scientists in the STAR collaboration 

aimed to detect this spin by detecting the 

particles generated by the plasma as it cools. 

October 2017 

IMAGE COURTESY OF WIKIPEDIA 

►The quark gluon plasma kicked off the start 

of the radiation era of the universe’s history 

from 10e-12 to 10e-6 seconds after the big 

bang, right after cosmic inflation. 


13

FOCUS 

particle physics 

IMAGE COURTESY OF BERKELEY LABS 

►The color charge acts such all matter must be 

locally white, binding quarks into combinations 

that preserve this colorlessness and preventing 

the sustained existence of free quarks. 

IMAGE COURTESY OF GETTY IMAGES 

►This image, taken near RHIC at Brookhaven 

Laboratory depicts a subset of the STAR 

collaboration. 

Any angular momentum in the system will 

be passed on to the particles it generates, 

whose spins are aligned with the whirling 

structures from which they came. On average, 

those spins will indicate the net angular 

momentum created by the system. As 

Yale’s Professor Caines, spokesperson for 

the collaboration described, “when you collide 

them just a little bit edge on edge you 

set it spinning, and that’s basically what we 

measured, how fast it’s spinning collectively. 

We can detect that angular momentum.” 

The experiment used two instruments for 

this measurement. The first of these was the 

Time Project Chamber, which is filled with 

gas that surrounds the collision and allows 

scientists to track the particles released 

from the collision and therefore generated 

by the QGP. This detector measures protons 

created by the plasma. The second instrument, 

the Beam-Beam Counters, measures 

deflections in the paths of particles which 

whiz by one another and indicates the magnitude 

and direction of angular momentum 

in each collision. Correlating this measured 

angular momentum with aligned direction 

of the detected protons, STAR scientists 

searched for preference in direction that 

will indicate the vorticity of the system. 

This measurement indicates that the 

QGP is the most vortical fluid known, a 

measured value surprising in its magnitude. 

The vorticity of the QGP exceeded 

all predicted values – whirling faster than 

tornados, Jupiter’s red spot, and previous 

vorticity record-holder superfluid helium. 

This high vorticity is allowed to perpetuate 

by the low viscosity of the fluid – since high 

resistance to flow would dampen whirls prior 

to measurement. Vorticity is a property of 

the flow – it’s not intrinsic to the medium, 

but results from the medium and its motion. 

But since we know the conditions that 

produced the flow inside of the collider, it’s 

possible to gain useful information about 

the fluid properties. Knowing the specifics 

of the collision that generated it allows us to 

firm up our theories of how the QGP interacts 

and responds to forces. 

Changes in temperature and pressure induce 

phase transitions. Think briefly of ice: 

increasing the temperature will turn it to 

water, then to vapor. At 4 trillion degrees 

Celcius, the quark gluon plasma is very hot, 

which is why the strong mutual interactions 

of its constituent particles is puzzling. The 

QGP behaves more like a fluid than like a 

gas. Instead of expanding out evenly in all 

directions, it’s preferential in its flow. Is it a 

relic of the strong force, which governs interactions 

between its constituent parts? Or 

perhaps the extreme pressure of the cosmic 

soup? In future experiments, the STAR collaboration 

hopes to deduce the equation of 

state for the quark gluon plasma to resolve 

these questions and test theories about the 

strong force. 

This vorticity measurement will aid in 

improving theories of the plasma and how 

it affected the properties of the early universe. 

Most importantly, spinning charges 

produce magnetic fields, making this measurement 

an important first step in making 

the first measurements of the magnetic 

properties of the QGP, an important step 

in better understanding the weird physics 

surrounding this hot, flowy, whirling 

soup. Although the significance of such 

fundamental science isn’t always immediately 

clear, Yale’s Li Yi, a scientist with the 

collaboration sees this as exciting infinite 

possibility. “Maybe it sounds like science 

fiction, but in all of the modern world most 

of the technology is based on QED (quantum 

electro dynamics), our theory of the 

electromagnetic force. For example, we 

transfer the messages and communications 

through electromagnetic waves - this is all 

through the QED because we really understand 

what we can do. QCD we don’t know 

exactly how it works - or what we could use 

it for.” The STAR Collaboration’s measurements 

of the QGP are among the most important 

measurements for formulating and 

testing this theory. 

ABOUT THE AUTHOR 

SOPHIA SANCHEZ-MAES 

SOPHIA SANCHEZ-MAES is a junior Physics and Astrophysics double major 

in Timothy Dwight college. She works with Professor Jun Korenaga on studying 

the origin processes of plate tectonics, and topics in complex systems. 

THE AUTHOR WOULD LIKE TO THANK Professor Helen Caines and Dr. Li 

Yi for their incredible knowledge and willingness to share it. 

FURTHER READING 

The Star Collaboration. (2017). Global Λ hyperon polarization in nuclear 

collisions. Nature. Retrieved October 1, 2017. 


THE SEARCH 

Mathematical model explains 

diversity in cancer cell movement 

by Charlie Musoff | art by Anusha Bishop

FOCUS 

cell biology 

You lost your keys again. Without any idea as to where they went, you dart from room to room, 

pursuing each lead for just a moment before giving up and trying something else. As you search, 

you piece it together and suddenly remember where they are: the refrigerator. Turning away from your 

hamper, you make a beeline for the kitchen, and the keys are recovered within moments. The way you 

went about finding your keys—the indiscriminate giving way to the direct—is not unique to forgetful 

humans. All living things—dogs, bees, cancer cells—devise these strategies as they explore the world 

around them. In the last case, however, this probing can do more harm than good. The more cancer cells 

move in a persistent beeline, the more efficiently they will spread and the more lethal the cancer will be. 

A team at the Yale Systems Biology Institute 

led by professor Andre Levchenko 

and postdoctorate researcher JinSeok Park 

wanted to more comprehensively understand 

how cancer cells find their proverbial 

keys. To start, it is important to understand 

how cells interact with their direct 

outside environment, a network of proteins 

called the extracellular matrix (ECM) that 

cells secrete themselves. Coming into contact 

with a neighboring cell’s ECM triggers 

two signaling pathways that mediate cell 

movement. The balance between the different 

behaviors that these two pathways 

trigger—the cell’s polarity, so to speak— 

influences cells’ migration behavior, their 

switch from frenzy to beeline. Previous research 

implied that cell contact with the 

ECM was responsible for these different 

patterns, but how the cells went about this 

was poorly understood. Levchenko and 

Park derived a mathematical model to predict 

a given cell’s behavior based on the activity 

of the two principal signaling pathways, 

which both cements the link between 

cell-ECM contact and migration and, more 

importantly, clarifies a new avenue for cancer 

treatment. 

Migration 

The type of cancer called melanoma 

rarely kills at its origin, the skin, but rather 

takes lives when it attacks other organ 

systems, or metastasizes. Therefore, it is a 

disease that relies heavily on movement, 

a trait that made it a useful model for the 

team to study. The critical moment in melanoma 

progression happens when the cancer 

stops expanding across the skin and begins 

tunneling downward. At that point, 

it is only a matter of time until melanoma 

cells find their way to a blood or lymphatic 

vessel, the anatomical highways necessary 

for metastasis. But first, these cells have to 

navigate the fibers of the dermis, the layer 

of tissue right below the skin. 

These tissue fibers are like ropes that cells 

can pull to move around. There are three 

types of cell movements. When the cells 

rapidly pull ropes in different directions, 

their behavior is random; when cells alternate 

pulling forward and backward on the 

same rope, their behavior is oscillatory; 

and when cells consistently pull one rope in 

one direction, their behavior is persistent. 

The oscillatory pattern is a cell-specific behavior 

and complicates the model—once 

a target has been established for the cell, 

it continues to travel back and forth in the 

vicinity instead of heading straight there. 

Levchenko likes to think of oscillation as 

a cell overshooting its target and doubling 

back repeatedly. Regardless, if a cell is to 

reach a destination, persistent behavior is 

the most efficient, which, in the context of 

cancer, means a faster progression towards 

metastasis. 

Migration patterns do not happen by 

chance. Cells’ direct contact with the fibers 

of the ECM sets off two sets of signals 

that influence cell movement and so 

determine whether cells will display random, 

oscillatory, or persistent behavior. 

One of these signals is characterized by a 

protein called Rac1 and the other by a protein 

called RhoA. The two sets of signals 

work towards the same goal—to mediate 

cell movement—but perform opposite 

functions, as Rac1 acts as an accelerator to 

RhoA’s brakes. To complicate matters further 

RhoA functions to halt cell migration, 

its presence is also required for migration 

in the first place. This somewhat paradoxical 

mechanism only highlights the complexity 

of these networks. Research in oncology 

typically has focused on how cancer 

cells grow and replicate, but these convoluted 

and poorly understood processes of 

cell migration pushed Levchenko and Park 

to establish a coherent model and reconcile 

the three migration patterns. 

Polarization 

The model the researchers derives uses 

advanced mathematics to integrate these 

three behaviors into the same framework, 

an unprecedented feat. The model shows 

how cells’ contact with the ECM changes 

the balance between the levels of activity 

of the Rac1 and RhoA pathways, which 

in turn impacts migration. By plotting the 

two activation rates on the same axes, the 

researchers were able to establish discrete 

regions for each migration pattern. For example, 

if a cell has a high Rac1 activation 

rate and a low RhoA activation rate—a lot 

of accelerator and little brakes—it will display 

persistent behavior. 

The model accounts for not only the balance, 

but also the location of this pathway 

activation within a given cell. By tracking 

sites of high signaling activity, the researchers 

were able to visualize the spatial 

distribution of these two pathways. In 

randomly migrating cells, signaling was 

sporadic; in oscillating cells, hotspots of 

activity alternated between the front and 

the back; and in persistently moving cells, 

activity was high on one side and inhibited 

on the other. These signals are consistent 

with the aforementioned “ropes” of the 

ECM and helped Levchenko and Park affirm 

that their model accurately represented 

cell movement. 

This model is unique because Levchenko 

and Park were able to map specific populations 

of cells onto diagrams that were generated 

using the model. Within the same 

cancer or even the same tumor, different 

cells will display different behaviors, and 

the model accounts for these varied responses. 

“[Cells] all get the same piece of 

information, but they interpret that information 

in very different ways,” Levchenko 

said. Understanding how real cells move 

within and correspond to the rigid math- 


cell biology 

FOCUS 

ematical model was an especially rigorous 

step that confirmed the model’s validity. 

Manipulation 

IMAGE COUTESY OF JINSEOK PARK 

►Professor Andre Levchenko , director of the Yale Systems Biology Institute, worked with 

professor JinSeok Park on this research. 

Once a model had been established, the 

next step was to manipulate it. One determinant 

of cell migration is the density of 

the ECM. To mimic the ECM, the researchers 

placed artificial nanoscale posts on a 

cell adhesion surface. As more posts were 

added, the fraction of persistently migrating 

cells decreased. “[The cells] are getting 

too much input from the surface, so they 

are confused,” Park said. When there were 

fewer posts, cells seemed to perceive their 

organization into rows and so had stronger 

directional cues, but when there were many 

posts, the cells were less able to navigate. 

The proportions of the migration patterns 

as predicted by the model were backed up 

with experimental data from real melanoma 

cells, and as expected, the more persistent 

cell migration was, the farther cells 

migrated. 

Levchenko and Park went on to alter a 

whole host of factors in order to understand 

the model’s viability outside their 

tightly regulated conditions. When either 

the Rac1 or RhoA signaling pathway was 

perturbed, the fraction of persistently moving 

cells decreased, a finding that is consistent 

with the networks’ modulation of cell 

movement. Similarly, when a drug that inhibits 

the formation of microtubules, elements 

of the cytoskeleton that play a role 

in migration, was administered, persistent 

cells decreased. Lastly, the researchers 

tested whether using a different cell line 

would yield the same results. All the previous 

experiments were done in a cancer 

cell known to be particularly invasive. To 

determine whether the model would fit a 

less aggressive melanoma, it was tested in a 

non-invasive cell line for which fewer persistent 

cells were expected, as a less invasive 

cancer metastasizes less efficiently. Despite 

the change in the aggressiveness of the cancer, 

the model held, which suggests its application 

in a much broader context of cancer 

therapy. 

