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Yale Scientific<br />

THE NATION’S OLDEST COLLEGE SCIENCE PUBLICATION • ESTABLISHED IN 1894<br />

OCTOBER 2022<br />

VOL. 95 NO. 3 • $6.99<br />

14<br />

USING FIREFLIES TO<br />

COUNT HIV REPLICATION<br />

PERSONAL MATTERS<br />

12<br />

ON ABORTION<br />

THE WORLD<br />

16<br />

IN PROTEINS<br />

TURNING THE KNOTS<br />

19<br />

IN RESONATORS<br />

HOW TO GROW<br />

22<br />

A HEART


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TABLE OF CONTENTS<br />

VOL. 95 ISSUE NO. 3<br />

More articles online at www.yalescientific.org<br />

& https://medium.com/the-scope-yale-scientific-magazines-online-blog<br />

COVER<br />

14<br />

A R T<br />

I C L E<br />

Using Fireflies to Count HIV Replication<br />

Connie Tian<br />

The red queen hypothesis states that a species must constantly adapt and evolve for survival,<br />

because competing organisms are also evolving. To combat the evolving human immunodeficiency<br />

virus, we must continue to develop new retroviral drugs to treat affected individuals. Firefly<br />

bioluminescence could be key to developing new HIV treatments.<br />

12 Personal Matters on Abortion<br />

Van Anh Tran<br />

Sharing personal stories about abortion has been a powerful advocacy tool in the past to<br />

destigmatize abortions and to help others not feel alone in their experience. But a Yale study has<br />

found that the direct effects of storytelling on stigma may not be as clearcut.<br />

16 The World in Proteins<br />

Krishna Dasari<br />

Biologists have had to settle for proxy measures of cellular protein levels for decades. Now, an<br />

unexpected collaboration between an evolutionary biologist and a protein biologist has paved the<br />

way to study biodiversity and evolution at the level of the proteins themselves.<br />

19 Turning the Knots in Resonators<br />

Yusuf Rasheed<br />

Our world and beyond is filled with oscillators—piano strings, air particles, and colliding<br />

comets—and thus, understanding how they resonate is critical. The Harris and Read Labs<br />

at Yale recently discovered how topological structures called knots and braids are essential<br />

to oscillators. This opens the door to improving any system that has them, including<br />

computers, radios, and watches.<br />

22 How to Grow a Heart<br />

Catherine Zheng<br />

Engineered heart tissues grown from stem cells are often used in cardiac research and studies to<br />

model a mature human heart. Researchers from Professor Campbell’s research group at Yale have<br />

developed a new protocol that significantly reduces the time required to produce these mature<br />

heart tissues.<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 3


A TRUE LOVE STORY:<br />

MOSQUITOES X US<br />

&<br />

THE NOT SO FOREVER CHEMICALS<br />

By Matthew Zoerb<br />

In 2018, Robert Bilott filed a lawsuit against three major chemical<br />

companies, 3M, DuPont, and Chemours, on behalf of every<br />

American exposed to per- and poly-fluoroalkyl substances<br />

(PFAS). PFAS are used in many water-resistant products ranging<br />

from waterproof jackets to non-stick pans. Since 1951, hundreds of<br />

thousands of tons of waste containing perfluorooctanoic acid (PFOA),<br />

a specific type of PFAS, have been dumped into the Ohio River and<br />

spread throughout the global biosphere. The ongoing litigation<br />

alleges that these companies have spread PFAS into the bloodstreams<br />

of ninety-nine percent of Americans while withholding information<br />

about their harmful side effects. Unfortunately, PFASs are resistant to<br />

degradation, and due to their long-lasting environmental presence,<br />

they are known as “forever chemicals.”<br />

Traditional methods to break apart PFAS involve pressurized<br />

incineration at one-thousand degrees Celsius. However, these<br />

techniques are costly and can spread the toxic compound into the<br />

atmosphere. A team at Northwestern University and UCLA recently<br />

discovered a new method to decompose PFAS. The researchers<br />

noticed an irregularity among the chain of tightly-bound atom<br />

clusters: a hydroxyl group or a chemical group composed of<br />

oxygen bonded to a hydrogen atom. This group could be broken<br />

off when mixing PFAS with two common solvents: DMSO and<br />

sodium hydroxide. By targeting the weakest bond and sequentially<br />

disassembling the PFAS at only one hundred degrees Celsius, the<br />

study suggests it is possible to convert PFAS into environmentally<br />

harmless products efficiently. This technique has limitations<br />

since bulk quantities of DMSO are prohibitively expensive for<br />

widespread use. Still, this result suggests that pollution from PFAS<br />

may not truly be around “forever.”■<br />

By Lea Papa<br />

Mosquitoes are perhaps most well-known for causing 725,000<br />

human deaths annually and being extreme nuisances. The<br />

blood-suckers appear and are attracted to unique human<br />

odors. They then pierce human blood vessels and feed.<br />

The solution seems simple: to find a way to disable the<br />

mosquitoes’ sense of smell. However, according to a recent<br />

Rockefeller and Boston University study on the mosquito<br />

olfactory system, it may not be so straightforward. When<br />

researchers deleted chemoreceptors—channels on the<br />

mosquitoes’ cells stimulated by human odors—from the<br />

mosquito genome, they found that the mosquitoes were still<br />

attracted to humans.<br />

Typically, an animal’s olfactory neurons allow it to smell and<br />

express one type of chemoreceptor that detects one odor. In the<br />

mosquitoes’ case, researchers found that the antenna receptors<br />

detecting the human odor 1-octen-3-ol, a chemical in breath and<br />

sweat, are also stimulated by amines found on human skin and<br />

sweat. The expression of multiple chemoreceptor genes in olfactory<br />

neurons provides them with a fail-safe for finding human blood,<br />

even when their human-smelling sensors are blocked.<br />

For this reason, simply removing or blocking olfactory<br />

receptors from the mosquito genome will do little to prevent<br />

them from detecting humans. Still, this finding may be a step<br />

toward finally breaking free from the age-old relationship<br />

between humans and mosquitoes.■<br />

4 Yale Scientific Magazine October 2022 www.yalescientific.org


The Editor-in-Chief Speaks<br />

THE SCIENCE AND<br />

TECHNOLOGY OF HUMANITY<br />

Science may present itself as rigid and automated—it is easy to get lost in objective<br />

formulas, theorems, and conclusions. However, this issue of the Yale Scientific<br />

Magazine highlights that science is, at its core, a human endeavor done by<br />

humans and for humans. Behind each formula, theorem, and conclusion is a person<br />

and a story. We are honored to tell a few of these stories from Yale and beyond.<br />

Our cover article highlights research from the Yale School of Medicine that used<br />

fluorescence technology in an HIV pathway for the discovery of small molecule<br />

treatments for the disease, which affects over thirty-eight million people (pg.<br />

14). Our other stories range in scale. One study investigated the effect of sharing<br />

personal abortion experiences on stigma and advocacy (pg. 12). Another studied<br />

the connection between proteins and biodiversity, paving the way to understanding<br />

our evolutionary history in a novel way (pg. 16). At the cellular level, research<br />

on stem-cell maturation works to model mature human heart tissue, making<br />

strides in the fight against cardiac diseases (pg. 22). And in physics, research on<br />

the mathematic fundamentals of resonators has implications for many systems<br />

around us, from watches to computers. This project highlights the teamwork and<br />

human communication required for successful science (pg. 19).<br />

In our own backyard, the Yale community sees science interacting with<br />

humanity from various angles, highlighted by this issue’s profiles. At just twenty<br />

years old, Yale College sophomore Shervin Dehmoubed co-founded and runs<br />

EcoPackables, a company providing sustainable packaging—an example of<br />

science harnessed for social good (pg. 34). In Yale’s Chemistry department,<br />

third-year graduate student Tyler Myers makes it a priority to inspire interest in<br />

organic chemistry by putting students first (pg. 35).<br />

While the study of science will inevitably be filled with the objectives, humans<br />

bring subjectivity to the equation, the good and the bad. However, the competition,<br />

greed, and dishonesty often seen in scientific research and applications are<br />

overshadowed by empathy, passion, and an ambition to leave the world better<br />

than it was. Science and technology cannot be separated from humanity. For our<br />

aspiring scientists, we hope you carry these human values throughout your career<br />

and appreciate all aspects of human connection along the way.<br />

And to our very human <strong>YSM</strong> staff, masthead, readers, and advisors, we<br />

sincerely thank you for your continued support.<br />

About the Art<br />

Jenny Tan, Editor-in-Chief<br />

MASTHEAD<br />

October 2022 VOL. 95 NO. 3<br />

EDITORIAL BOARD<br />

Editor-in-Chief<br />

Managing Editors<br />

News Editor<br />

Features Editor<br />

Special Sections Editor<br />

Articles Editor<br />

Online Editors<br />

Copy Editors<br />

Scope Editors<br />

Website Editor<br />

PRODUCTION & DESIGN<br />

Production Manager<br />

Layout Editors<br />

Art Editor<br />

Cover Artist<br />

Photography Editor<br />

BUSINESS<br />

Publisher<br />

Operations Manager<br />

Advertising Manager<br />

Subscriptions Manager<br />

OUTREACH<br />

Synapse Presidents<br />

Synapse Vice President<br />

Synapse Outreach Coordinators<br />

Synapse Events Coordinator<br />

WEB<br />

Web Managers<br />

Head of Social Media Team<br />

Social Media Coordinators<br />

STAFF<br />

Sanya Abbasey<br />

Luna Aguilar<br />

Ricardo Ahumada<br />

William Archacki<br />

Dinesh Bojja<br />

Risha Chakraborty<br />

Kelly Chen<br />

Gia-Bao Dam<br />

Leah Dayan<br />

Chris Esneault<br />

Erin Foley<br />

Mia Gawth<br />

Simona Hausleitner<br />

Tamasen Hayward<br />

Katherine He<br />

Miriam Huerta<br />

Sofia Jacobson<br />

George Karadzhov<br />

Jenna Kim<br />

Catherine Kwon<br />

Charlotte Leakey<br />

Charlize Leon Mata<br />

Ximena Leyba Peralta<br />

Yurou Liu<br />

Samantha Liu<br />

Helena Lyng-Olsen<br />

Kaley Mafong<br />

Georgio Maroun<br />

Alexandra Martinez-<br />

Garcia<br />

Cindy Mei<br />

Lee Ngatia Muita<br />

Lea Papa<br />

Hiren Parekh<br />

Himani Pattisam<br />

Emily Poag<br />

Madeleine Popofsky<br />

Tony Potchernikov<br />

Zara Ranglin<br />

Yusuf Rasheed<br />

Alex Roseman<br />

Ilora Roy<br />

Ignacio Ruiz-Sanchez<br />

Noora Said<br />

Jenny Tan<br />

Tai Michaels<br />

Maria Fernanda Pacheco<br />

Madison Houck<br />

Alex Dong<br />

Sophia Li<br />

Cindy Kuang<br />

Ethan Olim<br />

Tori Sodeinde<br />

Breanna Brownson<br />

Hannah Han<br />

Kayla Yup<br />

Anna Calame<br />

Hannah Huang<br />

Meili Gupta<br />

Catherine Zheng<br />

Ann-Marie Abunyewa<br />

Brianna Fernandez<br />

Malia Kuo<br />

Anasthasia Shilov<br />

Jenny Wong<br />

Jared Gould<br />

Lauren Chong<br />

Sophia Burick<br />

Shudipto Wahed<br />

Krishna Dasari<br />

Lucy Zha<br />

Rayyan Darji<br />

Hannah Barsouk<br />

Risha Chakraborty<br />

Bella Xiong<br />

Katherine Moon<br />

Emily Shang<br />

Anavi Uppal<br />

Abigail Jolteus<br />

Elizabeth Watson<br />

Jamie Seu<br />

Pranet Sharma<br />

Kiera Suh<br />

Yamato Takabe<br />

Joey Tan<br />

Kara Tao<br />

Connie Tian<br />

Van Anh Tran<br />

Sheel Trivedi<br />

Robin Tsai<br />

Sherry Wang<br />

Elise Wilkins<br />

Aiden Wright<br />

Elizabeth Wu<br />

Nathan Wu<br />

Johnny Yue<br />

Iffat Zarif<br />

Hanwen Zhang<br />

Lawrence Zhao<br />

Celina Zhao<br />

Matthew Zoerb<br />

This issue’s cover depicts a firefly!<br />

Fireflies, beyond being a beautiful<br />

source of luminescence, have<br />

been used to study potential Rev<br />

inhibitors which may be used to<br />

create novel HIV antivirals.<br />

Anasthasia Shilov, Cover Artist<br />

The Yale Scientific Magazine (<strong>YSM</strong>) is published four times a year by Yale<br />

Scientific Publications, Inc. Third class postage paid in New Haven, CT<br />

06520. Non-profit postage permit number 01106 paid for May 19, 1927<br />

under the act of August 1912. ISN:0091-287. We reserve the right to edit<br />

any submissions, solicited or unsolicited, for publication. This magazine is<br />

published by Yale College students, and Yale University is not responsible<br />

for its contents. Perspectives expressed by authors do not necessarily reflect<br />

the opinions of <strong>YSM</strong>. We retain the right to reprint contributions, both text<br />

and graphics, in future issues as well as a non-exclusive right to reproduce<br />

these in electronic form. The <strong>YSM</strong> welcomes comments and feedback. Letters<br />

to the editor should be under two hundred words and should include the<br />

author’s name and contact information. We reserve the right to edit letters<br />

before publication. Please send questions and comments to yalescientific@<br />

yale.edu. Special thanks to Yale Student Technology Collaborative.