Humanization 

To expand their discovery, Levchenko 

and Park hope to shed further light 

on the role of cell-ECM communication 

in cancer research. Once a complete map 

of the key signaling networks that dictate 

a cancer’s behavior is understood, 

targeted therapies can infiltrate them. If 

the networks can be manipulated to limit 

the proportion of persistently migrating 

cells, then even a cancer that has begun 

to spread can be delayed. Prolonging the 

period of time before a cell makes a beeline 

for a blood or lymphatic vessel in this 

fashion is an untapped therapeutic avenue 

towards which this model makes great 

strides. On the clinical side, the model allows 

for much more accurate predictions 

of the interval of time between the onset 

of a primary tumor and the cancer’s metastasis, 

which can undoubtedly improve 

cancer prognosis. 

Cancer treatment is ultimately about patients’ 

well-being. If this model can delay 

the cell search and prevent persistent cell 

migration, it could prolong life by months, 

which can make a significant difference for 

a highly aggressive cancer like melanoma, 

which has only a 15-20% 5-year survival 

rate in its most advanced form. Understanding 

how we can target the molecules 

that modulate cells’ search period is an 

important therapeutic step towards an increase 

in these rates. Maybe one day melanoma 

cells will never find their keys. 


CHARLIE MUSOFF 

CHARLIE MUSOFF is a sophomore in Davenport College and a molecular, 

cellular, and developmental biology major. Besides being Yale Scientific’s 

Outreach Designer, Charlie enjoys running, singing with the Baker’s Dozen, 

and teaching with Community Health Educators. 

THE AUTHOR WOULD LIKE TO THANK Professors Andre Levchenko and 

JinSeok Park for their time and insights. 


Holmes, William R., et al. “A Mathematical Model Coupling Polarity Signaling to 

Cell Adhesion Explains Diverse Cell Migration Patterns.” PLOS Computational 

Biology, vol. 13, no. 5, 4 May 2017, doi:10.1371/journal.pcbi.1005524. 


October 2017 


17

TURNING back the CLOCK 

New drug restores 

memory in mice 

with fewer side 

effects 

August would be the first patient diagnosed 

with Alzheimer’s Disease. After her 

death, Dr. Alzheimer examined her brain 

and reported the presence of peculiar alterations 

in August’s brain tissue, which would 

later be called plaques and tangles. These 

changes are now considered hallmarks of 

a disease that contributes to the progressive 

decline in cognitive function of more 

than five million people in the United States 

alone. 

Researchers in the Strittmatter Lab at the 

Yale School of Medicine used a new drug to 

restore the memory and learning abilities 

of mice with Alzheimer’s. Unlike other Alzheimer’s 

drugs that are sometimes linked to 

adverse side-effects, this drug, called SAM, 

specifically targets the proteins linked to the 

disease without affecting essential proteins 

in the brain. 

A sticky disease 

by WILLIAM BURNS 

art by SIDA TANG 

Over a century has passed since German physician Dr. Alois Alzheimer 

documented the case of August Deter, a patient whose 

misunderstood and senseless behavior earned her admittance at 

a mental institution in Frankfurt in 1901. When Dr. Alzheimer asked 

for her name, August responded with the now eminent phrase, 

“I HAVE LOST MYSELF.” 

Plaques are sticky clusters made up of proteins 

called beta-amyloid that accumulate 

between nerve cells in the brain. Recent evidence 

suggests that small aggregates of beta-amyloid 

plaques are more damaging than 

the massive plaques themselves. These aggregates, 

called oligomers, cluster in synaps- 

es—the small gaps separating neurons of the 

brain—and block cell-to-cell communication. 

When synapses are disrupted, neurons 

cannot send electrical signals to each other, 

a dysfunction that ultimately contributes to 

the loss of memory and brain function characteristic 

of Alzheimer’s disease. 

On a molecular level, research has shown 

that the interaction between two particular 

proteins leads to Alzheimer’s disease. These 

two proteins are called cell-surface glycoprotein 

(PrP) and metabotropic glutamate 

receptor 5 (mGluR5). The interaction between 

these two proteins relays neurotoxic 

signals across the brain, damages synapses, 

and drains the brain’s cognitive capacity. Beta-amyloid 

peptides play a role in this process 

by strengthening the disease-causing 

interaction between PrP and mGluR5. 

The catch, however, is that these proteins 

also serve important roles in the normal 

functioning of the body. GluR5, for example, 

is a receptor found on membranes of neurons 

and interacts with glutamate, a chemical 

messenger that relays signals across the 

synapses of neurons. Glutamate plays an essential 

role in a wide range of neural functions, 

including learning, memory, and synaptic 

plasticity, or the ability of synapses in 

the brain to adapt to new information and 

strengthen over time. The more closely neurons 

are “wired” together at their synapses, 

the more robust the brain’s ability to communicate 

between neurons will be. 

Introducing SAM 

Alzheimer’s drugs that block glutamate interactions 

with mGluR5 have been shown to 

trigger visual hallucinations, insomnia, and 

cognitive dysfunction. As a result, designing 

an Alzheimer’s drug that specifically targets 

the interaction between beta-amyloid, 

PrP, and mGluR5 while leaving glutamate 

signaling undamaged has been the goal of 

researchers for many years. “A few years 

ago, we did an experiment with a drug that 

blocks mGluR5, and it ameliorated some 

Alzheimer’s conditions, but the drug also 

blocks glutamate,” said professor Stephen 

Strittmatter. “What we really need, however, 

is a drug that stops Alzheimer’s but preserves 

the normal physiology of glutamate.” 

The researchers contacted the American 

pharmaceutical company Bristol Myers 

Squibb and requested a schizophrenia drug 

called SAM. The researchers noticed that 

SAM acted on the same mGluR5 pathway 


neuroscience 

FOCUS 

they were studying and predicted that SAM 

would have an effect on their Alzheimer’s 

mice. Encouragingly, the researchers found 

that SAM blocks the interaction of a beta-amyloid 

with PrP and mGluR5 but leaves glutamate 

signaling unaffected in mice. To determine 

this, the researchers measured the 

amount of calcium ions released inside the 

neurons, since glutamate signaling is known 

to be involved with the release of that ion. Because 

SAM did not alter calcium levels in the 

brain, the researchers concluded that SAM 

does not disturb glutamate signaling. “We 

found that SAM blocks one type of signaling 

through GluR5 but maintains another: glutamate 

signaling," Strittmatter said. "It stops the 

pathology but leaves the physiology." 

Like most Alzheimer’s drugs, SAM binds 

to PrP and mGluR5 in a way that changes 

the overall shape of the group. This prevents 

beta-amyloid peptides from sticking to the 

group and forming the toxic protein clusters 

that damage synapses. Further, the researchers 

showed that SAM does not alter 

the strength of signals transmitted between 

neurons in mice brains. Thus, SAM selectively 

targets the disease-causing mechanism of 

Alzheimer’s while leaving normal functions 

undamaged. 

Maze trials 

The researchers examined whether SAM 

could ameliorate memory deficits in mice 

models of Alzheimer’s. The mice’s first task 

was a water maze. “When the mice are 

young and they don’t yet have accumulated 

amyloid in the brain, they can learn tasks 

like how to figure out a maze, but as the mice 

age, accumulate amyloid, and lose synapses, 

they become unable to learn,” Strittmatter 

said. The Alzheimer’s mice, the Alzheimer’s 

mice treated with SAM, and the healthy 

mice were all given the task to navigate the 

same maze and find a platform submerged 

in a pool. 

For the next three days, the mice became 

familiarized with the layout of the maze. The 

researchers positioned the mice at 24 different 

starting points but kept the location of 

the platform constant in an effort to enforce 

learning. After the third day of training, the 

mice were put to the test. While the Alzheimer’s 

mice were slow to reach the platform, 

Alzheimer’s mice treated with SAM demonstrated 

significant improvement, arriving to 

the platform only a few seconds behind the 

healthy mice. 


Then, the researchers removed the platform 

from the pool and observed how the 

mice navigated the maze. The healthy mice 

spent a significant amount of time swimming 

around the zone that the platform used 

to be located, showing that they had successfully 

learned to correlate the general location 

of the platform with safety. In contrast, the 

Alzheimer’s mice swam around the pool at 

random, indicating that they didn’t “remember” 

where the platform should have been. 

Mice treated with SAM exhibited restored 

memory and spent a comparable amount 

of time in the platform zone to the healthy 

mice. Accordingly, SAM successfully rescued 

memory and learning deficits in Alzheimer’s 

mice. 

Fighting instinct 

"Another innate behavior of mice is that 

they scurry around the room and jump into 

dark holse in the corner," said Santiago Salazar, 

a graduate researcher in the Strittmatter 

Lab and second author of the paper. This 

natural behavior spurred the researchers to 

design another experiment to test the power 

of SAM in recovering the learning and 

memory aptitudes of mice. The researchers 

divided a chamber into a well-lit side and a 

dark side. On the dark side, they plated the 

floor with a surface that delivered a mild 

shock to the mice. 

The mice were placed in the light chamber 

for 90 seconds before the door separating 

the light and dark chambers was opened. As 

expected, the mice initially jumped through 

the hole to reach the dark chamber only to 

be greeted with an electric shock. Eventually, 

the healthy mice and the SAM-treated mice 

learned to associate the aversive shock with 

the dark chamber. In contrast, the Alzheimer’s 

mice were not able to make that association 

as successfully. “The Alzheimer’s mice 

forget that they’re going to get shocked and 

jump through the hole much quicker than 

the healthy mice type and the mice treated 

with SAM do," Salazar said. 

Strittmatter, Salzaar, and other lab members 

are currently at work to determine the 

ideal dose for SAM and the longevity of the 

drug’s effects. If all goes well, Strittmatter 

hopes to take SAM to clinical trials. Designing 

an effective Alzheimer’s drug has been 

difficult, partially because there is still a lot 

about the disease that we still do not know. 

Perhaps the ability of SAM to specifically target 

only abnormal protein interactions without 

interfering with normal mechanisms in 

the brain will yield more promising results. 

October 2017 

IMAGE COURTESY OF SANTIAGO SALAZAR 

►Amyloid beta plaques in the hippocampus of a mouse brain. Blue highlights cell nuclei and 

green highlights the plaques. Plaques like these interfere with cell-to-cell communication in 

synapses of the brain. 


WILLIAM BURNS 

WILLIAM BURNS is a sophomore Neuroscience major in Morse College. 

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

Professor Forscher’s lab studying the cytoskeletal dynamics underlying 

neurodegenerative diseases. 

THE AUTHOR WOULD LIKE TO THANK Professor Strittmatter and Santiago 

Salazar for their time, and for sharing their passion and dedication to their 

research. 


Haas, Laura et al. “Silent Allosteric Modulation of mGluR5 Maintains 

Glutamate Signaling While Rescuing Alzheimer’s Mouse Phenotypes.” Cell 

Reports, vol. 20, no. 1, 5 July 2017, pp. 76–88. 


19

IMAGE COURTESY OF THE SALTZMAN LAB 

►The nanoparticles synthesized in the 

Saltzman lab are optimized to be low in 

toxicity and are capable of delivering and 

releasing siRNA over a few weeks. 

Our immune system is the most 

useful protection we have from 

the world around us—until it 

turns on us. While the immune system 

is necessary to protect us from the invasion 

of harmful substances, it is also 

responsible for numerous rejections of 

organ transplants every year. One out 

of every four kidney recipients and almost 

half of all heart recipients experience 

an organ rejection within one year 

of transplant. When donor organs are 

so few and far between—20 people die 

each day waiting for a transplant, having 

your body attack your newly transplanted 

organ would be unfortunate. 

However, scientists are working on 

various methods of preventing transplant 

rejections. One team, led by 

Yale professors Mark Saltzman and 

Jordan Pober, is attempting to sneak 

past the checks of the immune system. 