NEWS<br />

Ecology & Evolutionary Biology / Environmental Science<br />

HUMMINGBIRDS:<br />

MASTERS OF<br />

COLOR<br />

REPURPOSING<br />

THE URBAN<br />

FOREST<br />

BY SHEEL TRIVEDI<br />

BY ELISE WILKINS<br />

IMAGE COURTESY OF FLICKR<br />

IMAGE COURTESY OF FLICKR<br />

What comes to mind when you think of hummingbirds?<br />

You might think of their rapid heart rate. Or maybe<br />

their lightning-fast wing speed. But hummingbirds<br />

have another superpower under their beak: color.<br />

Bird feathers, known as plumage, display many hues. Researchers<br />

at Yale University calculated the hummingbird plumage color<br />

gamut, a value representing the color diversity of hummingbird<br />

plumage as seen by other birds. Birds see ultraviolet and visible<br />

light, whereas humans can only see the latter, so human vision<br />

falls short when considering hummingbird plumage.<br />

Gabriela Venable (YC ’19), a researcher on the study, spent<br />

hours at the Peabody Museum and American Museum of Natural<br />

History using a spectrometer to gather colorful spectra from<br />

1,600 plumage patches on 114 hummingbird species. “We can<br />

plot the spectra into a [model accounting for bird vision] and<br />

calculate the volume from all the points in the model, and that<br />

can measure color diversity,” Venable said.<br />

The data revealed that the hummingbird gamut was, in some aspects,<br />

more diverse than the previously calculated gamut of all other birds<br />

combined. One justification points to hummingbird barbules, which<br />

are micro-structures in a feather. “[Barbules] allow [hummingbirds]<br />

to make saturated colors and many different color combinations,”<br />

Venable said. This strengthens hummingbird evolutionary benefits,<br />

like defending floral patches or attracting mates.<br />

Though they discovered new information about coloration<br />

mechanisms in birds, there is still work to be accomplished.<br />

As the first study targeting one family of birds, this research<br />

facilitates more in-depth analyses of plumage color diversity and<br />

increases the accuracy of the calculated avian color gamut. ■<br />

Trees in urban areas contribute to pollution control and<br />

enhance biodiversity. But what happens to dead leaves,<br />

fallen branches, and other forms of tree waste that<br />

pile up along curbs? Typically, tree waste is sent to landfills<br />

or incinerated, what experts call the “end-of-life” states. Each<br />

year, these methods release much of the twenty million metric<br />

tons of carbon generated by the urban forest as methane and<br />

carbon dioxide, contributing substantially to global warming.<br />

To explore the possibilities for circular utilization of tree<br />

waste, researchers at the Yao Lab at Yale studied five methods<br />

of tree waste repurposing. Researchers found that the<br />

optimal scenario consisted of composting leaf waste, selling<br />

lumber as logs or wood chips, and using residue to produce<br />

biochar—a substitute for traditional charcoal. Kai Lan, a<br />

postdoctoral associate on the study team, told the Yale School<br />

of the Environment, “This aligns with the circular economy<br />

concept—turning waste into something of value. But it’s not<br />

just traditional waste like paper and plastic. Tree waste is<br />

very important, too.” This valuable process can reduce global<br />

warming and eutrophication—when water sources become<br />

overrun with nutrients and algal growth, deteriorating water<br />

quality. Additionally, the benefits extend to stimulating the<br />

economy through lumber sales and the possibility of new jobs<br />

to facilitate tree waste management.<br />

While cities may see differing benefits depending on their<br />

abundance of tree waste, the study offers new insight into the<br />

benefits of implementing a circular economy in a surprising<br />

area, demonstrating that even plants in their “end-of-life” state<br />

still have much to contribute. ■<br />

6 Yale Scientific Magazine October 2022 www.yalescientific.org


Medicine / Medicine & Biochemistry<br />

NEWS<br />

THE IMPACT OF<br />

YOUTH ARRESTS<br />

ON HEALTH IN<br />

T<br />

SOCIETY<br />

ZOMBIE CELLS<br />

BY JOHNNY YUE<br />

BY MIA GAWITH<br />

IMAGE COURTESY OF FLICKR<br />

IMAGE COURTESY OF DAVID ANDRIJEVIC<br />

Arrests and incarceration have been pertinent issues in<br />

society for decades. Destiny Tolliver, an assistant professor<br />

in the pediatrics department at the Boston University<br />

Chobanian & Avedisian School of Medicine, has recently<br />

discovered a startling correlation between arrests and health.<br />

Tolliver and her team analyzed data from the National Longitudinal<br />

Study of Adolescent to Adult Health, examining cohorts from 1994<br />

to 2018. They gathered information about participants’ sex, race,<br />

and ethnicity, as well as the timeline and occurrence of arrests and<br />

different physical and mental health measures, including clinical<br />

biomarkers for diseases such as hypertension and diabetes.<br />

Her analysis found that arrests made before the age of twenty-five<br />

were associated with higher rates of suicidal thoughts, depression,<br />

and worsening general health scores. On top of that, youth arrest<br />

and related policies didn’t impact all communities equally. “There<br />

are well-documented racial and socioeconomic disparities in who<br />

experiences arrest, with Black children and children in lowerincome<br />

households disproportionately impacted,” Tolliver said.<br />

Contributing to the problem is the minimum juvenile<br />

prosecution age, which is currently only ten for the state of<br />

Connecticut. “I think Connecticut can do more in this area by<br />

raising the minimum age at which children can be prosecuted<br />

in the juvenile court system to at least fourteen years of age, and<br />

instead focus on diverting youth to health-promoting systems in<br />

their communities,” Tolliver said.<br />

So what’s next? Many states have already implemented changes<br />

to decrease the number of young people who are arrested.<br />

Tolliver hopes to research the effects of these modifications on<br />

youth health to create a model for other states to follow. ■<br />

Images of the “living dead” linger in our minds: Frankenstein<br />

resurrecting his monster, zombies stumbling around with<br />

contorted limbs, and what seems to be a never-ending<br />

stream of episodes of “The Walking Dead”. But is it possible<br />

to bring a mammal back from the dead? A research team at<br />

the Yale School of Medicine says yes, at least on the cellular<br />

level. Using a new technology termed OrganEx, scientists<br />

have successfully restored cellular functions in dead pigs.<br />

A team of scientists explored the possibility of preventing<br />

cell death in large mammalian bodies. Per Yale University’s<br />

ethical guidelines, the scientists induced fatal cardiac arrest<br />

in female pigs. An hour after their death, these same pigs were<br />

hooked up to the OrganEx system, a two-part device equipped<br />

with oxygenation machines and a synthetic solution. Since<br />

cells do not die instantly, this technology allowed researchers<br />

to intervene during the cell death process and reverse it. The<br />

changes were remarkable: oxygen and metabolic levels went<br />

back to normal, circulation was restored, and organs showed<br />

fewer signs of damage than with previous technology.<br />

While not the key to zombies, this discovery answers<br />

important issues in healthcare. For David Andrijevic, a<br />

leading co-author from the department of neuroscience,<br />

the potential applications are staggering. “If you can<br />

recover the organs after loss of blood flow for so long, then<br />

we might actually increase an organ donor pool for organ<br />

transplantation,” Andrijevic said. Future developments will<br />

focus on expanding these results to the clinical setting.<br />

Perhaps zombies should take a hint from scientists—how<br />

else will fiction become a reality? ■<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 7


NEWS<br />

Chemistry / Physics<br />

Anthracene-phenol-pyridine<br />

(An-PhOH-Py) triad<br />

EXPANDING<br />

CHEMISTRY<br />

A novel fundamental<br />

chemical reaction opens<br />

door to new technologies<br />

BY GEORGE KARADZHOV<br />

PHOTOGRAPHY BY EMILY POAG<br />

Last August, a collaboration between the Hammes-Schiffer<br />

and Mayer groups at Yale and researchers from the<br />

Hammarström group at Uppsala University led to the<br />

discovery of a new fundamental photochemical reaction relevant<br />

to our understanding and application of chemistry.<br />

The finding follows unexpected results the groups observed in 2019<br />

when working with the motif anthracene-phenol-pyridine (An-PhOH-<br />

Py), which contains the three chemical groups connected by single<br />

bonds. The teams found that when different variations of the An-PhOH-<br />

Py motif are excited with light, only some of their molecules go through<br />

a known pathway: the molecule starts at the ground state, the anthracene<br />

subunit absorbs light energy, and that new energy promotes an electron<br />

to move from the phenol subunit to the excited anthracene (*An). At the<br />

same time, a proton transfers to the pyridine unit to form a new chargeseparate<br />

state (CSS). This CSS represents a different arrangement of<br />

charge and energy in the molecule that can be utilized later in reactions<br />

like photosynthesis. The researchers discovered that molecules return<br />

from the CSS to the ground state through a proton-coupled electron<br />

transfer (PCET) process that is slowed down by increasing the driving<br />

force. Surprisingly, the groups did not observe any CSS for certain<br />

variations of their molecules. Speculating that there was some other way<br />

for these molecules to react to light and yield a lower energy product,<br />

researchers computationally predicted and experimentally detected the<br />

formation of a local electron-proton transfer (LEPT) excited state in<br />

place of a CSS for some of their reagents.<br />

The LEPT itself isn’t new. A PhOH-Py molecule can be excited to<br />

trigger an excited-state proton transfer and give us a *PhOH-Py LEPT<br />

species. Similarly, the PhOH-Py fragment in the An-PhOH-Py triad<br />

can be excited to a LEPT state (*PhOH-Py). The direct transformation<br />

from the excited anthracene fragment in the An-PhOH-Py triad<br />

to the excited PhOH-Py fragment LEPT (as confirmed by further<br />

experiments), however, goes beyond existing theories, hinting at a new<br />

photochemical reaction responsible for these observations.<br />

With further research, it became clear that that was exactly the<br />

case! Researchers described a new reaction where a proton transfer<br />

within the PhOH subunit is coupled to an energy transfer from<br />

the *An to the PhOH subunit without a charge separation. Rather<br />

than the reaction involving proton and electron movement, it<br />

relies on a proton and energy moving throughout the molecule in<br />

a new way that had never been observed.<br />

This reaction, appropriately coined a proton-coupled energy<br />

transfer (PCEnT), also challenges our rules about light absorption<br />

and fluorescence. Since the energy to excite the LEPT state comes<br />

from the *An, the fluorescence energy from the *An has to match the<br />

absorption energy of the PhOH-Py. However, according to Coraline<br />

Tao, a senior PhD student in the Hammes-Schiffer Lab at the time<br />

of the project and now a postdoctoral researcher at the University<br />

of Pennsylvania, the observed fluorescence of LEPT from *An runs<br />

counter to expectation. “[LEPT’s fluorescence [is] counterintuitive<br />

because [the] energy giver has to have enough energy to charge the<br />

acceptor, but here they don’t,” Tao said. Where does that extra energy<br />

come from? The groups show that the proton transfer can physically<br />

reconfigure the molecule, making this fluorescence possible. The<br />

details of how the transferring proton couples with the energy transfer<br />

process, however, are still unclear, prompting questions about how<br />

spatial relationships contribute to energy movement across molecules.<br />

Often, fundamental discoveries have a curious tendency to pop up<br />

in many unexpected places—think the Schrödinger equation used in<br />

economics. This is no different. PCEnT describes a powerful process<br />

that could have significant future applications. Since the LEPT product<br />

is closer in energy to the *An intermediate than other reagents we<br />

could use to get the same thing, there is now a way of executing this<br />

chemical transformation using lower excitation energy. According to<br />

Tao, this could have important implications for designing molecules<br />

for solar dyes, solar panels, and other technologies to store and<br />

use photochemical energy. PCEnT may also already be present in<br />

photosensitive biological systems, and we haven’t thought to look!<br />

It could be the case that differences between PCET, PCEnT, and<br />

other photochemical reactions serve as regulatory mechanisms for<br />

biological pathways. This new knowledge of PCEnT also allows<br />

researchers to access new configurations and arrangements of<br />

molecules that could be synthetically or technologically useful. ■<br />

8 Yale Scientific Magazine October 2022 www.yalescientific.org


Astrophysics<br />

NEWS<br />

A TALE OF<br />

TWO GALAXIES<br />

An unexpected collision<br />

behind the formation of<br />

two dwarf galaxies<br />

BY HANWEN ZHANG<br />

IMAGE COURTESY OF FLICKR<br />

Galactic collisions usually resemble a carefully<br />

choreographed ballroom dance: picture a pair of galaxies<br />

pinwheeling into each other’s arms, their gravitational<br />

centers merging together. But in the case of the two dwarf galaxies<br />

DF2 and DF4—initialed in honor of the Dragonfly telescope that<br />

captured them—researchers suspect the cause of their formation<br />

might have been closer to a collision between two bullets.<br />

The van Dokkum Lab, a Yale astrophysics research group, proposed<br />

a bullet-dwarf collision model which describes an event where<br />

a pair of galaxies run into each other with enough speed to form<br />

two entirely new ones in their wake. The model is a culmination of<br />

years of observation and careful telescopic tracking. Van Dokkum’s<br />

research team first discovered DF2 and DF4 sometime around 2018.<br />

Both galaxies are members of a space neighborhood roughly sixtyseven<br />

million light years away from Earth.<br />

What surprised the group was the virtual absence of any dark matter<br />

in both DF2 and DF4. The researchers were baffled by the speeds of the<br />

galaxies’ stars. “They [had] very low velocity dispersion, which means<br />

that […] these galaxies don’t contain a lot of dark matter,” said Zili Shen,<br />

a graduate researcher in the lab. The intensity of gravity directly dictates<br />

the motion of stars, and since most of a galaxy’s gravitational force comes<br />