They accomplished this by removing 

the tags on transplanted organs 

that immune cells recognize 

and react violently to. To achieve invisibility, 

they deliver small interfering 

RNA (siRNA) to the tissue using 

nanoparticle vehicles. Astonishingly, 

human arteries pretreated with siR- 

NA-loaded nanoparticles exhibited 

an 80 percent decrease of the tag. The 

results are promising for lowering rejection 

rates of various types of organ 

transplants, including the most common—the 

kidney. 

Hiding from ourselves 

There are currently many approaches 

to dampening the damaging response 

of the immune system to transplanted organs. 

Some groups tackle this challenge by 

improving immunosuppressive therapy, a 

treatment in which patients take drugs that 

reduce the strength of the body’s immune 

system. But since immunosuppression cripples 

the entire immune system , it also leads 

to increased risks of infections and malignancies. 

There are alternative approaches, 

such as the modification of the graft after 

the transplant operation to reduce its ability 

to activate the immune system. 

Saltzman and Pober are looking at this 

problem in a different way. Instead of 

tackling the immune system itself, they 

want to alter the transplant so that it is 

invisible to the immune system. If the 

transplant isn’t recognized as alien material, 

then the immune system wouldn’t 

have any reason to reject it. 

Cells of the immune system monitor the 

blood for foreign agents, much like guards 

at a watchtower looking out for intruders. 

All is peaceful—until the immune system 

detects a protein called class II major histocompatibility 

complex (MHC II), found 

on the surface of the transplant’s endothelial 

cells. The memory T cell, a type of immune 

cell, attaches to MHC II, activating 

and alerting the other parts of the immune 

system to the foreign tissue and triggering 

system-wide inflammation in response. 

www.yalescientific.org

molecular biology 

FOCUS 

However, if researchers can somehow remove 

the MHC II proteins that alert the immune 

system to false danger, the transplanted 

organ may be able to avoid attack. To reduce 

the amount of MHC II proteins displayed, researcher 

can deliver molecules called small interfering 

RNA (siRNA) to the transplant. Normally, 

the MHC II proteins are translated, or 

produced, using a messenger RNA (mRNA) as 

template. mRNA is a direct copy of DNA, our 

genetic blueprint, and serves as the instructions 

for making any type of protein. siRNA 

works by dismantling mRNA and preventing 

mRNA from participating in translation and 

thus protein production. However, the delivery 

of siRNA to the transplant’s endothelial cells, a 

cell type lining the interior surface of blood 

vessels, poses some complications. Not only is 

siRNA unstable, but it also has a hard time permeating 

the cell membrane. 

Scientists have attempted to overcome these 

challenges by engineering a special delivery vehicle 

for these siRNA molecules. While these 

approaches work in test tube conditions, the 

highly charged delivery vehicles are often cytotoxic 

inside living organisms. Furthermore, 

they only hold and release siRNA for up to three 

days, while the transplant is susceptible to rejection 

up to several weeks after the operation. 

Saltzman and Pober developed a biodegradable 

nanoparticle called PACE that is able to get 

the job done. Not only does it hold more siRNA, 

thereby lengthening the treatment duration, but 

the nanoparticle also demonstrates long-lasting 

effects on MHC II reduction in test tubes and 

in living cells, without damaging the cells. The 

siRNA is released over a longer period of time 

for increased effectiveness. The resulting reduction 

of MHC II on the surface of endothelial 

cells prevents the activation of memory T cells. 

Without their activation, the rest of the immune 

system cannot further damage the endothelial 

cells of the transplanted organ. 

Furthermore, the timing of PACE delivery 

in relation to the transplant operation gives the 

approach an advantage. Before a transplant operation, 

the donor organ is kept perfused with 

blood ex vivo, that is, outside the body, using a 

machine. The perfusion system preserves the 

quality of the organ. “We recognized that if the 

organ is ex vivo, being perfused with blood, 

there is an opportunity for treatment during 

this period,” Saltzman said. 

Thus, instead of injecting the patient 

post-operatively with siRNA-loaded nanoparticles, 

healthcare providers may be able to first 

treat the donor organs with nanoparticles and 

then carry out a transplant procedure. 

Tuning the nanoparticles 

PHOTOGRAPH BY JARED PERALTA 

►Endothelial cells are being treated with 

drug-loaded nanoparticles. 

There are many characteristics and features 

of a nanoparticle that can be optimized. “Toxicity, 

how readily they are taken up [by endothelial 

cells], how slowly they release siRNA, 

and how much siRNA they can carry are all 

important,” Saltzman said. 

To tackle the issue of cytotoxicity, Saltzman 

and Pober looked at adjusting the amount of 

the molecule 15-pentadecanolide (PDL), a 

component of the PACE nanoparticles. PDL 

content had been previously shown to decrease 

cytotoxicity by neutralizing the surface 

charge of the nanoparticles. Nanoparticles 

are typically positively charged, and highly 

charged particles inside cells can be deadly to 

them. To assess these effects, they tested siR- 

NA-loaded PACE nanoparticles of different 

PDL composition, ranging from 50 to 90 percent, 

for cytotoxicity. As expected, very high 

levels of PDL in the composition of the PACE 

nanoparticles greatly reduced the cytotoxicity. 

However, extremely high levels of PDL 

in the composition of the PACE nanoparticles 

severely hindered the ability of the PACE 

nanoparticles to deposit siRNA and suppress 

MHC II. As a compromise, Saltzman and Pober 

chose a PACE nanoparticle with 70 percent 

PDL composition, which greatly reduced 

cytotoxicity and still suppressed more than 90 

percent of MHC II. 

The potential of their nanoparticle delivery 

system shines through in several key experiments. 

The team pretreated human arteries 

with siRNA-loaded nanoparticles for six 

hours ex vivo. They then transplanted these 

treated arteries into mice without functioning 

immune systems, so the arteries would be accepted. 

This led to remarkable results, reducing 

MHC II expression in the transplanted arteries 

for up to six weeks after the transplant. 

“We tuned the nanoparticles to slowly release 

the siRNA,” Saltzman said. They also demonstrated 

that when an ex vivo siRNA-treated 

human artery was transferred from a donor 

mouse to a recipient mouse, the artery was 

protected from T cell infiltration, meaning 

that in a mouse model, at least, the arteries 

could be transplanted without rejection. 

These findings have many future implications 

for organ transplant success. Already, 

the research team has shown the successful 

delivery of nanoparticles without siRNA into 

kidneys ex vivo. “We are initially proposing 

to test the benefits of reducing expression of 

the molecules most strongly targeted by the 

recipient's immune system,” said Pober. After 

this step, the scientists may move on to 

further trials to test the new technology on 

organ transplants. With 25,000 organs transplanted 

a year, the reduction of organ rejection 

would improve the lives of many thousands 

for the better. 


CHERYL MAI 

CHERYL MAI is a junior Molecular Biophysics & Biochemistry major in 

Davenport College. She is the Special Sections Editor for the Yale Scientific 

Magazine and works in Professor Ruslan Medzhitov’s lab studying the function 

and regulation of sleep. 

THE AUTHOR WOULD LIKE TO THANK Professor Saltzman for his time 

and insights. 


Kseniya Gavrilov and W. Mark Saltzman. 2012. “Therapeutic siRNA: 

Principles, Challenges, and Strategies.” Yale J Biol Med. 85(2): 187-200. 


October 2017 


21

FOCUS 

organic chemistry 

PUTTING A PATCH ON RESISTANCE: 

A total synthesis of pleuromutilin opens the door to new long-lasting antibiotics 

by SAM BERRY | art by JASON YANG 

You’ve heard the news—bacteria have been quickly evolving immunity to the 

antibiotics that we’ve long used to fight them off, and diseases that are now 

easily treatable could come back in full force. We desperately need new 

antibiotics—yet few pharmaceutical companies are willing to invest in developing 

a product that natural selection will so quickly render obsolete. 

That’s why a team of Yale chemists, 

including chemistry professor Seth 

Herzon, postdoctoral associate Stephen 

Murphy and graduate student Mingshuo 

Zeng, have come up with a new way to 

synthesize the antibiotic pleuromutilin, 

known to slow the process of bacterial 

resistance. It isn’t the antibiotic itself 

that was significant about the discovery—it’s 

been around for decades—but 

rather the process of creating it, which 

potentially will allow scientists to create 

more potent forms of the drug. By devising 

a new synthetic scheme for pleuromutilin, 

they have opened the doors 

for a new world of potential antibiotics 

that can provide us new weapons in the 

fight against resistance. 

Our antibiotic world 

We’ve all grown up in an antibiotic 

world. Ever since Alexander Fleming’s 

accidental discovery of penicillin in 

1927, lifespans have grown longer and 

many diseases across the developed 

world have been all but eradicated. But 

even as antibiotics have changed the 

way that we live our lives, a new threat 

has begun to emerge. Rampant antibiotic 

use promotes the survival and 

proliferation of bacteria with special 

mutations in their genes that 

render antibiotics ineffective. 

Over time, more and 

more strains of antibiotic-resistant 

bacteria begin 

to appear as only those with 

protective mutations survive rounds of 

antibiotic treatment. 

Though we desperately need 

new antibiotics to counter the rising 

threat of resistance, this isn’t 

happening. There are fewer and 

fewer new antibiotics being developed. 

“The reason that we 

have so much resistance and 

no new drugs is this really 

weird, twisted conflation 

of economics and 

evolution,” Herzon said. 

Antibiotics aren’t like 

other drugs: patients 

usually only use them 

for short periods of time, and existing 

ones are, in Herzon’s words, “dirt cheap.” 

And worst of all, antibiotics often last 

only a few years before resistance develops 

in bacteria, making the actual lifetime 

of an antibiotic much shorter than 

that of other drugs. 

“The result is that there’s a terrible 

downward economic pressure not to do 

this,” Herzon said of antibiotic development. 

And while funding has increased 

slightly for small biotech startups in the 

past few years, far more new antibiotics 

are needed than are currently being 

made. 

A longer-lasting antibiotic 

In 1951, researchers at Columbia first 

isolated a powdery white substance from 

the edible mushroom Pleurotus mutilis 

and showed that it had antibacterial 

properties, naming it pleuromutilin. It 

was not until 2007, just as the antibiotic-resistant 

bacterial strain MRSA was 

making a global appearance in a major 

outbreak, that the very first antibiotic 

derived from pleuromutilin, retapamulin, 

was approved for human use. But retapamulin 

is different from other antibiotics: 

as of 2014, no bacterial resistance 

against the drug has emerged during the 

seven years that it’s been on the market. 

This is a much longer lifespan than the 

couple of years most antibiotics last before 

emerging resistance makes them 

obsolete. 

This key property is likely a result of 

a special mechanism of action unique 

to this compound. Pleuromutilin and 

its derivatives function by binding to an 

important region of the ribosome, the 

www.yalescientific.org

organic chemistry 

FOCUS 

key player in cellular protein synthesis. 

This region is essential to bacterial life 

and its sequence is common to almost 

all species of bacteria, making it especially 

difficult for bacteria to evolve resistance. 

Because of this, pleuromutilins 

are unique among classes of antibiotics 

in in that they treat disease while barely 

fostering resistance. 

Modifying in the middle 

Scientists have been exploiting this 

feature of pleuromutilin derivatives by 

developing a large number of variants 

through a process known as semisynthesis. 

Unlike a total synthesis, in which the 

product is made from scratch, semisynthesis 

involves starting with chemical 

compounds isolated from natural sources 

and then chemically modifying them. 

In this case, the process has involved 

taking purified natural pleuromutilin 

and typically modifying it at single carbon 

atom, called C14 because of its position 

in the molecule. C14 is attached to 

a chemical group that is easily removed 

and replaced with other, customized 

groups that afford the chemical new 

functionality without resorting to complex 

synthetic methods. More than 3,000 

derivatives have been made by changing 

the chemical groups attached at only 

that position. 

However, there are many more positions 

that could theoretically be modified. 