from dark matter, both DF4 and DF2 must be strikingly devoid of it.<br />

Dark-matter deficient galaxies are uncommon—they are so<br />

rare, in fact, that DF4 and DF2 remain just a few of the handful<br />

scientists currently know. This is because most galaxies depend<br />

on dark matter for their creation. Clumps of dark matter—a<br />

substance virtually undetectable except by its gravitational<br />

presence—often serve as whirlpool-like centers that collapse<br />

clouds of gas. There, temperatures can rise to levels nearly double<br />

the sun’s surface temperature, giving birth to a sizzling new galaxy.<br />

Without dark matter to create its stars, DF4 and DF2 must have<br />

come into existence following a script of their own. Analyzing the<br />

data, the team reasoned that two-parent dwarf galaxies met side-on<br />

in a high-speed collision, generating an extraordinary amount of force<br />

that compressed their clouds of gas. This might have been enough to<br />

form DF2 and DF4. “High-speed collision of dwarf galaxies is a viable<br />

explanation for galaxies without dark matter,” Shen said.<br />

www.yalescientific.org<br />

Under normal conditions, the comparatively lower speeds<br />

would have trapped the dark matter of both parent galaxies<br />

and caused them to merge. But for DF4 and DF2, the collision<br />

likely occurred with so much velocity that the two haloes of dark<br />

matter simply bypassed each other. With nothing left to bind<br />

their constituent star clusters together, the once-organized parent<br />

galaxies scattered apart. The result: diffuse clouds of gas and stars<br />

strewn across space, the DF2/DF4 duo among them.<br />

Their data seems to confirm this. The group’s most recent<br />

paper identified a linear arrangement of seven to eleven dimlylit<br />

objects, exactly the kind of structure they would expect to<br />

find from a cosmic collision like this. Most structures were also<br />

abnormally large for their relative brightness, offering further<br />

evidence that they might be the galactic shrapnel of interest.<br />

But like the star clusters of newly formed galaxies, the model<br />

remains hazy. At least two other competing theories have<br />

attempted to explain this phenomenon. One suggests that DF4<br />

and DF2 simply arose after a normal dwarf galaxy drifted too<br />

close to a larger galaxy and lost its dark matter. It fails, though,<br />

to explain the presence of two dark-matter deficient galaxies.<br />

The second—the tidal dwarf theory—proposes that they arose<br />

from gas that was stripped off from larger galaxies, but the lab<br />

has since disproven this through the age and metallicity of both<br />

galaxies’ constituent stars.<br />

For now, the bullet-dwarf collision remains a tentative—if<br />

attractively convincing—hypothetical scenario. “This is mostly<br />

a theory that explains the data we already have,” Shen said.<br />

Confirming the bullet-dwarf collision will require more empirical<br />

evidence, which includes calculations of the individual clusters’<br />

velocities and positions. The group has already started processing<br />

data from the Hubble Telescope to further validate their theory.<br />

Studying dwarf galaxies like DF2 and DF4 has its benefits.<br />

Shen explained that dwarf galaxies, being almost one thousand<br />

times smaller than our Milky Way, are relatively easier to model.<br />

That doesn’t make piecing together our strange cosmic past any<br />

simpler, but it might just help reveal new ways of being and of<br />

becoming that we had previously not known. ■<br />

October 2022 Yale Scientific Magazine 9


NEWS<br />

Molecular Biology<br />

THE<br />

MOLECULAR<br />

CLOCK<br />

Modifying the dynamics<br />

of cellular movement<br />

BY CHRISTOPHER ESNEAULT<br />

PHOTOGRAPHY BY JESSICA LE<br />

Albert Einstein once said: “The distinction between the<br />

past, present, and future is only a stubbornly persistent<br />

illusion.” Time is an idea that has been talked about and<br />

debated for centuries. For physicists, philosophers, and others in<br />

between, the meaning of time and space and temporality has kept,<br />

and will continue to keep, people wondering.<br />

Though some may believe that judgment of time is only left<br />

to complex, multicellular organisms, that is not quite true. In<br />

fact, researchers in Andre Levchenko’s lab at the Yale University<br />

Systems Biology Institute are currently looking into the cellular<br />

mechanisms that drive the molecular clock: a new way of<br />

conceptualizing time on a cellular level.<br />

Researchers found this clock is controlled by two negative<br />

feedback mechanisms mediated by microtubule polymerization,<br />

GEF-H1, and GTPase RhoA. GTPase RhoA is a Ras homolog<br />

family member A that regulates actin reorganization, a mechanism<br />

that plays a role in cell migration and motility. Sung Hoon Lee, a<br />

postdoctoral researcher from the Levchenko Lab, said that though<br />

his background is actually in electrical engineering, he wanted to<br />

help build a systems-level understanding of a biological network.<br />

Why do cells actually migrate? Lee said that it is because cells are<br />

dynamic in nature, and thus, cells migrate, proliferate, communicate,<br />

and die. For example, in the case of extreme and unwanted cell<br />

dynamism, metastatic cancer cells migrate throughout the body to<br />

invade other tissues. Levchenko joined in this explanation, saying<br />

that “when an organism develops, there are many cases of cells<br />

undergoing movements to undergo relocalization.” This dynamic<br />

cellular movement and reorganization rarely occur in adults, where<br />

cells are generally pretty settled in the body. However, “the general<br />

idea for the cells is to figure out how to move and successfully<br />

relocalize to the desired location,” Levchenko explained.<br />

While cell movement is normally studied in two-dimensional settings<br />

like Petri dishes, very little research has dug into the mechanisms of<br />

movement in three-dimensional settings like the body. In these threedimensional<br />

settings, cellular activity is controlled by a squeezing motion<br />

from the posterior end of the cell that propels the cell forward. However,<br />

little is understood about how this squeezing movement operates.<br />

Lee found that cells navigate the three-dimensional<br />

extracellular matrix—the complex network of molecules and<br />

proteins that forms the connective tissues between cells—using<br />

a periodic squeezing movement. The molecular clock controls<br />

the frequency of these squeezing movements and, consequently,<br />

the speed of cell movement. Furthermore, this clock is<br />

mediated by two coupled negative feedback loops. “Microtubule<br />

polymerization is an important component that can enhance<br />

the abundance of the molecule GEF-H1,” Lee said. This rapid<br />

polymerization of tubulin inside the cell underpins the dynamics<br />

of cell movement. “Microtubule polymerization can also inhibit<br />

the activity of GEF-H1. These two feedback loops modulate the<br />

molecular clock’s frequency,” Lee continued.<br />

Furthermore, Lee found that cellular migration was mediated<br />

by cyclic changes in a small molecule called GTPase RhoA. And<br />

this GTPase RhoA is dependent on the activity and abundance<br />

of GEF-H1. By understanding the players underpinning cell<br />

migration, Lee was able to manipulate the frequency of the<br />

clock and make cells move, in some cases, three times as fast as<br />

they normally would. Funnily enough, Levchenko said, “For a<br />

while, the American Society for Cell Biology had an annual cell<br />

race where you could put engineered cells on race tracks and<br />

compete with other cells. While the competition does not take<br />

place anymore, Sung Hoon would likely win the competition.”<br />

And while the research conducted by Lee has proven valuable<br />

in our present understanding of the dynamics of cell movement,<br />

the implications of his findings are arguably even more valuable.<br />

Through perturbation of the molecular clock’s frequency, they<br />

can potentially find new ways of controlling the speed of cell<br />

movement. In theory, manipulation of this clock could speed up<br />

the rate at which the repair of cell tissues occurs. Conversely,<br />

in the case of cancer metastasis, this same clock that controls<br />

aggressive tumor cells could be slowed down.<br />

Looking towards the future, it is clear that, with the help of<br />

the scientific progress made by Lee and Levchenko, the field<br />

is on the brink of tremendous possibilities regarding systems<br />

biology and the molecular clock. ■<br />

10 Yale Scientific Magazine October 2022 www.yalescientific.org


Applied Math<br />

NEWS<br />

SOLVING THE<br />

UNSOLVABLE<br />

A novel approach to<br />

calculating a key<br />

Fourier series<br />

BY EMILY SHANG<br />

IMAGE COURTESY OF FLICKR<br />

Have you ever wondered about the math behind a radio signal?<br />

Or telephones? Scientists who study electromagnetic<br />

physics and mathematics constantly are: their work is<br />

founded upon partial differential equations. These equations are<br />

unlike the differential equations we encounter in calculus: they<br />

are three-dimensional and extremely difficult to solve because<br />

they vary with both time and space, even for simple shapes. As a<br />

result, designing cell phone antennas and radio telescopes is extremely<br />

challenging. To solve these wave equations, scientists use<br />

a technique that separates the part which varies with time and the<br />

part which varies with space, also known as “Helmholtz’s equation.”<br />

However, Helmholtz’s equation is still a differential equation,<br />

which is hard to solve. Scientists have been using a trick called<br />

Green’s functions to solve these sorts of problems for over a hundred<br />

years. Green’s functions are powerful techniques that let you<br />

solve a differential equation by computing an integral, making the<br />

solution easier to attain. However, even though they can convert<br />

these problems from differential equations into integral equations,<br />

they still have to do it in 3D, which is extremely hard.<br />

However, for certain types of symmetric objects, like a radar<br />

dish, there is a trick that turns a 3D problem into a 2D problem.<br />

However, it comes at a price. The Green’s function would have<br />

to be split up into its individual frequencies using the Fourier<br />

series technique. For each frequency, a very difficult integral,<br />

called “the modal Green’s function,” would have to be computed.<br />

This Green’s function is tricky: it oscillates incredibly quickly<br />

between massive positive and negative values, but somehow,<br />

they all end up adding up to something tiny. Any attempt to<br />

estimate the integral by “adding it up” essentially adds and subtracts<br />

infinity trillions of times, causing so much error that the<br />

estimate is useless. Scientists have been struggling with how to<br />

compute this integral since the 1960s.<br />

To handle difficult integrals, mathematicians will often solve<br />

them using complex analysis, the field of math that studies imaginary<br />

numbers. Real numbers are plotted on the “real line,” ranging<br />

from negative to positive infinity. In contrast, complex numbers<br />

have a real and imaginary components, meaning they live<br />

in a 2D space called the “complex plane.” Amazingly, for many<br />

functions, the integral can either be computed along the real line<br />

or as a “contour integral” through the 2D complex plane, a technique<br />

invented by the mathematician Augustin-Louis Cauchy in<br />

the nineteenth century. By carefully choosing the contour, sometimes<br />

those integrals can be made very simple. For example, some<br />

functions oscillate between negative one and positive one on the<br />

real line, but in the complex plane, they never oscillate.<br />

For decades, scientists had written off using this contour trick<br />

because no matter which contour they picked, part of the Green’s<br />

function wildly exploded and oscillated. James Garritano, along<br />

with his mentors Yuval Kluger, Rokhlin, and Kirill at the Kluger<br />

Lab in the Yale School of Medicine, recently overcame the oscillations<br />

of Green’s function by ignoring the real line and integrating<br />

it into the complex plane by using a contour invented in 2010 by a<br />

scientist named Mats Gustafsson. The key idea of their paper was<br />

to replace part of the Green’s function with an approximation that<br />

does not grow in the complex plane. Then, they could use Gustafsson’s<br />

contour and avoid wild oscillations.<br />

“Dr. Kluger and Dr. Rokhlin, who I work for, are both famous for<br />

creating fast algorithms to solve problems in physics and genomics,”<br />

Garritano said. For example, with his student Leslie Greengard,<br />

Rokhlin created the fast multipole algorithm, named one<br />

of the top ten algorithms of the twentieth century. It became the<br />

basis for a wide range of physics simulations ranging from modeling<br />

gravitational bodies to electrons. Kluger recently developed<br />

the fastest method for clustering data in single-cell experiments by<br />

using insights from computational physics to accelerate one of the<br />

key algorithms of data science.<br />

This work has paved the way to create ultra-fast physics solvers<br />

for rotationally symmetric objects such as antennas and radar dishes.<br />

Also, their work showed that Cauchy’s contour-trick could be<br />

applied to more problems than previously thought. ■<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 11


FOCUS<br />

Women's Health<br />

PERSONAL MATTERS<br />

ON ABORTION<br />

What we can learn<br />

from abortion<br />

storytelling and its<br />

impact on stigma<br />

BY VAN<br />

ANH TRAN<br />

On June 22, 2022, the United States<br />

Supreme Court overruled Roe v.<br />

Wade, which provided constitutional<br />

protection for the right to abortion for nearly<br />

half a century. Two months after the decision<br />

was overturned, over twenty million women<br />

in the United States lost access to elective<br />

abortions in their home states.<br />

The New York Times published a piece<br />

sharing the stories of people who got abortions<br />

before Roe stating that an important part of<br />

advocating for abortion is learning from the<br />

experiences of Americans who have had<br />

unsafe abortions before the court decision. On<br />

Twitter, Representative Alexandria Ocasio-<br />

Cortez trended for sharing her personal<br />

sexual assault story during an abortion rally.<br />

In the video, she told the crowd that she was<br />

glad to know she at least had a choice if she<br />

did end up being pregnant because of readily<br />

accessible abortion care in New York City.<br />

In 2017, Abigail Cutler YSPH '19, a doctor<br />

and clinical instructor in the Department of<br />

Obstetrics and Gynecology at Yale School of<br />

Medicine, noticed the increased prevalence<br />

of abortion storytelling in social media<br />

campaigns. Many of these campaigns’<br />

messages were to normalize abortions and<br />

denounce the stigma associated with it so that<br />

those who had or were seeking care feel like<br />

they are not alone in their experience.<br />

These campaigns inspired Cutler<br />

to examine whether forms of public<br />

storytelling—in which storytellers don’t<br />

necessarily know their audience—could<br />

decrease community-level abortion<br />

stigma or the stigma people feel towards<br />

others who seek or have abortions.<br />

This stigma commonly manifests as<br />

discrimination against<br />

people who have abortions<br />

and structural barriers<br />

against abortion care.<br />

Evidence from years of<br />

polling research shows clearly<br />

that the public tends to be most<br />

supportive of abortions involving<br />

rape, incest, threats to maternal life, and fetal<br />

anomalies—none of which reflect the most<br />

common reasons people seek an abortion.<br />

“We know these stories are already effective<br />

for warming public opinion,” Cutler said.<br />

However, she endeavored to know whether<br />

“non-exceptional” stories—stories centered<br />

on the most common circumstances for<br />

seeking abortion—would impact the hearts<br />

and minds of the public.<br />

Formation of the Study<br />

ART BY<br />

LUNA<br />

AGUILAR<br />

To test this, Cutler’s team conducted<br />

a randomized trial on a large, nationally<br />

representative set of U.S. adults selected<br />

using the Ipsos Knowledge Panel. They<br />

showed the subjects three videos of people<br />

sharing their abortion experiences. They<br />

then measured community-level stigma<br />

immediately after showing the videos and<br />

then in a three-month follow-up.<br />

12 Yale Scientific Magazine October 2022 www.yalescientific.org


Women's Health<br />

FOCUS<br />

The authors developed a conceptual<br />

model to measure community-level abortion<br />

stigma and its facets. This model measures<br />

stigma through three scales: one primary<br />

scale measuring judgment (Community<br />

Abortion Attitudes Scale), one measuring<br />

how the context of an abortion affects opinion<br />

(Reproductive Experiences and Events Scale),<br />

and one measuring expectations of silence and<br />

secrecy surrounding abortion experiences<br />

(Community Level Abortion Stigma Scale).<br />

The crucial part of this experiment was the<br />

selection of the three videos of people telling<br />

their experiences, which would be shown to<br />

the audience. Cutler recognized that, as a cis<br />

white woman leading a research team of white<br />

women, the group needed to be mindful of<br />

how their biases could adversely affect their<br />

study design. They formed an advisory<br />

board with racially and ethnically<br />

diverse members with professional<br />

or personal backgrounds in<br />

abortion stigma and storytelling,<br />

including several non-profit<br />

abortion organizations.<br />

The essential qualities<br />

welcomed an intersectional<br />

analysis and would include<br />

speaking to the common<br />

reasons for seeking abortions,<br />

the ease or boundaries faced<br />

with healthcare, and whether the<br />

speaker told their story in a fluid and<br />

thoughtful manner. They sought to curate<br />

videos that would give the viewer a different<br />

perspective on abortions. “We wanted to<br />

make the watcher look at abortion in a<br />

different way, in a way not highlighted every<br />

day in the media,” Cutler said.<br />

After developing a scoring matrix for the<br />

videos based on these essential qualities, the<br />

advisory board members selected three final<br />

videos to showcase various abortion stories.<br />

One video talked about a parent who had<br />

multiple abortions before. Another video<br />

was about a woman who spoke about the<br />

barriers to obtaining an abortion in Texas and<br />

who traveled to California for the procedure.<br />

The final video was on a Latina woman who<br />

attempted to acquire birth control through<br />

the military and was facing difficulties doing<br />

so. Before she got deployed, she became<br />

pregnant. She spoke about how she made the<br />

decision to get an abortion in the context of<br />

her family and her values.<br />

“People don’t make these decisions<br />

in a vacuum, they don’t make it by<br />

themselves,” Cutler emphasized. These<br />

www.yalescientific.org<br />

videos were chosen because they reflected<br />

the intersectionality and politicized nature<br />

of the abortion conversation through real,<br />

lived experiences of the most common<br />

demographics that seek an abortion.<br />

Reflecting on the Results<br />

The results of the study showed that<br />

intervention exposures to these three videos<br />

both immediately after watching and three<br />

months later showed no association with<br />

decreased stigma by the judgment scale<br />

(CAAS) or the silence and secrecy scale<br />

(CLASS). This means that exposure to these<br />

three different abortion stories did not<br />

lower community-level stigma. Although<br />

“Abortion storytelling can<br />

also help other people<br />

who have abortions who<br />

feel less alone.<br />

happen to see that<br />

”<br />

story<br />

there was a decrease in stigma in the<br />

context scale (REES) immediately after<br />

watching the videos, it was not significant<br />

after a three-month follow-up.<br />

This study approached the question of<br />

non-intimate storytelling and communitylevel<br />

stigma from a neutral standpoint,<br />

meaning that stories were not chosen<br />

because of their potential to elicit a response<br />

but to represent non-exceptional abortion<br />

ABOUT THE AUTHOR<br />

stories. Furthermore, lack of an effect could<br />

mean that intervention exposure could be<br />

dose-dependent and that a single exposure<br />

to storytelling would not be enough for<br />

a long-term change in community-level<br />

stigma but rather should be more frequent<br />

and prolonged. For instance, a social media<br />

campaign, such as #ShoutYourAbortion,<br />

could prolong exposure to abortion stories<br />

over the period of time that it is trending.<br />

Furthermore, newspapers such as The<br />

New York Times creating a section called<br />

Abortion News could also keep the abortion<br />

conversation present in the public’s mind.<br />

“I think it’s important to acknowledge<br />

the limitations of this study,” Cutler said, “I<br />

don’t think a takeaway from the findings of<br />

this study is that abortion storytelling does<br />

not have the power to change hearts<br />

and minds. It was one study, and<br />

it was conducted several years<br />

ago. The legal landscape is really<br />

different now.” She mentions that<br />

repeating this study, especially<br />

now post-Dobbs, would be<br />

interesting to see.<br />

Cutler emphasized that the<br />

results of this study do not mean<br />

that abortion storytelling isn’t<br />

important for other reasons. It<br />

is essential to recognize that the<br />

purpose of abortion storytelling<br />

is not just to change public opinion.<br />

People who decide to disclose their abortion<br />

experiences to the general public do so for<br />

various reasons, such as to feel empowered<br />

and take the reigns over an experience that<br />

ought to be discussed more.<br />

“Abortion storytelling can also help other<br />

people who have abortions who happen to<br />

see that story to feel less alone," Cutler said.<br />

"And that is arguably equally, if not more<br />

important, than changing public opinion.” ■<br />

VAN ANH TRAN<br />

VAN ANH TRAN (SY '24) is a Molecular, Cellular, and Developmental Biology major from South<br />

Windsor, CT. She has been involved in <strong>YSM</strong> since her first year at Yale. Outside of <strong>YSM</strong>, she is<br />

involved in Yale Rotaract Club, volunteers at HAPPY and Saint Francis Hospital, and interns at<br />

the National Alzheimer’s Buddies organization. Van Anh has done IBD research at the Abraham<br />

lab in the Yale School of Medicine. Van Anh enjoys watching movies with her friends, trying<br />

different types of coffee, and hanging out with her family.<br />

THE AUTHOR WOULD LIKE TO THANK Dr. Abigail Cutler for her time and enthusiasm about her<br />

research on abortion stigma.<br />

FURTHER READING<br />

Cutler, A. S., Lundsberg, L. S., White, M. A., Stanwood, N. L., & Gariepy, A. M. (2021). Characterizing<br />

community-level abortion stigma in the United States. Contraception, 104(3), 305–313. https://<br />

doi.org/10.1016/j.contraception.2021.03.021<br />

October 2022 Yale Scientific Magazine 13


FOCUS<br />

Medicine Biology<br />

USING FIREFLIES<br />

TO MEASURE HIV<br />

REPLICATION<br />

Co-opting bioluminescence for retroviral drug development<br />

BY CONNIE TIAN<br />

Have you ever seen a field of fireflies? If<br />

you have, you were probably thinking<br />

about how magical the experience was.<br />

Or maybe you were wondering how these insects<br />

somehow evolved the ability to bioluminescence.<br />

But chances are you were not thinking about how<br />

firefly luminescence would be a great tool for<br />

measuring protein-protein interactions.<br />

A History of Co-opting Bioluminescence<br />

The phenomenon of bioluminescence,<br />

which is the biochemical emission of light by<br />

living organisms, has fascinated humans for<br />

millennia and has been exploited for just as<br />

long. Roman naturalist Pliny the Elder wrote<br />

that one could create a torch by rubbing the<br />

slime of a luminous jellyfish onto a walking<br />

stick. In the 17th century, physician Georg<br />

Rumphius documented how indigenous<br />

peoples of Indonesia used bioluminescent<br />

fungi as flashlights in forests. Then, in 1875,<br />

Raphel Dubois reported the first in vitro<br />

demonstration of bioluminescence.<br />

Dubois made two extracts of the<br />

bioluminescent clam Pholas, one with hot<br />

water and another using cold water. The light<br />

in the cold sample eventually disappeared.<br />

Furthermore, when he heated the hot sample<br />

to near boiling, the glow stopped. But when he<br />

mixed those two samples together, he observed<br />

light emission once again. Dubois concluded<br />

from his observations that a key aspect of<br />

bioluminescence comes from a heat-stable<br />

organic molecule he named luciferin and an<br />

enzyme called luciferase. Today, we understand<br />

that luciferase is an enzyme that catalyzes a<br />

light-producing reaction in the presence of<br />

oxygen and the naturally occurring substrate,<br />

luciferin. But scientific interest<br />

in the chemistry of the luciferinluciferase<br />

reaction didn’t stop there.<br />

Currently, there are dozens of<br />

assays that rely on the activity of<br />

luciferase enzymes. For example, the split<br />

firefly luciferase complementation assay<br />

(SLCA) uses bioluminescence to quantify<br />

protein-protein interactions within<br />

living cells. The assay uses modified<br />

firefly luciferase (FFLUC) split into two<br />

pieces, named N-FFLUC and C-FFLUC.<br />

On their own, the two pieces of FFLUC<br />

are inactive and do not luminesce.<br />

When the N-FFLUC and C-FFLUC are<br />

brought into close proximity in the presence<br />

of oxygen, ATP, and magnesium, the FFLUC<br />

will oxidize to produce light. This system<br />

can be adapted to measure the interactions<br />

between any two small proteins by fusing<br />

each of the two interacting proteins to the<br />

N or C terminus of luciferase. When the<br />

two proteins bind and interact, it brings the<br />

N-FFLUC and C-FFLUC close together so<br />

that FFLUC will luminesce. The luminescence<br />

can then be quantified with a machine called<br />

a luminometer, which will provide insight<br />

into the level of protein interaction.<br />

Human Immunodeficiency Virus<br />

Recently, Yale undergraduate Tucker<br />

Hansen YC '22 and his mentor Richard<br />

Sutton developed an SLCA to quantify the<br />

Human Immunodeficiency Virus type 1<br />

(HIV-1) Rev-Rev interaction. The assay<br />

will identify inhibitors that specifically<br />

prevent the Rev-Rev interaction of HIV-1<br />

to stop infections.<br />

H u m a n<br />

immunodeficiency virus<br />

(HIV) is a virus that attacks the body’s<br />

immune system. While there are two common<br />

subtypes, HIV-1 and HIV-2, most people<br />

living with HIV have HIV-1. The virus infects<br />

CD4+ T cells, a type of white blood cell also<br />

known as helper T cells. These cells help fight<br />

infection by triggering the immune system to<br />

destroy pathogens in the body. In active CD4+<br />

T cells, infection is caused by the insertion of<br />

the viral DNA into the host genome and its<br />

subsequent expression into new viral particles.<br />

When left untreated, HIV-1 replication causes<br />

progressive loss of CD4+ T cells, raising the<br />

infected individual’s susceptibility to infectious<br />

diseases that would not usually cause illness in<br />

a healthy individual.<br />

There are currently over thirty-eight million<br />

people living with HIV-1. Most patients<br />

can maintain undetectable viral loads and<br />

near-normal life expectancy with the help of<br />

antiretroviral medications that inhibit HIV-<br />

14 Yale Scientific Magazine October 2022 www.yalescientific.org


Medicine Biology<br />

FOCUS<br />

1 replication. There are currently dozens of<br />

FDA-approved medications against HIV-1,<br />

including protease, reverse transcriptase, and<br />

integrase inhibitors. So why would there be a<br />

need for more inhibitors?<br />

A Case for New Inhibitors of Chronic<br />

Diseases<br />

Viral suppression through existing<br />

medications enables immune recovery and<br />

the near elimination of the risk of developing<br />

AIDS, the more severe and life-threatening<br />

stage of HIV infection. However, due to drug<br />

resistance, some patients do not respond to<br />

the existing medications well.<br />

HIV-1 drug resistance is caused by changes<br />

in the genetic structure of HIV-1 that interfere<br />

with the ability of medications to block viral<br />

replication. Since RNA viruses such as HIV-1<br />

have an especially high mutation rate that allows<br />

for quicker evolution, all retroviral drugs risk<br />

becoming ineffective due to the emergence of<br />

drug-resistant viral strains. Furthermore, drug<br />

resistance can more easily arise if there is poor<br />

adherence to prescribed medications. “As with<br />

any chronic disease, there is always a need for<br />

improvement in current medications, as well as<br />

the development of new antivirals,” Hansen said.<br />

Revving Engines<br />

The Rev protein is highly conserved in<br />

all subtypes of HIV and is necessary for<br />

transporting copies of viral RNA out of the<br />

nucleus of the host cell. Without Rev, HIV<br />

would not be able to replicate in its host. An<br />

essential property of Rev activity is that it must<br />

multimerize on the Rev-Response Element<br />

(RRE) of HIV RNA to successfully export<br />

that RNA from the nucleus to the cytoplasm<br />

of the host. This means that multiple Rev<br />

proteins must interact with each other to<br />

form a multimer. Since the multimerization<br />

of Rev is key to its mechanism of action, it<br />

could serve as a small molecule drug target.<br />

Sutton, an expert studying HIV for years,<br />

knew that the Rev protein was essential to<br />

HIV survival. But there are currently no<br />

HIV antiviral drugs that target the Rev<br />

protein. “[A Rev inhibitor could] be a firstin-class<br />

antiviral,” Sutton said.<br />

Hansen began his project by developing an<br />

SLCA that could quantify Rev-Rev interaction<br />

in cells. Hansen fused each of the luciferase<br />

domains, NLUC and CLUC, to a Rev protein.<br />

The fused protein was created by genetically<br />

engineering a fusion gene that combined the<br />

www.yalescientific.org<br />

sequence of the specific luciferase domain<br />

with the sequence of the Rev protein. Through<br />

a series of experiments, Hansen and Sutton<br />

eventually developed a highly sensitive screen<br />

for measuring Rev-Rev interaction. When Rev<br />

proteins were close enough to multimerize,<br />

the NLUC and CLUC would be brought close<br />

enough to luminesce. This assay works inside<br />

and outside of cells. Thus, even when using just<br />

the inner contents of cells, the assay can still<br />

accurately quantify Rev-Rev interaction.<br />

The goal of developing this assay is to find a<br />

small molecule inhibitor that can disrupt the<br />

Rev-Rev interaction. Hansen demonstrated that<br />

this assay could help by testing whether mutant<br />

Revs, which would inhibit the wild-type Rev<br />

interaction, reduce luminescence levels in the<br />

assay. Performing the assay with mutated Rev<br />

proteins fused to NLUC and CLUC resulted in<br />

much lower luminescence, indicating that this<br />

SLCA can be used to screen for an inhibitor that<br />

disrupts the Rev-Rev interaction. Similar to how<br />

a mutant Rev would not be able to multimerize,<br />

a putative inhibitor would be able to disrupt<br />

this interaction and result in a much lower<br />

luminescence reading. Thus, researchers could<br />

use this system to test an unlimited number<br />

of small molecules to see whether any can<br />

effectively prevent Rev-Rev interactions without<br />

being an inhibitor of the luciferase enzyme itself.<br />

When asked whether he could find such an<br />

inhibitor, Sutton admitted that it was unlikely.<br />

“Honestly, I don’t think our lab could ever do<br />

this,” Sutton said. “It really takes a commercial<br />

entity to do it. Can you imagine Tucker<br />

screening two-hundred thousand compounds<br />

on his own?” A pharmaceutical company,<br />

however, has the means and methods to<br />

perform large-scale screens to identify<br />

potential inhibitors of the Rev-Rev interaction.<br />

PHOTOGRAPHY BY HANNAH HAN<br />

Associate Research Scientist Edidiong Akang, a new<br />

member of the Sutton Lab, pipettes fluids into a<br />

microcentrifuge tube.<br />

Sutton is currently applying for a grant<br />

from the NIH to fund the next steps of this<br />

project. With this funding, he is considering<br />

partnering with the local pharmaceutical<br />

company, ViiV Healthcare, which focuses<br />

on delivering new treatment options for<br />

people living with HIV. Sutton and Hansen<br />

are hopeful that the potential Rev inhibitors<br />

identified through this partnership could<br />

serve as a new class of HIV antivirals and<br />

present another line of defense for HIV<br />

patients with drug-resistance complications.<br />

The work done by Hansen and Sutton is<br />

only one of many examples demonstrating the<br />

versatility in applications of firefly luciferase.<br />

This story highlights the ingenuity of using<br />

phenomena in the natural world to create<br />

tools and technologies that can facilitate our<br />

understanding of biological processes. As we<br />

continue to explore and rationalize more of<br />

the natural world, Hansen and Sutton’s work<br />

reminds us that existing biological processes<br />

can be the key to unlocking a whole new<br />

world of technology and discovery with<br />

innumerable benefits to mankind. ■<br />

A R T B Y K A R A T A O<br />

ABOUT THE AUTHOR<br />

CONNIE TIAN is a senior in Grace Hopper studying Molecular, Cellular, and Developmental Biology.<br />