A study showed that changing the 

arrangement of chemical groups at a 

different carbon atom, C12, can afford 

the molecule some degree of efficacy 

against a group of harder-to-treat bacteria. 

These bacteria are distinguished by 

their outer membranes and are harder to 

treat because this membrane blocks the 

uptake of many traditional antibiotics, 

including C14-modified pleuromutilins. 

While C12 modifications are theoretically 

possible by semisynthesis, they are 

much harder to access, and many other 

positions that could also potentially afford 

a wider range of effects cannot be 

accessed at all. 

“As a chemist, there’s an obvious hole 

here,” Herzon said. “What we don’t have 

is a way to modify the other positions 

in the molecule.” What they needed was 

not pleuromutilin, but a way to make 

pleuromutilin, and therefore a way to 

vastly broaden the substance’s antibiotic 

potential. 

Starting from scratch 

Expanding the number of possible 

pleuromutilin derivatives required the 

researchers to start from the very beginning. 

“What we’re doing is a total synthesis 

of pleuromutilin from scratch,” 

said Stephen Murphy, who spearheaded 

much of the technical work on the project. 

“That gives us total control of the 

compound, so we can explore a broader 

chemical space.” 

The individual steps of the synthesis 

can be modified to yield a wide variety 

of different products. The full synthesis 

process involves a total of seventeen 

steps, transforming easily purchased 

chemicals into the final product, pleuromutilin. 

But synthesizing the product 

isn’t the real goal. “What we really 

care about is making pleuromutilin-like 

structures,” Herzon said. “With this synthesis 

in place, we’ve identified the viable 

pathways to these structures.” Now 

that the researchers have the essential 

blueprints to build this molecule, they 

can make modifications to any part of it 

at any stage of the building process. 

They first reported their synthesis in 

June and, in the same report, demonstrated 

that the final steps of the synthesis 

could be easily modified to create 

pleuromutilin derivatives with a flipped 

arrangement about C12. The total synthesis 

allows for many more options to 

make antibiotic derivatives that have 

never been explored. Because they can 

IMAGE COURTSY OF WIKIMEDIA COMMONS 

►Antibiotic-resistant bacteria like methicillinresistant 

Staphylococcus aureus (MRSA), 

shown, provide an immediate threat to public 

health. 

begin making modifications from earlier 

intermediates in the process rather than 

working backwards from the finished 

product, they can now access synthetic 

routes to pleuromutilin-like molecules 

that are modified in ways that would 

be impossible by semisynthesis, with 

functions that have never been studied. 

Members of the Herzon Lab are well on 

their way to testing these new molecules 

for improved antibiotic properties. 

“Right now we’re shooting around 

in the dark,” Herzon said, describing 

the search for the next effective pleuromutilin-based 

antibiotic. “Once we 

find something more active, we can drill 

down and further refine structure with 

more precision.” 


SAM BERRY 

SAM BERRY is a junior in Ezra Stiles majoring in Molecular Biophysics & 

Biochemistry. He works in the in the lab of Alanna Schepartz, where he 

studies protein delivery by cell-permeant miniature proteins. 

THE AUTHOR WOULD LIKE TO THANK Professor Herzon and Dr. Stephen 

Murphy for their time and enthusiasm when discussing their research. 


Murphy, Stephen K., Mingshuo Zeng, and Seth B. Herzon. “A Modular and 

Enantioselective Synthesis of the Pleuromutilin Antibiotics.” Science 356, no. 

6341 (June 6, 2017). 


October 2017 


23

alumni 

FEATURE 

ESSAY 

CONTEST 

BREAKING THROUGH OCEAN ACIDIFICATION 

►BY CLARA BENADON from poolesvile high school 

As a Marylander, one of my favorite things to do is to make the 

trek up to the Chesapeake Bay. Its sparkling waters and abundant 

wildlife make it a prime jewel of the East Coast. Nothing can compare 

to the experience of paddling down the Potomac River on a 

sunny day, the boughs of a sycamore arching overhead. 

Apart from being a stunner, the Bay provides major cultural and 

economic benefits. Its unique way of life is perfectly encapsulated 

in the small towns of Smith Island, where watermen make a living 

from the estuary’s riches. On a recent visit, one local said, “We 

truly build our lives around the water.” From the individual fisherman 

to larger commercial operations, the Chesapeake provides 

$3.39 billion annually in seafood sales alone—part of a total economic 

value topping $1 trillion. 

The stability of these waters is endangered by growing ocean 

acidification due to absorption of carbon dioxide from the atmosphere. 

Acidification disintegrates the protective carbonate coverings 

of shellfish, killing off large amounts of oysters, mussels, and 

scallops. Without a thriving population of oysters, which filter the 

Bay, harmful pollutants run rampant. Acidity also causes low oxygen 

levels, hindering fish respiration. Even with survivable oxygen 

levels, low pH can be fatal for fish. 

The plummeting numbers of these Chesapeake staples make a 

dent on the economy. According to the Chesapeake Bay Foundation, 

Maryland and Virginia have suffered losses exceeding $4 

billion over the last three decades stemming from the decline of 

oyster health and distribution. High acidity stunts oyster growth, 

and shellfish fisheries cannot profit from the smaller shells. 

The losses aren’t economic alone. An estimated 2,700 species 

call the Bay their home, and the loss of even one species causes 

a ripple effect through the entire food web. According to a 2004 

study in Science, the survival of threatened and nonthreatened 

species is closely intertwined. Moreover, biodiversity keeps in 

check the amount of carbon dioxide in any body of water. Now, 

zooming out from the Chesapeake Bay, skyrocketing acidity is 

present in almost every aquatic biome on our planet. When pH 

is low, coral reefs cannot absorb the calcium carbonate that makes 

up their skeleton. Corals—along with snails, clams, and urchins— 

disintegrate. A particularly disturbing image of ocean acidification 

is its effect on the neurology of fish. Their decision-making skills 

are significantly delayed to the level where they sometimes swim 

directly into the jaws of predators. 

Economically, the UN estimates that ocean acidification will 

take a $1 trillion bite out of the world economy by the year 2100. 

This massive cost has direct human implications, including its 

harm on health, job security, and cultural heritage. In addition, 

the economies of many countries are wholly dependent upon reef 

-based tourism and other activities built around the water. 

We need a solution to our world’s rapidly acidifying oceans; 

solving this problem would be beneficial on an unprecedented 

scale. Methods that at first appeared brilliant have either been limited 

by their feasibility or have been rejected due to their negative 

side effects, ultimately prolonging the search for a solution. 

The method of dumping significant iron sulphate into the water 

is based on the principle that iron fertilizes phytoplankton, or 

microscopic organisms found in every body of water. The energy 

phytoplankton gain from the iron allows them to bloom, absorbing 

CO 2 

from the atmosphere and the ocean. When the phytoplankton 

die, they sink to the bottom of the ocean, locking the 

CO 2 

there for centuries. In 1988, the late oceanographer John 

Martin proclaimed, “Give me a half tanker of iron, and I will give 

you an ice age.” It is theorized that fertilizing two percent of the 

Southern Ocean could set back global warming by ten years. 

Why not implement this magic fix? A 2016 study in Nature determined 

that the planktonic blooms would deplete the waters of 

necessary nutrients. Additionally, when the large bloom dies, it 

would create large “dead zones,” areas devoid of oxygen and life. 

Side effects aside, this technique may be entirely ineffective. Carbon 

dioxide may simply move up the food chain when the phytoplankton 

are eaten and be respired back into the water. This was 

observed when the 2009 Lohafex expedition unloaded six tons of 

iron off the Southern Atlantic. 

Alternatively, planting kelp is less drastic. Revitalizing expansive 

forests of algae has proven to be effective in sucking up underwater 

CO 2 

. Kelp grows as quickly as 18 inches a day, provides a habitat 

for marine species, and removes nutrient pollution. Researchers 

from the Puget Sound Restoration Fund, who have been monitoring 

the capability of this process, have found that kelp forests are 

effective at diminishing acidification on a local scale. While planting 

carbonsucking species across the ocean would not be a feasible 

global solution, kelp forests could help solve the acidification crises 

found in less expansive areas. 

To date, there is no straightforward fix to combat ocean acidification. 

If a scientific breakthrough were to occur, it would perhaps 

be comprised of a combination of methods. However, as science 

continuously evolves, the key to deacidifying our oceans may well 

turn out to be something beyond our wildest dreams. 


genetics 

FEATURE 

NATURE AND NURTURE 

Examining genetic and environmental factors 

►BY ANNA SUN 

IMAGE COURTESY OF PIXABAY 

►This study’s enormous computational power unlocks new 

genetic and environmental connections between diseases. 

Imagine you have a factory that produces flaky concrete and 

that this concrete is shipped to construction sites across the city. 

You discover that one building has a crack in the roof, another 

has a crack in the walls, and a third has a crack in the basement. 

All of these incidents can be traced back to the brittle concrete 

produced by this one factory. Now imagine that, another day, 

an earthquake causes similar cracks in buildings made from 

smooth, unblemished concrete. What’s the difference? In this 

analogy, the first scenario represents the genetic contributions 

to diseases, while the second represents the environmental factors 

that affect diseases. 

This is how Andrey Rzhetsky, a researcher at the University 

of Chicago, explains the different contributions of genetics 

and the environment to diseases. In the past, disease classifications 

were largely arbitrary, based mostly on vaguely similar 

features or even cultural similarities. However, in a study 

published in Nature Genetics in August 2017, researchers from 

the University of Chicago, Microsoft Research, and Vanderbilt 

University developed a largely computational method of reclassifying 

diseases based on their shared genetic and environmental 

correlations. By analyzing data from over one-third of the 

U.S. population, they discovered that complex diseases might 

be unexpectedly more or less interconnected than we previously 

thought. 

Diseases that can be traced back to a variation in a single gene 

are classified as Mendelian disorders, whereas those affected by 

both genetic and environmental factors are complex disorders. 

The researchers examined vast amounts of health insurance 

data, ultimately deriving genetic and environmental correlations 

for a wide range of 29 complex diseases—including bipolar 

disorder, type I diabetes mellitus, asthma, migraine, irritable 

bowel syndrome, and cystitis/urethritis. Individual data were 

then grouped by families to better determine how diseases can 

occur non-randomly. The researchers used statistical models to 

estimate genetic correlations, which suggested that even seemingly 

unrelated complex diseases share some similarities. 

According to Rzhetsky, if the genetic correlation for a certain 

disease is low, the contribution must be mostly environmental. 

“This is good because we can prevent the diseases by putting 

patients away from the responsible environmental factors,” 

Rzhetsky said. For better visualization of their findings, the researchers 

transformed their correlations into relative distances 

in a refined tree model to portray the inherent similarities and 

differences between the selected diseases. Diseases with shorter 

branches in the model were more correlated and thus more 

similar than those separated by longer branches. 

As a result of the reclassification, the researchers were able to 

easily identify new, unexpected relationships between the complex 

diseases. For instance, a migraine, previously assumed to 

be similar to neuropsychiatric conditions, was found to have a 

closer distance to general immune system diseases, such as irritable 

bowel syndrome and cystitis/urethritis. 

Hallie Gaitsch, an undergraduate researcher from Yale University 

who also worked on this study, best portrays the significance 

of the research with the following scenario: no matter 

how many patients from different families with different genetic 

diseases visit a one doctor, that doctor would still not be able 

to grasp the links between the familial genetic and environmental 

contributions of these diseases. The possible onset of a 

complex disease could significantly increase with another related 

one, but comorbidity in patients could be masked for years 

since some diseases are assumed to have such vastly different 

causes and origins. Only with the enormous computational 

power utilized in this study would these unforeseen similarities 

between apparently different diseases come to light. 

An important implication is the potential use of pre-existing 

tools and treatments to treat similar diseases or perhaps even 

the discovery that a drug might have adverse effects on another 

disease. This research establishes a strong foundation in its 

interpretation of the intertwined relationship between genetics 

and the environment on complex diseases. 

“Our work is a hypothesis-generator for other scientists to 

use what we’ve shown statistically in going forth with their own 

experiments and seeing these new relationships,” Gaitsch said. 