Connie currently conducts research in the DiMaio Lab at the Yale School of Medicine. Her research<br />

focuses on engineering genetically expressible, small transmembrane proteins to facilitate the<br />

degradation of disease-relevant transmembrane proteins. Outside of <strong>YSM</strong>, she is involved in the Yale<br />

Club Soccer team, Community Health Educators, and Yale Undergraduate Science Olympiad.<br />

THE AUTHOR WOULD LIKE TO THANK Tucker Hansen and Dr. Richard Sutton for their time and<br />

enthusiasm in sharing their research findings.<br />

REFERENCES:<br />

CONNIE TIAN<br />

Jabr, F. (2016, May 10). The Secret History of Bioluminescence. Hakai Magazine. https://hakaimagazine.<br />

com/features/secret-history-bioluminescence/<br />

Rinaldi, A. (2007). Naturally better. Science and technology are looking to nature’s successful designs for<br />

inspiration. EMBO Reports, 8(11), 995–999. https://doi.org/10.1038/sj.embor.7401107<br />

October 2022 Yale Scientific Magazine 15


FOCUS<br />

Evolutionary Biology<br />

THE WORLD IN<br />

Characterizing<br />

mammal<br />

biodiversity<br />

and evolution<br />

at the protein<br />

level<br />

Into the World of Proteins<br />

You, me, a worm, and a cow. What<br />

makes us different? Shape, size,<br />

personality, and innumerable other<br />

characteristics create visible differences, of<br />

course—but all of that is ultimately founded<br />

on the invisible world of proteins.<br />

Proteins are the microscopic tools of life,<br />

each one serving a specific function related<br />

to communication, catalysis, structure,<br />

storage, and every other aspect of cellular<br />

business. By interacting with other proteins<br />

and biological molecules, proteins generate<br />

all of life’s characterizing features: birth,<br />

death, cognition, and<br />

reproduction, just to name<br />

a few.<br />

We can imagine<br />

understanding an<br />

organism<br />

as a<br />

composite<br />

of its protein inventory. Almost all of its<br />

characteristics and behaviors depend on the<br />

type, number, and activity of its proteins.<br />

In fact, although we often think about<br />

evolution solely in terms of DNA mutations<br />

creating new characteristics, the relationship<br />

between DNA and an organism's tangible<br />

features depends entirely on proteins,<br />

meaning proteins play a crucial role as<br />

mediators of evolution.<br />

A Serendipitous Encounter<br />

Propelled by a protein-focused perspective,<br />

Yansheng Liu found himself watching<br />

Gunter Wagner’s presentation on the curious<br />

case of cow cancer at a seminar on Yale’s West<br />

Campus. Wagner, an evolutionary biologist,<br />

was interested in understanding cancer by<br />

BY KRISHNA DASARI<br />

comparing<br />

it between<br />

species. To<br />

understand why cows<br />

are less prone to cancer than<br />

humans, Wagner had been studying<br />

connections between changes in gene<br />

expression—an indirect measure of protein<br />

levels—and cancer resistance.<br />

Gene expression can be used to<br />

approximate protein levels because of the<br />

“central dogma” of molecular biology: a<br />

single sequence of DNA, the primary set<br />

of instructions, is transcribed into many<br />

copies of RNA. The RNA is then read and<br />

used to build proteins—the final, functional<br />

product. Measuring gene expression<br />

normally means measuring RNA levels,<br />

and it had long been conveniently assumed<br />

that protein levels were proportional to<br />

RNA levels due to the central dogma.<br />

But this is not always the case. Protein<br />

levels don’t always follow RNA levels,<br />

and Wagner was well aware of the longstanding<br />

debate about how well RNA and<br />

protein levels correlate. He knew the value<br />

of measuring protein levels themselves.<br />

ART BY MALIA KUO<br />

16 Yale Scientific Magazine October 2022 www.yalescientific.org


Evolutionary Biology<br />

FOCUS<br />

PROTEINS<br />

However, at<br />

the time, there<br />

was no practical method<br />

to quantify protein levels across<br />

the whole collection of proteins in<br />

a cell. This lack of technology forced<br />

him and almost everyone else in the field<br />

to rely on RNA-based gene expression to<br />

approximate protein levels.<br />

This is where Liu comes in. As a proteomicist,<br />

someone who studies the world of proteins,<br />

he, like Wagner, had a keen interest in the<br />

biodiversity of proteins. “I was so inspired by<br />

Gunter’s talk,” Liu said. “He’s using this very<br />

different angle to compare species to get a clue<br />

about human beings…and I quickly related<br />

[it] to some of my previous work about the<br />

diversity between human individuals and<br />

suggested that we could…cover different<br />

species [with proteomics].”<br />

Liu wanted to go further than gene<br />

expression. Rather than approximate<br />

protein levels using gene expression, why<br />

not study biodiversity at the protein level?<br />

And for the first time, he developed the<br />

technology to answer this question. He<br />

had been part of a team building a tool to<br />

measure protein levels called DIA-MS, a<br />

variant of standard mass spectrometry that<br />

offers advantages in reproducibility<br />

and accuracy. With this<br />

method, he and Wagner<br />

had the tools and the<br />

experience to explore<br />

a new frontier<br />

with Wagner:<br />

investigating<br />

biodiversity<br />

not with<br />

approximations<br />

of protein levels<br />

but with direct<br />

measurements.<br />

www.yalescientific.org<br />

Where to Go and<br />

What to Do?<br />

While Wagner’s original presentation<br />

focused on cancer, the two saw value in<br />

expanding their scope to perform an initial<br />

survey of protein-centric biodiversity across<br />

mammals. With the powerful ability to<br />

quantify complete protein profiles across<br />

species, Liu and Wagner were now faced<br />

with the difficult task of choosing what<br />

questions to ask.<br />

To both, it was clear that they must provide<br />

an answer to the fundamental debate: how<br />

well does RNA-based gene expression<br />

correlate with protein levels? They could<br />

test the validity of an assumption that the<br />

field had been relying on for decades, and<br />

now in multiple species.<br />

Beyond this highly practical aspect of the<br />

RNA-protein relationship, they also wanted to<br />

investigate the evolutionary history of the RNA<br />

and protein profiles. Could these two intimately<br />

intertwined yet distinct bodies evolve together<br />

across the tree of life? Or do intervening<br />

mechanisms disrupt the tethers between the<br />

two, separating the evolution of RNA levels<br />

from protein levels? We know of many possible<br />

sources of disruption, such as those that affect<br />

RNA stability or modify or degrade protein<br />

independently of RNA levels. Even further, we<br />

must consider the most significant difference<br />

between proteins and their nucleic acid<br />

cousins, DNA and RNA: proteins are the final,<br />

functional product! They’re made to interact<br />

with molecules or other proteins; can<br />

these interactions selectively<br />

constrain<br />

o r<br />

accelerate only<br />

protein evolution and not<br />

RNA?<br />

Consistent with their interest<br />

in protein biodiversity, the researchers<br />

were also curious about how their answers<br />

to these previous questions might vary<br />

between different species and individuals of<br />

the same species. Liu had previously revealed<br />

significant variability in the protein profiles<br />

of different humans, and they now<br />

had the chance to extend this<br />

work across species.<br />

Finally,<br />

t h e y<br />

considered<br />

what<br />

unique<br />

insight they could<br />

gain from proteins as<br />

opposed to DNA or RNA.<br />

Liu expressed interest in<br />

phosphorylation sites—spots<br />

on proteins that can bind or release<br />

phosphate molecules to activate<br />

or deactivate the protein. These<br />

sites are responsible for complex<br />

signaling pathways that regulate<br />

everything from cell growth and death<br />

to movement and secretion, so they receive<br />

much attention for understanding cell<br />

regulation or designing protein-inhibiting<br />

drugs. Liu and Wagner gained the ability to<br />

catalog the biodiversity of phosphorylation<br />

sites based on actual proteins rather than<br />

DNA or RNA.<br />

From fundamental questions of molecular<br />

biology to structural biochemistry to<br />

evolution, the new technologies and the<br />

unexpected collaboration between an<br />

evolutionary biologist and proteomicist<br />

thrust a new probe into previously murky<br />

waters of biology. With so much inbuilt<br />

potential, they had no reason to constrain<br />

themselves to one field of questions. “You<br />

have to use your biological intuition to<br />

understand what nature is trying to tell us<br />

here, and that’s fundamentally a creative<br />

process,” Wagner said. The world of proteins<br />

had much to tell about every field of biology,<br />

and Liu and Wagner were there to listen.<br />

Discoveries from the Protein World<br />

From their venture, the team<br />

recorded an invaluable dataset of<br />

protein diversity amongst mammals.<br />

October 2022 Yale Scientific Magazine 17


FOCUS<br />

Evolutionary Biology<br />

With this in hand, we can finally<br />

understand what differentiates you and<br />

me from cows on the protein level, with<br />

applications to tracking our evolutionary<br />

histories or informing medical research.<br />

They also used this data to determine that<br />

RNA and protein levels are moderately<br />

well correlated, though far from perfect.<br />

The good news is that the correlation<br />

does not invalidate decades of prior gene<br />

expression work, but it still sheds light on<br />

the importance of going directly to the<br />

source: proteins.<br />

Further, they discovered correspondence<br />

between variability in RNA and protein<br />

levels, suggesting that despite the many<br />

possible disruptions, RNA and protein levels<br />

do tend to coevolve. The tethers between<br />

these two spheres of molecular biology<br />

overall remain strong, though the exact<br />

relationship is protein-function-dependent.<br />

For example, some classes of proteins—<br />

such as those involved in protein<br />

degradation—show little variation in<br />

both RNA and protein levels, while<br />

other classes—such as those filling<br />

the extracellular region—feature high<br />

variation in both, contributing to increased<br />

evolvability. However, certain proteins defy<br />

this trend. Proteins involved in large protein<br />

complexes feature less protein variability<br />

than RNA variability because intimate<br />

dependence on other proteins pressures<br />

individual proteins to be less variable.<br />

Overall, protein profiles were slightly<br />

more variable than their RNA counterparts,<br />

suggesting that evolution can occur in<br />

proteins rather than solely on DNA/RNA.<br />

Furthermore, Liu and Wagner discovered<br />

more variability amongst phosphorylation<br />

sites relative to protein profiles. This<br />

variability may reflect the evolutionary value<br />

of tightly regulating protein activity or of<br />

generating new cell signaling possibilities.<br />

The team also constructed a network of<br />

coevolution amongst phosphorylation<br />

sites, providing insight into the complex<br />

interactions between signaling<br />

pathways.<br />

Finally, Liu and Wagner<br />

established<br />

that variability<br />

in protein<br />

between<br />

profiles<br />

species<br />

mirrors<br />

variability<br />

within<br />

species. In<br />

other words,<br />

PHOTOGRAPHY BY SANYA ABBASEY<br />

Dr. Yansheng Liu (right), Barbara Salovska (left), Dr. Wenxue Li (middle right), and Dr. Yi Di (middle left).<br />

if levels of a protein are highly variable<br />

between humans, they are also likely to be<br />

variable between humans and other species.<br />

Returning Home<br />

We have learned much about the protein<br />

world, but what do these results mean for<br />

biology on a broader scale? For one, they<br />

tell us that we can reasonably trust gene<br />

expression while still acknowledging that<br />

protein levels are more variable because of<br />

their functional role. The data also reveals<br />

significant diversity in protein profiles not<br />

only between species but also between<br />

individuals. And most importantly, Liu<br />

and Wagner have opened doors for an<br />

incredible array of studies. Evolution<br />

can now be interpreted not just from<br />

ABOUT THE AUTHOR<br />

changes in the genome, but by studying<br />

the proteins themselves—the tools that<br />

perform the tasks that evolution evaluates.<br />

Biodiversity, disease, and cell biology can all<br />

be approached from a more protein-centric<br />

perspective. In essence, a new method of<br />

understanding biology awaits us.<br />

Pondering the future of the field, Wagner<br />

concluded, “It’s still very difficult. It’s<br />

pioneering, but it’s clear that this is<br />

the direction it has to go in the long<br />

run.” Trekking through the protein<br />

world may remain challenging for<br />

years to come, but it promises<br />

to light the way toward a<br />

pivotal new<br />

understanding<br />

of diversity and<br />

evolution. ■<br />

KRISHNA DASARI<br />

KRISHNA DASARI is a junior in Pierson College majoring in Molecular, Cellular, and Developmental<br />

Biology with a Certificate in Data Science. As well as writing for <strong>YSM</strong> he also co-leads the outreach<br />

branch, Synapse, and conducts research on the evolutionary genetics of cancer at the Yale School of<br />

Public Health.<br />

THE AUTHOR WOULD LIKE TO THANK Gunter Wagner and Yansheng Liu for their time and thrilling<br />

explanations of their research.<br />

FURTHER READING<br />

Ba, Q., Hei, Y., Dighe, A., Li, W., Maziarz, J., Pak, I., Wang, S., Wagner, G. P., & Liu, Y. (2022). Proteotype<br />

coevolution and quantitative diversity across 11 mammalian species. Science Advances, 8(36). https://<br />

doi.org/10.1126/sciadv.abn0756<br />

Wagner, G. (2019, November 25). Can Cows Teach us how to beat Cancer Malignancy? Nature Ecology<br />

and Evolution. Retrieved October 12, 2022, from https://ecoevocommunity.nature.com/posts/56631-<br />

can-cows-can-teach-us-how-to-beat-cancer-malignancy<br />

18 Yale Scientific Magazine October 2022 www.yalescientific.org


Theoretical Physics<br />

FOCUS<br />

TURNING<br />

THE KNOTS IN<br />

RESONATORS<br />

RESONATORS<br />

Bridging elegant math and practical physics<br />

BY YUSUF<br />

RASHEED<br />

ART BY<br />

CHARLOTTE LEAKEY<br />

What do piano strings, air particles, and colliding comets have<br />

in common? Each of them is an oscillator, broadly defining<br />

anything that can vibrate. Oscillators are ubiquitous—they<br />

can be electrical, mechanical, optical, and astronomical, varying from<br />

smaller than an atom to larger than a planet.<br />

Every oscillator has a discrete set of frequencies at which it<br />

naturally vibrates. These are known as its resonance frequencies or<br />

eigenfrequencies, collectively known as the object’s spectrum. You may<br />

have encountered these in physics class in the form<br />

of standing waves, which are the various waves that<br />

naturally “fit” into a given object. For a very simple<br />

object like a guitar string, these are just sine waves, which “fit” whenever a<br />

half-integer number of their wavelength fits into the length of the string.<br />

Each wave will vibrate with its own frequency or eigenfrequency, which<br />

can be changed by adjusting anything that affects the system. In the case<br />

of a guitar, factors such as the tension of guitar strings, the type of wood,<br />

and the temperature of the environment can be used<br />

to tune its spectrum.<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 19


FOCUS<br />

Theoretical Physics<br />

Physicists know that any oscillator’s<br />

resonance frequencies are always given<br />

by the roots of a polynomial equation.<br />

When the oscillator is free from friction,<br />

all of the roots of this polynomial are real<br />

numbers, which is quite reasonable given<br />

that frequencies are usually thought of<br />

as real numbers. However, when friction<br />

is considered in the model, these roots<br />

become complex. This means that the root<br />

contains an imaginary number i, equivalent<br />

to √-1. When the model for an oscillator’s<br />

resonance frequencies includes friction,<br />

it is known as a non-Hermitian system.<br />

In contrast, a Hermitian system does not<br />

include friction in its model. The complex<br />

root takes the form (a + bi), where a is<br />

the real part of the root representing the<br />

resonance frequency, and b<br />

is the decay<br />

rate, or how<br />

quickly the<br />

oscillator<br />

s t o p s<br />

oscillating.<br />

O n e<br />

example<br />

is a guitar’s<br />

strings<br />

coming<br />

to rest<br />

after being<br />

plucked.<br />

To visualize the relationship between a<br />

system’s parameters and its spectrum of<br />

resonance frequencies, it is helpful to use two<br />

graphs: one showing the parameters that are<br />

being changed and the other showing the<br />

system’s resonance frequencies with each<br />

frequency being a point in the complex plane.<br />

This pair of two graphs can be seen in the<br />

figure below with pairs of plots “c” and “f,”<br />

“d” and “g,” or “e” and “h,” where plots “c,” “d,”<br />

and “e” are the parameter graphs, and plots<br />

“f,” “g,” and “h” are the resonance frequencies<br />

graphs. Continuing the example of a guitar, the<br />

parameter graph would have the tension in its<br />

strings, the type of wood, and the temperature<br />

of the environment, while the spectrum graph<br />

would have time as its vertical axis, representing<br />

how far along the control loop we are, and the<br />

complex eigenfrequencies in the horizontal<br />

plane. The spectrum graph can be thought of<br />

as plotting the complex eigenfrequencies in the<br />

horizontal plane and then stacking these planes<br />

on top of each other as time passes. When the<br />

parameters are gradually changed and then<br />

returned to their original values, a loop is<br />

formed in the first graph, known as a control<br />

loop. This control loop can be seen below in<br />

the figure as the green, red, or blue loop in<br />

plots “c,” “d,” and “e,” respectively. Such a loop<br />

may or may not enclose points corresponding<br />

to a choice of parameters that would produce<br />

a spectrum in which two or more<br />

eigenvalues are<br />

equal,<br />

known as a<br />

degeneracy.<br />

These points can be seen<br />

below in the figure<br />

as the points along<br />

the yellow “trefoil<br />

knot”-shaped<br />

structure in plots<br />

“c,” “d,” and “e.”<br />

When the parameters are varied<br />

around a control loop, a “braid”<br />

topological structure is created in the<br />

spectrum graph. Much like one can braid hair<br />

into different styles, these spectral braids also<br />

can twist and turn in a variety of ways. The<br />

specific braid that is created depends on the<br />

manner in which the control loop encloses the<br />

PHOTOGRAPHY BY MATTHEW ZOERB<br />

The light beam is guided through several prisms<br />

before entering the metal cube, where a 50<br />

nanometer thin piece of silicone nitride is.<br />

degeneracy points. These braids can be seen<br />

below in the figure as the triplet of green, red, or<br />

blue lines in plots “f,” “g,” and “h,” respectively.<br />

This relationship between polynomials<br />

and their roots was previously wellunderstood<br />

for a system with two oscillators<br />

(N=2). The braid would twist once if the<br />

control loop encloses a “degeneracy”–a<br />

point in the parameter graph at which two<br />

or more resonance frequencies of the system<br />

are equal. If the control loop does<br />

not enclose a degeneracy, the<br />

braid, in turn, does not<br />

twist.<br />

T h e<br />

relationship<br />

becomes more<br />

complex for a system<br />

with three oscillators<br />

(N=3). Mathematicians have<br />

known for a long time that the<br />

degenerate solutions of polynomial<br />

equations result in a curve/structure with<br />

non-trivial ‘topology’–the degeneracy curve<br />

forms a trefoil knot in the parameter graph for<br />

N=3. Topology is the branch of mathematics<br />

that deals with the shapes of geometric objects.<br />

For example, a donut has a different topology<br />

than a sphere, as the former has a hole<br />

while the latter does not. This topology had<br />

historically been almost exclusively explored<br />

in mathematics, not physics. Physicists knew<br />

that the braids twisted in various ways, but<br />

they did not know why, though they knew it<br />

had something to do with degeneracies.<br />

This project changed that through the<br />

combined forces of the Harris Lab and the<br />

Read Lab, whose researchers elucidated how<br />

this mathematical relationship defines systems<br />

with any number of oscillators. In other<br />

words, N is arbitrary. In addition, they showed<br />

systems with N=3 already exhibit several<br />

striking features that are absent from the N=2<br />

case. Lastly, they demonstrated these features<br />

20 Yale Scientific Magazine October 2022 www.yalescientific.org


Theoretical Physics<br />

FOCUS<br />

in the measurements of a system with three<br />

oscillators. Jack Harris and Nicholas Read<br />

are both Professors of Physics and Applied<br />

Physics, but Harris is an experimentalist, while<br />

Read is a theorist. Read was familiar with the<br />

mathematics of degeneracy curves forming a<br />

trefoil knot in the parameter graph for N=3<br />

and thus provided the missing piece to Harris’s<br />

exploration of how the braids twist. “[Read’s]<br />

the one who explained all the math to us. It<br />

happened because I had heard about this field<br />

and was confused about it… and I knew that<br />

[Read] knew a lot about math. After multiple<br />

conversations, we both agreed that this was<br />

something really interesting and we should try<br />

and pursue it.” Harris said.<br />

The groups found that the braiding<br />

process was defined by how the control loop<br />

encircled the trefoil knot of degeneracies.<br />

In the figure from the Nature paper below,<br />

graphs “c”, “d”, and “e” show the trefoil<br />

knot topological structure and the control<br />

loop, which is colored green, red, and blue,<br />

respectively. When the control loop doesn’t<br />

enclose the trefoil knot, a trivial braid is<br />

formed—mathematically, a braid without<br />

twists and turns is still a braid, just a trivial<br />

one (graph “f ”), as opposed to when the<br />

control loop does enclose the trefoil knot,<br />

the braiding depends on how many times<br />

the control loop encloses the trefoil knot<br />

(once in graph “g” and twice in graph “h”).<br />

“Relating this topology of the degenerate<br />

roots of polynomials to the physics of<br />

resonators, and realizing that the twists and<br />

turns of the braids [in the spectrum graph]<br />

are intimately related by a mathematical<br />

correspondence to how the control loop<br />

[in the parameter graph] entwines with<br />

that topological structure took us some<br />

time to develop and appreciate, and then<br />

experimentally verify,” Patil said.<br />

The researchers have also experimentally<br />

confirmed their findings using an<br />

optomechanical system of three oscillators<br />

(N=3). The apparatus they used was a<br />

radiation pressure system with three lasers<br />

that is analogous to a solar sail. Solar sails use<br />

large mirrors to reflect photons from the sun<br />

while traveling in space—each photon has<br />

momentum that it transfers to the solar sail<br />

upon impact, resulting in the propulsion of the<br />

whole spacecraft. Similarly, the apparatus they<br />

used had three lasers with differing powers<br />

that were pointed at a vibrating membrane<br />

of silicon nitride, allowing the researchers<br />

to control the membrane’s stiffness and<br />

www.yalescientific.org<br />

IMAGE COURTESY OF PATIL ET AL.<br />

Measurements of the EP2 knot K and the eigenvalue braids.This figure is pulled directly from the paper this<br />

article focuses on, which is cited below.<br />

damping and, thus, its resonance frequencies.<br />

Three different colors were also used; red,<br />

green, and blue, adding another dimension to<br />

the experiment. The researchers empirically<br />

saw for this system of N=3 oscillators that<br />

the topological structure of degeneracies in<br />

the parameter graph is indeed a trefoil knot.<br />

They saw that the twists in the experimentally<br />

realized braids indeed correlate with how the<br />

control loop entwines this trefoil knot.<br />

In addition to Professor Harris and Professor<br />

Read, both Dr. Yogesh Patil and graduate<br />

student Judith Höller played key roles in the<br />

project’s success. Patil ran the experiments,<br />

working with the lasers and oscillators. “[The<br />

project] was very demanding in terms of the<br />

sheer amount of time and [precision] with<br />

how the system needed to be controlled.<br />

[Patil] provided two years of solid leadership<br />

and guidance through the pandemic. This<br />

whole project happened during lockdown<br />

ABOUT THE AUTHOR<br />

because he was able to take [it on].” While<br />

Patil was in the lab, Höller was a crucial bridge<br />

between Harris and Read. “It was clear from<br />

the start that Nick’s elegant story about the<br />

math could–in principle–be realized with<br />

the equipment in our lab. But making this<br />

translation was too complicated at first. It was<br />

Judith who made this translation possible.<br />

The three of us had many long conversations<br />

in which Nick would describe the theory,<br />

and then Judith would explain it to me. Then<br />

I would describe what we could do with the<br />

lasers, and Judith would explain it back to<br />

him. She was a key catalyst,” Harris said.<br />

Given the ubiquity of oscillators,<br />

this discovery opens the door to future<br />

improvement of any system that contains<br />

them, including computers, radios, and<br />

watches. Technological advancements in this<br />

area no longer need to be limited to systems<br />

with only two oscillators. ■<br />

YUSUF RASHEED<br />

YUSUF RASHEED hails from the Bay Area and is a sophomore in Trumbull College majoring in<br />

Biomedical Engineering. He has a deep interest in physician-patient relationships and how budding<br />

medical professionals can develop their soft skills during and after their education. He hopes to apply<br />

his experience in engineering to a clinical setting in the future by improving and personalizing patient<br />

care. Yusuf also believes in the power of writing to effect change at all levels, whether that’s personally<br />

through a journal or publicly through the Yale Scientific Magazine. He encourages all interested<br />

students to get involved with the magazine and try their hand at writing an article.<br />

THE AUTHOR WOULD LIKE TO THANK Professor Jack Harris and Dr. Yogesh Patil for their valuable<br />

time and support for this article.<br />

FURTHER READING:<br />

Patil, Y.S.S., Höller, J., Henry, P.A. et al. Measuring the knot of non-Hermitian degeneracies and noncommuting<br />

braids. Nature 607, 271–275 (2022). https://doi.org/10.1038/s41586-022-04796-w.<br />