She believes that future research could not only more deeply 

analyze the interconnectedness of certain diseases, but also test 

the efficacy of treatments on these closely related diseases. 


October 2017 


25

FEATURE 

geology and geophysics 

ARCTIC OCEAN CRATERS 

Sudden methane release linked to ice sheet retreat 

►BY THEO KUHN 

In the depths of the arctic Barents Sea, north of the northernmost 

point of Norway, the seafloor is pocked with large craters and 

mounds. These craters don’t have their origins in fire, but in ice. Researchers 

believe that they formed due to the sudden breakdown 

of gas hydrate—an ice-like substance found both in seafloor sediments 

and on land, which can rapidly transition from a solid to 

a gas. New research led by Karin Andreassen at the University of 

Norway suggests that these craters released great expulsions of gas 

at the end of the last Ice Age. Furthermore, the study concludes that 

receding ice sheets were a primary factor in drawing these gases— 

which mostly consist of methane, a powerful greenhouse gas—out 

of the seafloor and potentially releasing them into the atmosphere. 

Gas hydrates are substances that form when hydrocarbon gases 

interact with water and sediment under the appropriate conditions 

and crystallize. Though they are relatively simple compounds, 

the factors that control their stability—determining whether they 

remain solid or decompose into gas and liquid water—are surprisingly 

complex. The most important factors are pressure and temperature; 

the pressure must be high and the temperature must be 

low for the hydrate to remain solid. 

To develop a model for the origin of the craters, Andreassen’s 

team combined their observations of the seafloor with a chemical 

analysis of the hydrates and a model of the physical conditions that 

would have existed in their study area over the past 30,000 years. 

Their findings paint a picture in which crater formation was the direct 

result of deglaciation. 

Near the end of the last Ice Age, which occurred 17,000 years 

ago, more than a kilometer of solid ice lay on the seafloor at the 

study location. Underneath it, there was a large zone with the optimal 

conditions for methane hydrate formation. But within two 

thousand years, that ice sheet receded from the area due to the 

warming climate. “It happened quite fast,” Andreassen said. 

The loss of such a large mass of ice caused a sudden change in 

pressure, and, to a lesser extent, temperature, that shrank the zone 

in which methane hydrates were stable. As methane hydrates became 

unstable and decomposed, the newly-released gas collected 

underneath a shrinking cap of solid hydrate. Eventually, the high 

concentration of gas and hydrate in a dwindling area caused the 

seafloor to distend and fracture, further lowering the pressure and 

allowing the remaining hydrates to suddenly decompose. The 

scars of this runaway process are the craters that remain to this 

day. 

Andreassen’s model is especially intriguing because it doesn’t 

just connect the sudden decay of gas hydrates to ice sheets; it also 

suggests that glaciation helps to form large quantities of gas hydrates 

in the first place. Methane typically leaks towards the surface 

from hydrocarbon deposits that lie in the bedrock far beneath 

the surface—the types of formations that can be drilled into for natural 

gas extraction. As an ice sheet advances over these area, its immense 

weight forces gas upwards and towards the surface where it 

can form gas hydrates, and as ice sheets recede, much of this hydrate 

then decomposes. “It’s like a big bulldozer going back and forth,” 

Andreassen said. “The ice will pump the gas up from the deeper 

reservoirs and into the shallow surface, where it can form gas hydrates.” 

Methane is 25 times more potent than carbon dioxide as a greenhouse 

gas. Methane is currently seeping from the seafloor, but most 

of it doesn’t reach the atmosphere—its slow release rate allows seawater 

to absorb it before it breaches the surface. In contrast, the 

events that formed the craters are believed to have occurred abruptly. 

Thus, these large quantities of gas released may have been able to 

bubble to the surface and enter into the atmosphere. 

Researchers hope to find traces of these events in atmospheric 

records that will help them determine if the events contributed to 

the change in climate that occurred at the end of the last Ice Age. In 

the short term, Andreassen’s team hopes to understand the extent 

of gas hydrates and craters across the Arctic Ocean, since large areas 

have experienced a similar glacial history and may have undergone 

the same process of hydrate production. By developing a clearer 

picture of the history of gas hydrates in Arctic areas, researchers 

may be able to predict how a similar process might unfold in the 

future—to find ice sheets that are quickly receding, one may need 

not look back fifteen millennia. 


► Methane hydrate from the seafloor near Oregon. Methane 

hydrate can be found within sediments and sedimentary rocks, 

primarily within the continental shelves of the world’s oceans. 


geology and geophysics 

FEATURE 

ΜICROBIAL DIVERSITY 

How environmental niches affect biological diversification 

►BY JIYOUNG KANG 

IMAGE COURTESY OF NIAID/RML 

►Researchers examined the diversification of microbes by 

studying rock formations that are millions of years old. 

Have you ever marveled at the diversity of life on Earth? 

Over the past 500 million years, the development of new 

environmental niches has played a huge role in the diversification 

of plants and animals. These macro-organisms 

have colonized new continents and expanded to various 

habitats, developing novel evolutionary adaptations that 

have led to radiation of species. But what about the microbes? 

Even though we cannot see them with our naked 

eye, they have evolved for a much longer period of time: 

the past four billion years. A team of researchers sought 

out a possible explanation for their diversification in ancient 

rocks. 

Led by Eva Stüeken at University of St. Andrews, the 

team investigated whether the diversification of microbial 

populations was also prompted by the expansion of 

environmental niches. They studied five formations in 

the Neoarchean lower Fortescue Group, located in Western 

Australia. The depositional settings possess distinct 

hydrogeologic properties, meaning that they differ in 

what elements they are made out of and whether water 

constantly flows in and out of the lakes. But they were all 

formed about three million years ago, which assures that 

any diversity in microbes observed by the researchers is 

due to the difference in habitats and not time. To assess 

the biological and geological properties of the formations, 

they gathered samples from drill cores and measured 

traces of different elements. 

This allowed the researchers to identify the type of 

bacteria that lived in the region. When some bacteria 

eat, they change the type of carbon left in the environment, 

while other bacteria change the type of sulfur. If 

researchers found more of a certain type of carbon or 

sulfur, then they would be fairly certain that the corresponding 

bacteria was once in the area. 

After taking these measurements, the researchers concluded 

that geographic and hydrologic parameters indeed 

impact the diversification of microbes. For example, 

Mt. Roe Formation is made out of basaltic rocks that 

can react with water to generate methane. The researchers 

examined the site’s carbon isotope values and inferred 

the presence of methanotrophs—bacteria that use 

methane as their main source of energy. Similarly, they 

found evidence of different metabolisms present in other 

formations with various environmental properties. This 

is because distinct minerals release different types of elements, 

which shape the biological pattern of microbial 

populations as the organisms evolve to utilize different 

nutrients. 

“It is a pretty new concept that environmental diversification 

may have triggered microbiological diversification”, 

Stüeken said. In fact, the implications of the research 

extend even to astrobiology, in the effort to find 

extraterrestrial life. Based on the data, it may be important 

to focus on planets with diverse environments. “If 

you have a planet that only has a big ocean and no land 

masses, then it would perhaps be much more difficult to 

develop a diverse biosphere,” Stüeken said. Since there 

are fewer niche spaces, there would also be fewer types 

of bacteria. 

Naturally, there were challenges that followed the study 

of ancient rocks. The scientists had to work with the possibility 

that the rocks could have been metamorphosed 

from the exposure to great heat and pressure over the 

years, potentially skewing the data. Gathering samples 

was also difficult, as they are quite weathered and scarce. 

Still, the researchers hope to further the study by analyzing 

older and younger rocks with a similar method 

by comparing marine rocks to non-marine rocks. This 

work opens a new window into the field and may be an 

important step towards acknowledging the effect of environmental 

diversity on biological diversity. 


October 2017 


27

FEATURE 

astronomy 

S T A R R Y 

FUEL TANKS 

What fuels the 

starburst phases 

of galaxies? 

A long time ago, in galaxies far, far away, stars were 

churned out at unprecedented rates; over 100 solar masses 

were produced annually. These luminous, dusty starburst 

galaxies were 1000 times more common in the very early 

universe than they are today. But the light from these stars 

is only now reaching the earth, ending its multi-billion year 

journey through the cosmos as it reaches our telescopes. 

By looking out into the universe and back into the past, we 

gain a better understanding of how these starburst galaxies 

formed and how they sustained such rapid rates of star 

production. 

In the early universe, galaxies differed in their abilities to 

produce stars. Many of the galaxies at this time were unable 

to support such rapid star formation, as the process blasted 

away the hydrogen gas, preventing the creation of future 

stars. Yet others continued to produce hundreds of stars per 

year for periods up to 100 million years, long after other 

galaxies had subsided. Why did some galaxies remain fertile 

while others died down? Recent research suggests that we 

can find the answer with the help of CH+, a rare but useful 

cation (a positively-charged, electron-deficient molecule). 

Using the Atacama Large Millimeter Array (ALMA) 

radio telescopes in Northern Chile, astronomers studied six 

early starburst galaxies. They found that CH+ is abundantly 

present in all of them, providing insight into what set these 

galaxies apart from the others. CH+ is very rare and was 

only discovered in 1941, as it can only form in extremely cold 

temperatures of about 20 Kelvin and with extremely high 

energy inputs equivalent to 4000 Kelvin. With such a high 

by ELIZABETH RUDDY || art by SONIA RUIZ 

energy requirement, CH+ must be formed in the presence 

of strong ultraviolet radiation or mechanical energy. It also 

has an extremely short lifespan, so it cannot be transported 

far. Therefore, its presence in these galaxies suggests that they 

must have recently undergone violent energy shocks. 

“CH+ traces how energy flows in a galaxy. Think of plankton 

fluorescence which is excited by little shocks that generate 

turbulence in the water. When you throw a stone in, you 

light up trails of fluorescent plankton,” said Edith Falgarone 

of the École Normale Supérieure and Observatoire, where 

the research was conducted. 

Falgarone and her team of researchers studied the emission 

and absorption spectral lines of this CH+ cation in samples 

from the six starburst galaxies. Each spectral line emitted 

by the interstellar gas corresponds to a different compound 

present in the galaxy, so the CH+ spectral lines can tell us a 

lot about how the CH+ was formed. The lines revealed the 

presence of extremely turbulent hydrogen gas surrounding 

the galaxies, extending far outwards from the cores where 

stars form. 

The discovery of this turbulent gas elucidates how galaxies 

grow and how these star-forming engines are fueled. 

The width of the CH+ lines are broader than 1000 kilometers 

per second, suggesting that it was born in enormous 

shock waves. The researchers suggest that these motions 

are powered by energetic outflows originating in the core 

of the galaxy. These outflows exit the galaxy in such a way 

that leaves matter trapped within the galaxy’s gravitational 

pull. This culminates in vast, turbulent reservoirs of cool, 


low-density gas circling the galaxy, up to 30,000 light-years 

from the galaxy core. 

While it may seem that these high-powered inner-galactic 

winds would quench the starburst phase of the galaxy, 

slowing the rate of star production by blowing out much of 

the hydrogen gas needed to create new stars, the researchers 

suggest that the opposite is actually true. Transforming 

previous models for galaxy formation, Falgarone and her 

team propose that the winds actually extend the star-formation 

phase by feeding these vast reservoirs of “fuel” for future 

stars. 

“What we have found with CH+ is that this stellar feedback 

generates turbulence in the galactic environment, so energy 

is lost and the outward momentum of the gas is lost too. 

Indeed, most of the gas expelled from the galaxy eventually 

astronomy 

FEATURE 

gas reservoir surrounding the galaxy but would like to see 

some more data before making the conclusion that this 

reservoir is what prolongs the starburst phase. “I don’t see 

the jump personally between the data and the conclusions,” 

Arce said. “This is not to say that the results are invalid in 

any way —just that the beauty of the data could have perhaps 

been more fully presented in a longer piece.” 

Larson and Arce also both expressed excitement about 

what Falgarone’s work means for future research into star 

formation. We are currently seeing very exciting results 

coming from the ALMA telescopes. They observe in the 

millimeter and sub-millimeter wavelengths, so they’re useful 

for observing dust and molecular-level matter such as CH+. 

“This paper is an example of the great work people are doing 

with the ALMA telescopes,” Arce said. 

IMAGE COURTESY OF ESO 

►An artist’s impression of how cold hydrogen gas fuels star production in distant starburst galaxies. The turbulent gases that surround the 

galaxy extend far beyond outwards of the starbust core where stars are formed. 

falls back on it, feeding further star formation instead of 

quenching it,” Falgarone explains. 

The study has, however, raised a few questions among relevant 

academic circles. “The authors suggest that turbulence 

in the outlying molecular gas slows down its infall and prolongs 

star formation. To me, this seems plausible but unproven. 

I don’t see how the generation of strong turbulence would 

contribute to the fueling of a starburst; if anything, I would 

expect it to inhibit gas infall,” said Richard Larson of the Yale 

Astronomy Department. 

Yale professor Héctor Arce, who is currently researching 

star formation in the Milky Way galaxy, had similar questions 

about the data. According to Arce, the CH+ indicates 

massive outflows of gas from the center of the galaxies. He 

agrees that this likely means that these outflows feed a cool 

The work acknowledges that the mass outflow rates 

caused by the winds alone do not completely account for 

the extreme rates of star production. Something else, still 

unknown, is nourishing these reservoirs. Falgarone and her 

team suggest that perhaps this extra mass is produced by 

galactic mergers or possibly accretion from streams of gas 

that are sucked into the gravity of the galaxy. 

Falgarone’s work sheds light on questions that have been 

puzzling scientists for years—they have wondered, how did 

starburst galaxies come by their extra fuel? We may now 

have some answers, but the result also raises new questions. 

What causes the hot, violent winds at the centers of certain 

galaxies, powering the cool gas reservoirs? Why do some galaxies 

have them and others do not? Astronomers continue to 

scour the cosmos for answers. 


October 2017 


29

FEATURE 


MOLECULAR SPEAK: 

How gut bacteria communicate with human cells 

by STEPHANIE SMELYANSKY | 

art by SUNNIE LIU 

More than 10,000 different bacterial species occupy the human 

body, outnumbering human cells ten to one. At first glance, those 

numbers may seem alarming, but fear not, we need these bacteria 

to live normal, healthy lives. These bacteria—from the ones in 

our stomachs to those on our skin—have a symbiotic relationship 

with us: we provide them with the nutrients they need to survive, 

and they help us digest food and defend our body against disease-causing 

agents. Our lives are so intertwined with these helpful 

bacterial species that the bacteria have perhaps learned how 

to speak the language of human cells. Researchers at Rockefeller 

University have identified gut bacteria that produce signaling 

molecules that can interact with human cells, opening the door 

for a wide variety of medical treatments for various gastrointestinal 

disorders. 

“The majority of FDA-approved drugs are either copies of, or 

inspired by, naturally-occurring compounds,” said Sean Brady, 



FEATURE 

a professor at Rockefeller University whose lab conducted the 

study. According to Brady, bacteria are an incredibly common 

source for those compounds. “Most of our antibiotics and immunosuppressants 

come from looking at products produced by 

bacteria,” Brady said. Many of these drugs were found by searching 

soil bacteria to see if they produced molecules with antibiotic 

properties, which is one of the main focuses of Brady’s lab. 

However, in this project, the lab decided to screen the human microbiome—the 

set of bacteria that live within the human body— 

for molecules that might be able to interact directly with human 

cells. The crux of the idea is simple: these bacteria already live in 

our bodies, so researchers wanted to find out whether we can use 

these microbes to manipulate human physiology. 

To get there, the scientists had a challenge to overcome: searching 

through the thousands of bacterial species living in the human 

body to find just one or two that can “talk” to human cells. 

A few decades ago, researchers would have had to do so by hand, 

culturing every bacterial strain individually and testing it for active 

molecules. In the twenty-first century, however, this task is 

much more feasible. The researchers had already identified one 

bacterial molecule, commendamide, that interacted with a class 

of human cell receptors called G-protein coupled receptors (GP- 

CRs). Commendamide is an N-acyl amide, a type of biologically 

active organic molecule, that is often produced by bacteria. Taking 

advantage of this fact, the researchers used the Human Microbiome 

Project database to search for all of the bacterial genes 

in the human microbiome encoding proteins that can produce 

N-acyl amides like commendamide. They identified a total of 143 

human microbial genes that code for such proteins, of which 44 

were unique enough to merit testing in the lab for biological activity. 

The researchers determined that these 44 genes comprised 

six distinct classes of N-acyl amides that are naturally produced 

by bacteria, four of which are produced by gut bacteria. 

The bacterial molecules identified by the researchers are quite 

similar to signaling molecules already produced by the human 

body; their structures mimic human signaling molecules incredibly 

closely. Furthermore, the bacterial molecules bind to the 

GPCR receptors just as well as the human signaling molecules 

do, such that the physiological result of GPCR activation is indiscernible 

between the human and bacterial molecules. Brady 

hypothesizes that as we learn more about the chemistry of the 

human microbiome, we’re going to find more cases of bacterial 

mimicry in the future. “More and more often you’re going to find 

molecules that maybe aren’t identical to, but resemble, the molecules 

that we as humans already make to target our own receptors,” 

Brady said. 

Since the molecules these bacteria produce have such a strong 

effect on human physiology, the researchers decided to see if they 

could harness that ability for medical purposes. These commensal 

bacteria can interact with GPCRs, which is a lucky coincidence 

for researchers because GPCRs are implicated in a wide variety of 

metabolic disorders. These receptors are the largest and most diverse 

group of human cell receptors, and GPCRs make up about 

one third to one half of all drug targets are. Many GPCRs are 

located in the human gut as well, which is where the N-acyl-amide-producing 

bacteria were isolated from. In fact, GPCRs in the 

gut have been implicated in hunger, glucose absorption, and diabetes, 

which is exactly what the researchers decided to study. 

IMAGE COURTSY OF WIKIMEDIA COMMONS 

►An electron microscopy image of E. coli cells isolated from the 

human small intestine—just one of the many bacterial species living 

in the human gastrointestinal tract. 

The different N-acyl amide ligands were surveyed to see if they 

would bind to 240 different GPCRs. Of these, one GPCR in particular—denoted 

GPR119—bound the bacterial molecules particularly 

well. GPR119 is implicated in the regulation of glucose 

homeostasis, and has historically been a drug target for Type 2 

Diabetes. Specifically, activation of GPR119 receptors in the gut 

can prevent the rapid change of blood sugar levels in hyperglycemic 

patients. Brady and his team wanted to see that activation 

of GPR119 with the bacterial N-acyl amides could produce the 

same effects as human signaling molecules. 

To see if the bacterial molecules were capable of affecting 

GPR119 receptors strongly enough to regulate glucose levels, the 

researchers infected mice with E. coli engineered to produce the 

molecules of interest. They then measured the blood sugars of the 

mice. As predicted, the mice that were infected with N-acyl-amide-producing 

bacteria had lower blood sugar levels than mice 

that weren’t infected with the genetically engineered bacteria. 

This shows that some bacteria produce biologically active molecules 

that not only can interact with GPR119 in the gut, but can 

also regulate blood sugar in ways similar to many blood sugar 

medications. 

Like any recently published study, these findings still have a 

long way to go from the lab to becoming viable medical treatments 

for diseases like diabetes. According to Brady, human 

physiology is incredibly complicated, and people are still working 

on how to apply these findings in mice and cell culture models to 

the human body. But that doesn’t stop Brady and his team from 

thinking about ways that these bacterial molecules could be harnessed 

as a drug. He suggests that perhaps people can ingest the 

pure molecule just like any other drug. “You could also imagine 

introducing the organism regularly, like in a yogurt,” Brady said. 

This is perhaps more enjoyable than taking a pill! Whatever the 

mode of action, these commensal bacteria provide us with ways 

to manipulate the human body in new, inventive, and potentially 

less invasive ways in the hopes of providing new treatments for 

common diseases. 


October 2017 


31

FEATURE 

ecology 

Researchers led by James Tour of Rice University, Robert Pal of 

Durham University, and Gufeng Wang of North Carolina State 

University recently developed and tested nano-sized molecular 

machines that may hold the key to treating diseases through 

mechanical attacks that leave healthy cells unharmed. The original 

design for these molecular motors was based on work by Nobel laureate 

Bernard Feringa. 

Collaboration between these three groups of scientists lent these 

nanomachines biomedical applications, opening the door to an exciting 

new frontier in medical treatment. The researchers at Rice synthesized 

ten molecular motors with novel functions, the most significant 

being the ability to drill through the lipid bilayer membranes that 

encapsulate cells. The North Carolina State researchers then tested 

these new motors on artificial lipid vesicles, which are fluid-filled 

cavities surrounded by a fatty membrane, and finally, the Durham 

researchers conducted experiments on live cells. 

The key difference between the molecular motors and traditional 

pharmaceuticals is their method of action. “It’s a whole new mechanism 

of treatment. We have a mechanical effect at the molecular 

level,” Tour said. The molecular motors, in effect, punch holes in the 

membranes of cells through pure force, an attack that is less vulnerable 

to cellular resistance than chemical attacks that interrupt cell 

processes like DNA replication. Unlike chemotherapy, which uses 

toxic chemicals to kill tumor cells, these nanomachines can target 

diseased cells more directly. 

These molecular motors, except for the controls, each consist of 

a UV light-activated rotor and a larger portion of the motor that 

remains fixed during rotation and provides a magnetic pole around 

which the rotor turns. When hit with the correct wavelength of 

light, the motor will rotate at a frequency of up to two or three 

million rotations per second. If the motors have attached themselves 

to a cell, when UV light causes rapid spinning of the motor, 

it effectively drills through the cell’s lipid bilayer, causing the cell to 

spill its contents and die. 

The sheer variety of motors developed provides a testament not 

only to the wide array of biomedical applications that these nanomachines 

can have, but also to the complex molecular interactions that 

govern the success of molecular motors. While the main components 

of each molecular motor are the same, each motor can vary 

and size and can be modified with different chemical groups to give 

it new capabilities. For example, the motors can be equipped with 

fluorophores, which are fluorescent chemicals that allow the motor 

to be tracked easily inside of cells. Several of the motors were also 


designed with attachments that bind specifically to protein groups 

found on cancer cells, thus testing the ability of the nanomachines to 

target specific cells. 

To confirm whether the motors could open bilayers, the 

researchers tracked the release of dye from vesicles in the presence 

of activated motors. In the first set of experiments, the Wang 

group encapsulated both dye and molecular motors modified with 

fluorophores inside of synthetic vesicles. Application of UV light 

significantly decreased the fluorescence intensity within these 

vesicles, as the dye and molecular motors diffused out. In contrast, 

in the absence of motors, the vesicles released negligible amounts 

of dye when exposed to UV light—proving that the vesicles burst 

because of the motors themselves, not the UV light. 

Next, the Pal group performed several experiments exposing live 

cells to the motors. The researchers first introduced the motors to cells 

without UV activation. Although cells internalize some of the motors 

through endocytosis—a normal cellular process by which cells take 

up materials from their extracellular environments—the experiments 

showed that cells remained healthy in the presence of the inactive 

motors, an important consideration for potential treatments. 

Armed with the knowledge that the inactive nanomotors are 

non-toxic, the researchers then activated the motors with UV 

light to observe how quickly the motors would accelerate cell 

death. The results were remarkable: the most effective motors 

killed both mouse fibroblast cells (a common cell-type found in 

connective tissue) and prostate cancer cells 50 percent faster than 

UV light did alone. In absolute terms, cells died within a matter 

of minutes after UV-activation. 