October 2022 Yale Scientific Magazine 21


FOCUS<br />

Biomedical Engineering<br />

HOW TO<br />

GROW<br />

A HEART<br />

Accelerating<br />

the maturation<br />

of engineering<br />

heart tissues<br />

BY CATHERINE ZHENG<br />

ART BY KIERA SUH<br />

22 Yale Scientific Magazine October 2022 www.yalescientific.org


Biomedical Engineering<br />

FOCUS<br />

Imagine a world where any organ<br />

could be grown in the lab. A sample<br />

from a cheek swab could become a<br />

functioning heart in just a matter of weeks.<br />

New hearts would be grown from patients’<br />

stem cells whenever they were needed,<br />

and organ transplant lists and waiting<br />

times would virtually disappear.<br />

While this world is still far in the future,<br />

researchers at the lab of Stuart Campbell,<br />

Yale Associate Professor of Biomedical<br />

Engineering & Cellular and Molecular<br />

Physiology, have taken major strides in<br />

accelerating the maturation of stem-cell<br />

derived cardiomyocytes (iPSC-CMs) to<br />

grow engineered heart tissues (EHTs) in<br />

the lab that can even contract in response<br />

to electrical stimuli.<br />

Growing Fetal Heart Cells<br />

The primary function of EHTs is to<br />

provide a model of the human heart to<br />

study its features and responses to stimuli<br />

without having to access a human heart<br />

directly. These models are created by<br />

differentiating induced pluripotent stem<br />

cells into cardiomyocytes—specifically,<br />

stem-cell derived cardiomyocytes<br />

(iPSC-CMs). This process involves first<br />

washing a thin slice of a pig heart in a<br />

detergent to clear away pig cells. The<br />

extracellular matrix is then used as a<br />

template for seeding a mixture of human<br />

heart cells, including iPSC-CMs and<br />

human cardiac fibroblasts.<br />

However, since stem cells can differentiate<br />

into any type of cell, iPSC-CMs are still<br />

relatively immature, representing fetal<br />

cardiomyocytes rather than mature ones.<br />

This limits their functionality as studies on<br />

them may not represent the characteristics<br />

of a fully grown human heart. Thus, to<br />

accurately represent mature heart tissue,<br />

iPSC-CMs need to undergo a maturation<br />

protocol that can currently take anywhere<br />

from forty days to six months.<br />

One proposed technique for speeding<br />

up the maturation of iPSC-CMs is<br />

progressive electrical ramp pacing, which<br />

involves exposing the cells to an increasing<br />

rate of electrical current pulses over time.<br />

Previous studies have shown that this leads<br />

to heart cells that are more mature as they<br />

have more advanced electrophysiology<br />

and better calcium handling.<br />

Calcium is also known to play a large<br />

role in cardiac physiology, as it is essential<br />

in inducing the contraction of the heart.<br />

When a membrane potential reaches the<br />

cardiac muscle, calcium channels open,<br />

allowing calcium to flow in and bind to<br />

troponin, which triggers the heart muscle<br />

cell contraction. Greater calcium levels<br />

increase contractile force. However,<br />

calcium’s role in the maturation of EHTs<br />

has not been previously considered.<br />

Most EHTs were grown in solutions<br />

containing only a fraction of the calcium<br />

concentration normally found in the heart.<br />

“When our group realized how<br />

underutilized and underrated those<br />

calcium mediums have been across the<br />

field, we thought it might be interesting<br />

just to try it out,” said Shi Shen, the primary<br />

researcher on this study. This curiosity<br />

led to the discovery that difference in<br />

response to calcium in these early stages<br />

can be a key driver in cardiomyocyte<br />

differentiation: results show that the<br />

amount of calcium present in the cell<br />

culture medium produced a significant<br />

change in the maturation of iPSC-CMs.<br />

Growing Mature Heart Tissues<br />

To further advance the maturation of<br />

iPSC-CMs, researchers tested whether<br />

the combination of electrical ramp<br />

pacing and an increase in free calcium<br />

ions, Ca 2+ , in culture could produce a<br />

scalable improvement in the maturation<br />

of EHTs compared to the standard<br />

maturation protocol.<br />

Four groups of EHTs—high-Ca 2+ nonpaced<br />

(HC-NP), low-Ca 2+ non-paced<br />

(LC-NP), high-Ca 2+ ramp-paced (HC-<br />

RP), and low-Ca 2+ ramp-paced (LC-RP)—<br />

were studied to determine the effects of<br />

electrical pacing and calcium level on<br />

their own and in conjunction. The team<br />

performed the ramp pacing at frequencies<br />

higher than that of a regular human heart<br />

rate. “The regular human heart rate would<br />

fit between one to two hertz, so putting<br />

it at three hertz is like putting a YouTube<br />

video at two times speed,” Stephanie Shao,<br />

an undergraduate researcher on this study,<br />

said. “You can really increase the frequency<br />

and speed it up without harming it. In this<br />

case, it benefits it because it makes the<br />

EHTs mature at an accelerated rate.”<br />

To test the functionality of these<br />

heart tissues, a variety of metrics were<br />

measured, ultimately showing that the<br />

HC-RP group performed much better<br />

than the other groups. One of the most<br />

notable improvements was the forcefrequency<br />

relationship (FFR). FFR<br />

reflects increases in the contractile force<br />

of the heart with increasing frequency<br />

stimulus. “This is one of the key results<br />

to determine whether our experiments<br />

are successful because healthy humans<br />

need this particular phenomenon to<br />

function, [...] and one of the hallmarks<br />

of a cardiac disease is the lack of increase<br />

in force,” Shen said.<br />

FFR is measured using a mechanical<br />

testing apparatus that measures force<br />

in response to 0.25-Hz increases in<br />

frequency from 1 to 3 Hz. While high<br />

calcium marginally improved the FFR<br />

of the groups with no ramp pacing,<br />

both groups still showed a negative<br />

FFR, meaning the force continuously<br />

decreased rather than increasing to a<br />

systolic peak force and dropping again.<br />

However, once the researchers induced a<br />

ramp pacing, they saw a positive FFR in<br />

the group with high calcium, whereas the<br />

FFR of the low calcium group was still<br />

negative. Healthy human myocardium<br />

has a positive FFR of up to 2-2.5 Hz,<br />

similar to that of the HC-RP group,<br />

which exhibited a FFR around 2 Hz.<br />

PHOTO COURTESY OF STEPHANIE SHAO VIA JENNA KIM<br />

Microscope image of heart tissue in a relaxed state (left) and a contracted state (right).<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 23


FOCUS<br />

Biomedical Engineering<br />

PHOTOGRAPHY BY JENNA KIM<br />

Undergraduate researcher Stephanie Shao working with the custom apparatus used to study the engineered<br />

heart tissues.<br />

Other metrics that measure heart tissue<br />

functionality are time-to-peak (TTP) and<br />

time-to-fifty percent relaxation (RT50).<br />

TTP is the time it takes for the tissue to<br />

reach its peak force, and RT50 is the time<br />

it takes for the tissue to reach fifty percent<br />

relaxation after its peak contractile force.<br />

Human tissues exhibit TTP and RT50<br />

values at around 200 ms and 120 ms,<br />

respectively. The HC-RP group showed a<br />

similar TTP of around 290 ms and RT50<br />

of around 120 ms, which is significantly<br />

faster than the other EHT groups.<br />

The effect of isoproterenol (ISO) on the<br />

EHTs was also observed by measuring<br />

FFR after exposure to ISO. ISO is a<br />

drug that increases the contractility of<br />

the heart. It is used for patients with<br />

weakened hearts to improve cardiac<br />

output. The increase in the systolic<br />

peak force for the HC-RP group was<br />

much more significant compared to the<br />

increase in the systolic peak force for<br />

the LC-RP group. These results indicate<br />

that the HC-RP group behaves more<br />

similarly to actual mature heart tissue in<br />

the presence of ISO.<br />

On top of these metrics, western blots<br />

and RNA sequencing were performed<br />

to analyze changes in protein and RNA<br />

levels on a molecular level that may have<br />

influenced improvements seen in the<br />

different groups. The results showed that<br />

markers associated with mature heart<br />

tissues were elevated in the HC-RP group.<br />

They also found that the genes expressed<br />

in the HC-NP and LC-RP groups were not<br />

the same, indicating that both electrical<br />

ramp pacing and high calcium are needed<br />

to produce the mature characteristics<br />

achieved in the EHTs.<br />

Growing Hearts<br />

With this improved protocol, the<br />

maturation of iPSC-CMs can be<br />

significantly shortened relative to<br />

previously published techniques. While<br />

EHTs cannot be used to grow hearts<br />

directly from stem cells, this advancement<br />

has significant implications for future<br />

research. Given that many researchers<br />

around the world are using iPSC-CMs<br />

for a variety of purposes, this technique<br />

has the potential to find widespread use<br />

and make mature, functional EHTs more<br />

readily available.<br />

“For something like a drug study, a lot<br />

less compound would be used,” Shao said.<br />

“Especially if it’s a drug that’s not out yet,<br />

you have to have a chemist make it, and<br />

that’s not easy to make large quantities of,<br />

which is what you would need for an in<br />

vivo study.”<br />

Another major advantage of using<br />

EHTs is that they are grown from stem<br />

cells derived from a specific patient.<br />

This means that any testing a patient<br />

may need to undergo can be performed<br />

on an EHT grown from their stem cells,<br />

which will more accurately represent the<br />

characteristics of their own heart.<br />

This study is a catalyst for future cardiac<br />

research exploring the vast applications of<br />

EHTs. “There’s a large segment of work that’s<br />

being done targeted towards implanting<br />

cells back into patients to repair the heart<br />

to replace or regenerate heart muscle,”<br />

Campbell said. “I would hope that the<br />

field takes notice of our protocol because<br />

if you’re repairing the heart, for instance,<br />

you want to generate a lot of mature cells,<br />

so someone’s going to have to decide how<br />

to treat those cells so that they’re as mature<br />

as possible.” Campbell hopes this paper will<br />

contribute to the growing body of literature<br />

for the most optimal maturing conditions.<br />

Moving forward, there are still other<br />

factors to investigate that may further<br />

improve the maturation of stem cells for<br />

EHT growth. “Something that we haven’t<br />

tried is combining a realistic pattern<br />

of mechanical loading, or maturation<br />

of mechanical loading—so what a<br />

fetus experiences in terms of the fetal<br />

heart versus a newborn versus an adult<br />

heart—modulating the mechanical load<br />

in conjunction with those heart rate<br />

changes”, says Campbell. While growing<br />

a functioning adult human heart is not<br />

yet in the cards, we are getting closer to a<br />

future where that is possible. ■<br />

ABOUT THE AUTHOR CATHERINE ZHENG<br />

CATHERINE ZHENG is a senior BME and CS major in Pauli Murray College. In addition to writing for<br />

<strong>YSM</strong>, she is the magazine’s production manager, she does research with Professor Staib, and is also the<br />

production manager for the Yale Undergraduate Research Journal.<br />

THE AUTHOR WOULD LIKE TO THANK Professor Campbell, Dr. Shi Shen, and Stephanie Shao for their<br />

time and enthusiasm in sharing their research.<br />

FURTHER READING<br />

Shen, S., Sewanan, L. R., Shao, S., Halder, S. S., Stankey, P., Li, X., & Campbell, S. G. (2022). Physiological<br />

calcium combined with electrical pacing accelerates maturation of human engineered heart tissue. Stem<br />

Cell Reports, 17(9), 2037–2049. https://doi.org/10.1016/j.stemcr.2022.07.006<br />