Perhaps most interestingly, the researchers were able to demonstrate 

that molecular motors could selectively target which cells they 

want to kill. In the experiments—performed on mammalian cells in 

petri dishes—the motors were modified with protein attachments 

physical chemistry 

FEATURE 

and were able to target cancer cells that were overexpressing certain 

protein groups. The motors were able to kill only these desired targets, 

and cell death was completed in just two to three minutes. This finding 

could mark the beginning of a new kind of photodynamic, or 

light-based, therapy research that could offer new sources of hope for 

patient treatment. 

Still, the molecular motors are not without their challenges when 

it comes to translating their functions into potential treatments. For 

example, UV light has poor penetration of human tissue, so the labs 

are actively investigating alternative sources of activation that have 

much deeper penetration. In the meantime, the labs expect the 

molecular motors to become viable options for diseases that occur at 

or near the surface of the skin, such as eczema and melanoma. Such 

treatments can have a strong impact: there are about 31.6 million 

people in the U.S. who live with eczema, and the American Cancer 

Society estimates that more than 87,000 new cases of melanoma will 

be diagnosed in 2017 alone. 

The molecular motors may also have a flexible range of functions 

beyond killing cells, such as in drug delivery. “We are looking first at 

cancers because we have a good understanding of cancer cells, but any 

cell that you need to kill can be targeted in this way,” Tour said. “You 

can also use molecular motors as a treatment source. In other words, 

turn on the molecular motors momentarily and then drugs can enter 

the cell.” With these options, molecular motors have the potential to 

enhance everything from antibiotic delivery to gene therapy. 

In the future, the labs will focus on applying the molecular motors 

to the issues of pancreatic cancer, carcinomas and eczema, and on 

developing different methods of activation that reach deep tissues 

within the body. Indeed, these motors provide hope for targeting 

nearly incurable diseases like pancreatic cancer in a way that minimizes 

side effects. As research progresses, a safe, quick, and effective 

photodynamic therapy could become a reality. 


► White blood cells defend the body from disease partly by 

distinguishing the body’s own healthy cells from pathogens and 

cancerous cells. Molecular motors can similarly target diseased cells 

within the body and selectively destroy them. 


► Prescription drugs come in many shapes and sizes. Molecular 

motors may in the future work independently of or alongside such 

drugs to enhance treatment, while causing less damage to patient 

cells and fewer side effects. 


October 2017 


33

COUNTERPOINT 

GOOD PROSPECTS FOR NEUTRINO PHYSICS 

►BY ISABEL SANDS 

In the time it takes you to read this sentence, more than 100 billion 

neutrinos from the sun will pass through your fingertip. You’re not 

likely to notice—the neutrino is a tiny, subatomic particle with virtually 

no mass. It interacts with matter through two of the four fundamental 

forces of nature: gravity and the weak nuclear force, which causes 

radioactivity. However, even this gravitational interaction is feeble due 

to the neutrino’s infinitesimal mass. And yet, despite its imperceptible 

nature, this elusive particle may be the key to unlocking some of the 

deepest secrets of the physical universe. 

Neutrinos have no electric charge and belong to a class of subatomic 

particles called leptons. Leptons possess very little mass, do not 

undergo strong interactions, and are characterized as the building 

blocks of matter. According to our current understanding of particle 

physics, there are three “flavors” of neutrino: the electron, muon, 

and tau neutrino. Each of these uncharged leptons associates with 

a specific type of charged leptin—the electron neutrino matches 

with the electron, while the muon and tau neutrinos pair with the 

electron’s heavier, less stable siblings: the muon and tau particles. 

Some physicists, however, have hypothesized the existence of a fourth 

flavor: a “sterile” neutrino that only interacts with gravity, making it 

difficult to detect. 

Recently, measurements from the Daya Bay power plant in China 

generated excitement over the possibility of sterile neutrinos. Nuclear 

reactors produce a flow of electron antineutrinos, which are the 

antiparticles of electron neutrinos. Physicists can model this flow by 

understanding the reactions that occur within the nuclear reactors. 

But at the Daya Bay power plant, these models predicted a higher 

number of flowing antineutrinos than were experimentally within the 

IMAGE COURTESY OF YALE WRIGHT LABORATORY 

►The result of a US-China-Russia collaboration, the Daya Bay reactor 

neutrino experiment promises to shed light on the mysterious nature 

of neutrinos. 

reactor. This phenomenon, called the “reactor antineutrino anomaly,” 

has also been measured at other sites. Neutrinos can spontaneously 

change flavors in a phenomenon called “oscillation,” so is it possible 

that some percentage of neutrinos are oscillating into undetectable, 

sterile neutrinos? 

Careful analysis of the data from Daya Bay initially seemed to 

rule out sterile neutrinos. As nuclear reactors consume fuel, the 

elemental composition of the fuel changes. Scientists found that the 

degree of antineutrino deficit varies with the fuel’s composition. Thus, 

they suspect that these elemental changes are responsible for the 

antineutrino anomaly. Specifically, they hypothesize that isotopes of 

uranium—forms of the atom with a different atomic mass—are the 

primary culprits. They believe they are overestimating the number 

of antineutrinos produced by uranium due to the variation between 

isotopes. However, further analysis has revealed that uranium isotopes 

cannot entirely explain the antineutrino anomaly. 

Karsten Heeger, a Yale physics professor and the director of Yale’s 

Wright Laboratory, is currently working on the Daya Bay experiment. 

“The immediate conclusion people jumped to was, ‘Oh, this might 

explain everything about the reactor antineutrino anomaly!’” Heeger 

said. “But it does not. People have now taken a closer look and realized 

that two effects could be taking place, wrong nuclear physics and 

sterile neutrinos.” The combined effect of the two theories fits the 

data better than that of either hypothesis alone, which leads Heeger to 

believe that multiple causes contribute to the anomaly. 

Heeger is now leading a new, Yale-led neutrino experiment called 

PROSPECT at the Oak Ridge National Laboratory’s research reactor. 

By using only one isotope in the fuel for the reactor at Oak Ridge, 

PROSPECT will be able to test nuclear reactor models more precisely. 

“We can see if over the distance of several meters, these neutrinos 

oscillate into sterile neutrinos,” he said. 

The implications of this research are certain to be profound. “Instead 

of neutrinos being a byproduct, we’re now starting to see them as a 

way to probe into nuclear reactions,” Heeger remarked. PROSPECT 

will hopefully provide data that allows scientists to refine their nuclear 

reaction models. 

PROSPECT also has the potential to transform modern physics: 

sterile neutrinos are not included in the Standard Model, the theory 

that describes all known elementary particles. If PROSPECT finds 

evidence for sterile neutrinos, “It would revolutionize particle 

physics,” Heeger said. “It would require us to come up with something 

completely new and different.” 

Researchers and students at the Wright Laboratory will complete 

construction on PROSPECT this fall, and installation at Oak Ridge 

National Laboratory will take place by the end of the year. Heeger says 

there may be a definitive answer to the antineutrino anomaly by 2018, 

but for now, he remains cautious. “I have no predictions,” he said. “We 

need to get the data.” 


INN VATI N 

STATION 

Decluttering our Landfills 

►BY LESLIE SIM 

Half of the plastics we use today are used once and then 

left to accumulate in landfills. This statistic is symbolic of 

a greater issue: given our ever-increasing rate of plastic 

consumption, overstuffed landfills will create dire problems 

for future generations. And while humans eventually will 

have to face the consequences of plastic pollution on land— 

if we aren’t doing so already—plastic pieces are currently 

floating in our oceans, being ingested by marine animals and 

contaminating natural habitats. 

Reducing our plastic consumption is certainly one way to 

address this issue, but researcher Yiqi Yang and his team at the 

University of Nebraska-Lincoln have an even better solution: 

biodegradable plastics. Yang believes that his lab may have 

found a way to create a cost-effective biodegradable plastic 

that targets the textile industry, where polyester plastics are 

a big source of plastic consumption. Production of these 

plastics requires a lot of petroleum, a limited resource. 

Other researchers have designed biodegradable plastics in 

the past. For example, polylactic acid (PLA) was the first and 

largest-scale biopolymer produced from annually renewable 

resources such as corn starch and sugarcane. Biopolymers 

like PLA are very long molecules consisting of a biologicallyrelevant 

repeating subunit. However, PLA’s limitations make 

it ineffective for use in the textile industry: “Others have 

been able to find biodegradable products such as PLA, but 

those products cannot be used widely in the textile industry 

because they are easily hydrolyzed at high temperature,” 

Yang said. Hydrolysis refers to the degradation of a plastic 

by breakdown into its subunits. PLA-based plastics risk 

being too soft and too easily broken-down, and are thus 

not suitable for textile materials. While engineers have 

made some progress, the main problem today isn’t finding 

a biodegradable product, but rather one that is both costeffective 

for manufacturers and has the properties necessary 

for a quality plastic. 

The plastics we use daily have the opposite problem. Most 

plastics are too stable and stick around in landfills or natural 

habitats for a long time, unable to biodegrade. After some 

experiments, however, Yang and his team have developed 

a biodegradable plastic without those shortcomings. In 

their experiments, the team obtained two biopolymers, 

poly-L-lysine (PLL) and poly-D-lysine (PDL). With these 

biopolymers, they formed plastic fibers and employed a 

thermal treatment to form tighter structures with strong 

interactions between the polymers. This key process 

ultimately decreased the plastic’s sensitivity to hydrolysis, 

especially at high temperatures. 

Several experiments testing the new plastic’s properties 

show that Yang’s team may indeed have the key to tackling 

the two main problems in plastic development (hydrolysis 

and softness at high temperatures). However, until their 

materials are examined in large-scale production, they can’t 

say for sure whether their plastic will work on the industrial 

scale. The next step for Yang and his team is to test the plastic 

on a small scale in the textile industry. From there, they can 

target other industries. Nonetheless, Yang and his team have 

gotten a step closer to making a product that will hopefully 

prove useful in decreasing, if not eliminating, plastic waste. 

The impact of a biodegradable plastic in reducing plastic 

pollution is far-reaching. Currently, animals on land and in 

oceans are easily harmed by ingesting plastic microparticles 

or by getting caught in large pieces of plastic. For humans, 

plastic remains in our landfills for far too long, and we’re 

running out of space. Yang also cautions that tap water from 

all around the world contains microscopic pieces of plastic, 

and without our knowing, we could be accumulating plastic 

in our bodies. 

Since demand for plastic is growing exponentially as the 

human population grows, it is especially critical for us to 

find a sustainable resource that meets our needs without 

damaging our environment. As we move in the direction 

of finding cost-effective and useful forms of biodegradable 

plastic, we can rest assured that researchers like Yang and his 

team are on the case. 


October 2017 


35

PETER WANG (TD ‘18) 

A MODERN DAY RENAISSANCE-MAN 

►BY ERIN WANG 

UNDERGRADUATE PROFILE 

IMAGE COURTESY OF ERIN WANG 

►Peter has a wide variety of interests, from molecular biology to 

hiking through Europe. 

Scientists are often stereotyped as people buried deep in research papers 

and focused singularly on the pursuit of science—this is hardly the 

case for current Yale College senior Peter Wang (TD ’18). Although he 

is majoring in Molecular, Cellular and Developmental Biology, his interests 

range from photography and poetry to violin-playing and graphic 

design. Science first caught his attention in middle school, but he wanted 

to be an architect when he was younger. “I got interested in appreciating 

structures, appreciating how things connect and form,” Wang said. 

This interest steered him towards science—specifically, to biomolecules. 

“The complexity and sheer scale of molecules are incredible,” he said. 

Wang’s scientific endeavors took off at Yale. Here, he has been immersed 

in classes that give him more nuanced understandings of subjects. 

Moreover, he has been able to engage in cutting-edge RNA research: 

the summer after his first year at Yale, Wang began working 

on methods to decipher the interactions and conformations of long 

non-coding RNAs in Matthew Simon’s lab, where he has been ever 

since. These RNAs play various important roles in cells, such as regulating 

gene expression, so studying their structures and functions is a 

worthwhile endeavor. He has thrown himself into research with a fervent 

passion—self-evident in his current juggling of multiple independent 

research projects within his lab and his recent second-author publication 

in ACS Biochemistry. 

Not only is Wang passionate about studying science himself, but he 

also wants to make science more accessible to others. In fact, his interest 

in communicating biology drove him towards graphic design. “Biology, 

because of its complexity, relies on a lot of concepts and processes that 

you need very clear visual tools to help people understand,” Wang said. 

He believes that in many cases, art is one of the most effective ways to 

improve science communication to the general public. 

Similarly, Wang has tried to improve the accessibility of research to 

students at Yale. He, along with his teammates at the Yale Undergraduate 

Research Association (YURA), felt that students were having difficulty 

searching through faculty to find suitable research mentors due to different 

department website layouts and the fact that key information, like 

faculty research interests, was often difficult to find. To this end, he led 

a five-person team in a yearlong endeavor to build the YURA Research 

Database, the first of its kind at Yale. This database gives students an easy 

way to sort through professors and their research interests. Under Wang’s 

guidance, the YURA Research Database is now an invaluable tool for students 

looking for research at Yale, and another improved version is in the 

works. 

Wang is also an avid environmentalist. As president of the Yale Student 

Environmental Coalition, he helped send four Yale student observers 

to the 2015 United Nations Climate Change Conference in Paris. 

He participated in The GREEN program, through which students learn 

more about the environment by global exploration. Through the program, 

he traveled to Iceland and Hawaii—places that have adopted virtually 

fully renewable energy standards. From these trips, Wang learned 

more about how their communities maintain sustainable lifestyles. 

Along the way, he built friendships with locals, learned more about their 

cultures, and experienced the natural beauty these places provided. 

Outside of exploring science, Wang also enjoys exploring the world. 

Recently, he went on a month-long solo trek in Europe. “I had never 

been to Europe. I wanted to travel. I wanted to explore somewhere I’d 

never been,” Wang said. He plotted a ten-city path through Europe, using 

Airbnb to find places to stay. “That was probably the most adventurous, 

exciting, packed, and happy month of my life,” Wang said. The 

most memorable moments of his journey took place at a Zürich train 

station. “The sunset reflected gold on the rail tracks, and the late evening 

trains brought back tired home-bound people from their work. 

It kind of encapsulated a lot of what that trip was—catching beautiful 

sights, and feeling what home felt like for different people around Europe,” 

Wang said. 

Wang is currently working on applications to graduate school. In ten 

years, he hopes to be working in academia on exciting projects in a lab 

with people he enjoys being around, all the while making meaningful 

contributions to science. He is not certain if he will be working on 

non-coding RNA in the future, but he would not hesitate to investigate 

it if the opportunity arises. 


ALUMNI PROFILE 

SANDY CHANG (YC ‘88) 

BUILDINGTHENEXTCREATIVETHINKERSINSCIENCE 

►BY JESSICA TRINH 

Sandy Chang wears a lot of hats. As a professor at the Yale School of 

Medicine, he signs out clinical cases and runs an NIH-funded research 

lab, studying telomeres and their relationship to cancer and aging. He 

holds professorships in the departments of Laboratory Medicine, Pathology, 

and Molecular Biophysics and Biochemistry. Last spring, he 

was appointed to the role of Associate Dean for Science and Quantitative 

Reasoning Education at Yale College, a role that involves overseeing 

the quality of STEM education and administration of undergraduate research 

fellowships. If that wasn’t enough, he also teaches a popular freshman 

seminar called “Topics in Cancer Biology.” For Chang, the time he 

invests is worth it, as his top priority is nurturing future scientists. 

Born in Taiwan, Chang moved to Sarasota, Florida at the age of seven, 

where his love of science blossomed. namored by the vast open skies, he 

became interested in astronomy. Despite doing astronomy-related research 

in high school as part of his dream of becoming an astronomer, 

Chang later found himself drawn toward molecular biology. So, in 1984, 

he attended a college well-known for its Molecular Biophysics and Biochemistry 

major: Yale University. 

While at Yale, Chang pursued a diverse array of interests, from writing 

about his undergraduate research for our very own Yale Scientific 

Magazine to joining the fencing team. He started conducting laboratory 

research during the summer after his first year at Yale. Immediately, he 

noticed the lack of funding resources available for undergraduate students, 

a problem he would always remember. 

Mentorship was key to Chang’s success. During his time in college, 

Chang found no shortage of mentors, from undergraduate seniors who 

gave him advice on MD-PhD programs to the principal investigators 

of research labs who nurtured his love of scientific inquiry. Outside of 

class, Chang volunteered in the pediatric oncology department at the 

Yale New Haven Hospital, where he engaged with patients. The combination 

of volunteer work and scientific research led Chang to realize he 

couldn’t just pursue an MD or a PhD degree—he wanted both. 

Chang graduated from Yale in 1988 and went on to the prestigious 

tri-institutional Weill Cornell/Rockefeller/Sloan-Kettering MD-PhD 

program. Afterwards, he did his residency in clinical pathology at the 

Brigham & Women’s Hospital and a postdoctoral fellowship at the Dana 

Farber Cancer Institute, Harvard Medical School. Chang then moved to 

Houston, Texas to start his first real job as an assistant professor at the 

MD Anderson Cancer Center. In 2010, Chang received an opportunity 

to return to Yale as a tenured associate professor at Yale Medical School. 

When it comes to scientific research opportunities for students, Chang 

believes in leveling the playing field. He is a firm believer that anyone 

who desires to do research should be able to do so, regardless of their 

financial obligations. In particular, the First-Year Summer Research Fel- 

PHOTOGRAPHY BY SUNNIE LIU 

►Between research and serving as Dean of Science and QR, Sandy 

Chang still finds plenty of time to mentor undergrads. 

lowship provides financial support that enables students to conduct research 

under the supervision of a Yale faculty member. The fellowship 

includes a stipend that is more than enough to cover Yale’s summer income 

contribution, allowing students to focus on their research. 

A recent survey of students who completed the fellowship show 

promising results: over 91 percent of rising sophomores stated they 

would continue research in the future. Chang strongly believes that early 

exposure to quality research opportunities is crucial for fostering a 

love of science. “The second you find yourself in a research laboratory 

with an inspirational mentor who guides you, it’s like being bitten by the 

research bug—you fall immediately in love with the research you are 

doing,” Chang said. Funding and support from fellowships are just one 

important component to building foundations for those interested in 

pursuing research—equally important is mentorship. 

For instance, Chang was the first-year advisor to Cayla Broton (ES 

’16). Following graduation, Cayla spent a year working with Chang, 

making important contributions to telomere biology. She is now getting 

interviews to top MD/PhD programs. In addition, in his “Topics 

in Cancer Biology” course, Chang guides first years through reading 

primary research articles and crafting their own research grant proposals. 

These are crucial tools that he believes students will utilize long after 

they finish the course. 

Today, Chang continues to make time for his undergraduates. You will 

often find him having meals with students. He loves to teach, to mentor, 

and to foster opportunities for undergraduates to be bitten by that research 

bug. “It’s a privilege to help students and to watch them blossom 

into scientists,” Chang said. 


October 2017 


37

FEATURE 

documentary and book review 

SCIENCE IN THE SPOTLIGHT 

DOCUMENTARY REVIEW : CHASING CORAL 

►BY CORY WU 

A pristine bed of corals shimmers pure white, surrounded by silence. 

Water calmly brushes over these stagnant structures, with no other life 

in sight. This seemingly beautiful scene is quite deceiving, as it depicts a 

coral graveyard after a mass bleaching event. The vivid, vibrant colors 

of ordinary corals have been usurped by a sickening white, and entire 

schools of fish that once relied on the coral have disappeared. Over just 

a two-month period, an entire coral reef ecosystem has been destroyed. 

The culprit? An increase in the average ocean temperature by two 

degrees Celsius. While two degrees seems minimal, even slight increases 

in ocean temperature can wipe out entire reefs. Heat waves cause coral 

to eject their main food source, symbiotic algae, and lose their vivid 

colors. Thus, begins the first stage of death for the coral: coral bleaching. 

Jeff Orlowski, director of the award-winning documentary “Chasing 

Ice,” recently released a follow-up documentary called “Chasing Coral,” 

which focuses on a lesser-known danger of climate change: coral 

bleaching. The film follows a team of divers who endeavor to bring the 

realities of climate change and coral bleaching to the public. Viewers 

follow the divers as they continue the daily struggle of watching beautiful 

fields of coral slowly wither away. 

The film truly excels at the art of “show, don’t tell.” Shocking facts 

are coupled immediately with haunting imagery. Salient side-by-side 

comparisons of coral before and after bleaching in the documentary 

illustrate how the bustling, lively nature of coral reefs is destroyed by 

BOOK REVIEW: THE TELOMERASE REVOLUTION 

►BY ROBERT LUO 

Death is an inevitable consequence of the passage of time. 

This notion underlies much of our literature and films, and even 

affects the choices we make in everyday life. Death and poor 

health plague our futures. But what if there were an elixir that 

might allow us to live even longer than today’s centenarians—a 

life devoid of age-related illnesses, like Alzheimer’s? It might 

sound like something out of a science fiction novel, but some 

scientists and physicians argue that sometime in the future, we 

could turn science fiction into reality. 

One of these physicians is Michael Fossel, MD-PhD and a 

professor of clinical medicine at Michigan State University, 

who studies the science of aging. In his book, The Telomerase 

Revolution, Fossel introduces telomerase as a component in 

treating illnesses like heart disease and dementia—and even 

in reversing aging itself. Telomerase is an enzyme that repairs 

telomeres, the regions at the ends of chromosomes. Within the 

last two decades, scientists have found that the shortening of 

telomeres causes cellular aging, thus giving rise to the telomere 

theory of aging. 

In the book, Fossel excellently explains the elegance of this 

theory. He contextualizes the theory with respect to other 

theories of aging—vitalist, hormonal, and genetic theories, 

amongst others—and proposes a strong unifying argument 

for telomeres as a cause of aging. Poignantly, Fossel illustrates 

the powerful implications of the telomere theory of aging; by 

activating telomerase in lab mice, signs of aging can not only 

bleaching, leaving only foreign algae 

to drape the skeletal remains of the 

coral. “Chasing Coral” masterfully 

illustrates the emotional impact coral 

bleaching can have on people, which is 

particularly apparent when the divers 

are visibly shaken by the destruction they 

photograph daily. 

In its middle, the film’s pacing 

becomes somewhat sluggish. It often 

focuses too deeply on the methodology 

of capturing images of coral, instead of 

analyzing the process of bleaching or the 

methods through which corals support 

ecosystems. The documentary also 

jumps between the perspectives of multiple people too quickly at times, 

which can detract from the significant experiences of each person. 

Still, the climax and ending masterfully cinch the documentary 

together by reassuring viewers of the many ways we can contribute in 

the fight against climate change. The film’s seamless combination of 

informative commentary and engaging storytelling make “Chasing 

Coral” not only an entertaining watch, but a necessary one to understand 

the full threat climate change already poses to our environment. 

be stopped, but also reversed. 

Through telomerase therapy, 

Fossel argues, humans have the 

potential to not only live longer, 

but also live more healthily. 

Although Fossel explains the 

effects of telomere shortening on 

the human body, he only does so 

on a surface level. Those curious 

about mechanistic explanations 

will be scratching their heads 

searching for deeper answers. 

Further, Fossel goes beyond the 

biology of telomerase to explain 

the highs and lows of telomerase 

therapy, often muddled in politics or stalled by lack of financial 

support. Finally, Fossel discusses the societal implications of 

telomerase therapy. How will we value life when we can all live 

into old age? To those curious about telomerase therapy and its 

potentially earth-shaking implications, this book is definitely 

worth a read. 

While the full implications of the purported “telomerase 

revolution” are still speculative, the book ends with a 

commentary about what we can currently do to fight the 

negative effects of aging. According to Fossel, the best answers 

are often the most simple: good diet, exercise, and meditation. 


cartoon 

FEATURE 

BEFORE/AFTER 

►BY LISA WU 

Interested in writing for 

Contact us at 

ysm@yale.edu!

YSM Issue 90.4

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