24 Yale Scientific Magazine October 2022 www.yalescientific.org


PAPER POWER<br />

Sustainable Energy<br />

FEATURE<br />

A WATER-ACTIVATED<br />

BIODEGRADABLE PAPER BATTERY<br />

BY CINDY MEI<br />

ART BY LUNA AGUILAR<br />

With great power comes great responsibility. In an age<br />

where the world has become increasingly reliant on<br />

technology, the threat of electronic waste or e-waste—<br />

including many discarded products containing batteries—has<br />

become increasingly dire. In 2019 alone, an estimated 48.6 million<br />

tons of e-waste was generated worldwide, a rapidly expanding<br />

issue that has only continued to grow. Because standard lithium<br />

batteries contain non-biodegradable and often toxic rare earth<br />

metals, the accumulation of e-waste releases harmful chemicals<br />

that can contaminate groundwater and the air, putting the<br />

environment and the health of billions at risk.<br />

The quest for green power seeks to eliminate the threat of e-waste<br />

by harnessing sustainable materials. This pursuit fascinated Gustav<br />

Nyström, head of cellulose & wood materials at the Swiss Federal<br />

Laboratories for Materials Science and Technology. By harnessing<br />

natural, environmentally-friendly materials, researchers in Nyström’s<br />

lab were able to power the crystal display of a LED alarm clock using<br />

a disposable paper battery activated by just two drops of water.<br />

The project, which also involved postdoctoral researcher<br />

Alexandre Poulin and doctoral researcher Xavier Aeby, sought<br />

to search for an environmentally-friendly battery high in<br />

density, important for a longer run time, that<br />

would be suitable for single-use devices<br />

such as sensors. “For instance, in<br />

biomedical industries, where<br />

many diagnostic tests are<br />

discarded after a single use due<br />

to hygienic and ethical reasons,<br />

there is a lot of plastic waste<br />

being generated,” Nyström said.<br />

An electrochemical battery<br />

stores and discharges energy through<br />

a series of oxidation and reduction<br />

reactions that occur at the anode<br />

and cathode, respectively. In<br />

addition to these components, a<br />

separator prevents the electrodes<br />

from coming in contact and<br />

short-circuiting, while the electrolyte<br />

facilitates the movement of ions between the anode and cathode.<br />

In battery fabrication, the material choice for these components<br />

is especially important for optimized, reliable function. “We<br />

made a strict selection based on what we thought were the most<br />

promising materials in terms of energy density and stability for this<br />

development,” Nyström said. “It’s about choosing the right type of<br />

materials that are not harmful to our environment. That’s a big and<br />

important goal for us.”<br />

www.yalescientific.org<br />

The ideal material is stable and highly conductive, with low<br />

contact resistance, high energy storage capacity, and a fast charging<br />

rate. After testing many combinations, the final design used a<br />

zinc anode, a graphite carbon air cathode, a paper separator, and<br />

a water-based salt electrolyte. The electrodes were stenciled onto<br />

the paper using multi-material inks that contained a mixture of<br />

ethanol, shellac, and sodium chloride ions which are required to<br />

form the conductivity needed in the battery for electron flow. The<br />

dry batteries can then be stored indefinitely until water is added,<br />

which permeates the paper membrane, dissolving the salt ions and<br />

activating the battery within twenty seconds.<br />

The battery inks were characterized by shear thinning behavior and<br />

yield stress, physical factors important in additive manufacturing.<br />

This method adds components by layering them and has great<br />

advantages in reducing manufacturing waste. “[Our goal is] also<br />

being responsible with the amount of material used,” Nyström said.<br />

“When you manufacture, you only need to use exactly the amount of<br />

multi-material inks that you need for those different components.”<br />

The researchers also performed electrochemical tests on the battery.<br />

A single cell demonstrated a 1.2 V potential, which is proportional<br />

to the energy delivered to the cells. Power capability was measured<br />

to reach 150 μW, enough to power<br />

an alarm’s LCD crystal display,<br />

hearing aids, and electronic<br />

watch calculators. With more<br />

printed batteries added in<br />

series, the voltage increases,<br />

accommodating devices with<br />

greater power usage. After one<br />

hour of operation, the voltage<br />

decreased as the paper substrate<br />

dried. However, upon the readdition<br />

of water, the performance was<br />

recovered, allowing for extended<br />

battery life by increasing how<br />

much water the paper could hold.<br />

In the future, the researchers<br />

hope to study the length of battery<br />

life following rehydration of the<br />

battery and explore further implementations of organic materials.<br />

Nyström believes that it has the potential to play a valuable part in<br />

the reduction of e-waste in powering single-use diagnostic tests and<br />

sensors, but there is still much work to be done. “We have had a lot of<br />

academic developments, and now is really the time to see what and<br />

how much can be transferred into real products,” Nyström said. “I<br />

think [paper] is quite a promising material, but we need to see what<br />

is feasible and where the best applications will be.” ■<br />

October 2022 Yale Scientific Magazine 25


ART BY EMILY<br />

BY KAYLA<br />

FEATURE<br />

Climate & Oceans<br />

LIGHTNING’S<br />

ACHILLES HEEL<br />

POAG<br />

YUP<br />

HOW SEA SPRAY PUTS LIGHTNING TO SLEEP<br />

In Greek mythology, any site struck by lightning is considered<br />

sacred. By that logic, the Earth’s land must be divine—a whopping<br />

ninety percent of lightning strikes land, leaving only a measly ration<br />

for oceans worldwide. Thanks to a study recently published in Nature<br />

Communications, we now know the secret to this phenomenon. Above<br />

the ocean, wind and water interact to form sea spray: salty particles<br />

suspended in the air. Scientists in Israel, China, and the US discovered<br />

that this spray could reduce lighting by up to 90 percent.<br />

Clouds are composed of droplets that typically form when<br />

water vapor condenses onto aerosols. The term ‘aerosol’ refers to<br />

any small solid particle suspended in the air. Previous research<br />

found that ‘fine aerosols,’ such as smoke, can encourage lightning<br />

formation by serving as sites for condensation. This has been<br />

used to link rising rates of air pollution to increased lightning.<br />

“Lightning is sort of the byproduct of clouds,” said Yannian Zhu,<br />

study co-author and associate professor at Nanjing University.<br />

“Normally, if you don’t have clouds, you don’t have lightning.”<br />

For clouds to become ‘electrified,’ they must reach a certain<br />

elevation. Rising currents of air—updrafts—help clouds grow to<br />

a height at which the temperature is below zero degrees Celsius.<br />

At this level, water droplets can freeze into ice crystals. Some<br />

of these ice crystals then collect the rest of the water droplets,<br />

forming larger sleet-like particles known as ‘graupel.’ The other<br />

ice crystals remain small and positively charged and continue to<br />

be pushed by updrafts toward the top of the cloud.<br />

Meanwhile, the graupel descends, carrying a negative charge.<br />

Electrical charge is transferred from the<br />

crystals to<br />

the graupel when they<br />

collide.<br />

O v e r<br />

time, an<br />

electrical<br />

field builds<br />

from the<br />

c o n s t a n t<br />

transfer of<br />

electrical<br />

charges<br />

between<br />

t h e<br />

oppositely<br />

charged<br />

particles.<br />

A f t e r<br />

sufficient<br />

buildup, the power of the electricity is strong enough to penetrate<br />

through the atmosphere, discharging as a flash of lightning.<br />

On land, fine aerosols are much more concentrated, largely due to<br />

air pollution, making them the main source for cloud formation. Over<br />

oceans, sea spray frequently serves as a condensation site, forming<br />

water droplets bigger and heavier than their fine aerosol counterparts.<br />

Fine aerosol particles are small and abundant, forming<br />

clouds with numerous small droplets. These droplets are slow<br />

to combine into raindrops, remaining small enough to ascend<br />

easily to a high enough level for freezing to occur. However, sea<br />

spray, which is considered a ‘coarse aerosol,’ has the opposite<br />

effect: large droplets form and quickly coalesce into rain.<br />

The large salt particles in sea spray can absorb water quicker and<br />

easier, forming large droplets that eagerly collect other droplets.<br />

As a result, these clouds will rain out too soon before reaching the<br />

sub-zero temperature height at which ice can form and electrify<br />

the cloud. This phenomenon also helps explain why small rain<br />

showers are more frequent over the ocean than on land.<br />

“If you live beside the sea, you will see that there are many [rain]<br />

showers every day without thunderstorms—just showering,” Zhu<br />

said. “It is a cycle, water vapor becomes clouds, and then the<br />

clouds become rain [and so on] ... this energy transition between<br />

surface and atmosphere is very fast.”<br />

The researchers drew upon over four years of satellite data<br />

measuring clouds, precipitation, aerosols, and meteorology. “In<br />

principle, people knew that the added sea spray particles enhanced<br />

rainfall, but they never had such comprehensive measurements from<br />

satellites to actually [demonstrate] the effect on a global scale,” said coauthor<br />

Daniel Rosenfeld, a meteorologist and professor at the Hebrew<br />

University of Jerusalem. “It’s one thing to know that something, in<br />

theory, could happen; it’s another thing to see that it is [in fact] really<br />

significant and has a large effect.” This study ultimately differentiated<br />

the contrasting effects of fine and coarse aerosols on clouds.<br />

Current weather prediction and climate models fail to consider<br />

the effect of sea spray on weather patterns. Knowing how aerosols<br />

can change the cloud’s physical processes will enable us to monitor<br />

convective clouds more accurately and potentially artificially alter<br />

them to avoid natural disasters, such as hail and tornadoes. Simply by<br />

deploying the right aerosols into the air, the practice of ‘cloud-seeding’<br />

has facilitated China’s attempts to trigger more rainfall for agriculture.<br />

“Our responsibility is to understand the whole aerosol-cloud<br />

interaction microphysical process and to give that knowledge…<br />

to help people do future climate predictions more accurately,” Zhu<br />

said. “We’re trying to save the world in a different way.” ■<br />

26 Yale Scientific Magazine October 2022 www.yalescientific.org


Robotics & Medicine<br />

FEATURE<br />

Black Mirror. Ex Machina. The Terminator. Why does<br />

television seem to vilify robots and artificial intelligence<br />

as a human invention bound to go wrong? Why are robots<br />

always portrayed as a perilous design destined to eradicate the<br />

human species? We see this smear of these intelligent machines<br />

in the media and pop culture, from movies that follow the<br />

expedition of an assassin robot to dystopian shows that alarm<br />

their audiences about the dangers of unrestricted technological<br />

advancements. However, let us not forget that robots are<br />

designed to facilitate human conventions and tasks, with<br />

great potential to revamp and advance biotechnology, medical<br />

procedures, and clinical treatments.<br />

In one of the latest clinically transformative<br />

cases, researchers at Stanford University<br />

designed a tiny origami robot capable of various<br />

movements in physiological environments to<br />

deliver organic cargo and liquid medicine. We often<br />

attribute origami to the Japanese paper-folding<br />

craft, but this technology fulfills the robot’s<br />

multifunctionality based on the geometric<br />

features of a specific origami structure: the<br />

Kresling. The Kresling is a triangulated<br />

hollow cylinder where ‘twist buckling’ a<br />

thin cylindrical sheet creates triangular<br />

elements throughout the structure. The<br />

twist buckling mechanism can be created<br />

by folding one sheet slightly higher than<br />

the next sheet, then repeating this process<br />

along the direction of the twist. Because<br />

the Kresling structure is always curved<br />

at the folds, the junctions between folds<br />

can be radially cut for liquid drug release.<br />

The buckling effect and high geometrical<br />

symmetry of the design allow for the robot’s<br />

sphere-like ability to roll, flip, and spin.<br />

“The Kresling origami is a special design<br />

that couples torsion—a twisting motion—and<br />

compression, which provides us with the foldability to<br />

develop a pumping mechanism for targeted drug delivery,”<br />

said Renee Zhao, assistant professor of mechanical<br />

engineering at Stanford University and one of the<br />

leading scientists on the project. The robot is<br />

prepared by attaching thin magnetic plates to the<br />

ends of the Kresling structure, which generates a<br />

twisting force as the robot’s rigid body rotation<br />

aligns with the magnetic field.<br />

www.yalescientific.org<br />

TINY<br />

ORI<br />

AM R G I<br />

THE FUTURE OF DRUG DELIVERY<br />

BY IGNACIO RUIZ-SANCHEZ<br />

OB OTS<br />

This all sounds very compelling and groundbreaking, but how<br />

does the robot’s origami structure improve the drug delivery<br />

process? After all, the robot is not being introduced to a generally<br />

dry environment, so why is on-ground locomotion relevant?<br />

Zhao and her team at Stanford characterize the tiny robot as<br />

amphibious in functionality, meaning that the robot can navigate<br />

both complex ground and aqueous environments. “On-ground<br />

locomotion is based on the robot’s interaction with a solid surface<br />

by rolling and flipping, and aquatic locomotion is based on the<br />

spinning mechanism that creates propulsion for the device to<br />

swim,” Zhao said. The magnet plates also activate the pumping<br />

mechanism to release liquid medicine into the body.<br />

For drug delivery, a needle and a liquid medicine<br />

container are inserted into the internal cavity of<br />

the robot. Once the device reaches the target<br />

area, the magnetic plates activate a rotational<br />

force to contract the robot, during which the<br />

needle punctures the liquid container. Gradually,<br />

the Kresling’s internal cavity shrinks and squeezes the<br />

liquid medicine out through the radial cuts into the environment.<br />

Similarly, the spinning-enabled feature from the magnets also<br />

allows for cargo loading and release, which follows the same<br />

locomotive process as the pumping mechanism. However, it first<br />

propels the robot to absorb solid objects from an environment,<br />

stores those objects in the internal container, and finally releases<br />

them via pumping once the robot reaches the target area.<br />

Despite the relatively small size of the millirobot, the internal<br />

cavity of the Kresling is still widely unoccupied, even after<br />

installing the needle and liquid container. Researchers<br />

have thus built sensors and cameras in the cavity to direct<br />

movements and record specific environmental conditions.<br />

“The internal cavity of the robot can actually be<br />

used to integrate other functional components,<br />

like cameras for biopsies and biosynthetic tissues<br />

to stop internal bleeding,” Zhao said. The potential<br />

biomedical applications for using the robot and its<br />

internal compartments are vast.<br />

Versatility, agency, and efficacy all seem to<br />

be leading features in the architecture of these<br />

innovative devices. Robots like the Kresling origami<br />

should remind us that robots were created to help us,<br />

not harm us. To this point, let’s stop giving robots such<br />

a bad rap in pop culture, especially if these cute, foldable<br />

robots could be designed to ultimately save our lives. ■<br />

ART BY CATHERINE KWON<br />

October 2022 Yale Scientific Magazine 27


FEATURE<br />

Developmental Psychology & Artificial Intelligence<br />

WHAT CAN A COMPUTER<br />

LEARN FROM A BABY?<br />

TEACHING PHYSICAL INTUITION TO AI MODELS<br />

BY NATHAN WU<br />

ART BY CATHERINE KWON<br />

Before we turn three months old,<br />

humans have already developed<br />

an intuitive sense of how the<br />

physical world works. If an infant knocks<br />

over a block tower, they know the blocks<br />

will tumble spectacularly down to the<br />

ground. If the blocks float in the air or<br />

fall straight through the floor, the infant<br />

might cry out in surprise.<br />

This sense of common intuition is<br />

dubbed our ‘intuitive physics engine,’<br />

fundamental to both biological and<br />

artificial intelligent systems operating<br />

in the real world. Understanding how<br />

a system’s physical actions will affect<br />

the world around them can guide what<br />

decisions and movements they must<br />

execute to carry out their intentions. In<br />

biological systems, the intuitive physics<br />

engine develops extremely rapidly,<br />

suggesting its importance for survival in<br />

the physical world.<br />

Despite the ubiquity of<br />

intuitive physics in<br />

intelligent<br />

biological<br />

organisms, the best artificial intelligence<br />

(AI) systems still struggle to replicate<br />

the same understanding of physics that<br />

even very young children have mastered.<br />

This difficulty continues despite the great<br />

progress made in the field. AI systems<br />

easily best humans in complex games, like<br />

Chess and Go, and have solved some of<br />

the most complicated scientific<br />

problems, like protein<br />

folding. The challenge of<br />

teaching intuitive physics<br />

to an artificial system lies<br />

within its pervasiveness.<br />

“Intuitive physics is everywhere,<br />

and when something<br />

is everywhere, it<br />

becomes hard to analyze because it’s<br />

interacting with so many things,” said<br />

Luis Piloto, a research scientist<br />

at DeepMind,<br />

a subsidiary of<br />

Alphabet, Google’s<br />

parent company.<br />

However, Piloto’s<br />

team has<br />

recently made great<br />

strides toward finding<br />

a solution by taking<br />

inspiration from the methods<br />

and findings of developmental<br />

psychology, ultimately<br />

creating an AI system that<br />

learns intuitive physics<br />

from visual data.<br />

Perhaps the most important<br />

novelty of Piloto’s work was how their<br />

AI model’s understanding of intuitive physics<br />

28 Yale Scientific Magazine October 2022 www.yalescientific.org


Developmental Psychology & Artificial Intelligence<br />

FEATURE<br />

was probed and evaluated. In developmental<br />

psychology, intuitive physics is separated<br />

into several distinct concepts, such as object<br />

permanence or object solidity. For each<br />

concept tested individually, human subjects<br />

are shown relevant scenes that are either<br />

consistent or inconsistent with the concept<br />

of interest. If subjects show surprise after<br />

seeing inconsistent scenes, which is usually<br />

measured by gaze duration, there is evidence<br />

that the subject understands that concept.<br />

This method of evaluating intuitive physics<br />

knowledge is known as the violation-ofexpectation<br />

(VoE) paradigm.<br />

Inspired by these methods used in<br />

developmental psychology, Piloto and<br />

his team constructed the Physical<br />

Concepts dataset. This dataset contains<br />

videos generated by a physics engine,<br />

each consistent or inconsistent with one<br />

of five distinct concepts from intuitive<br />

physics. These concepts included object<br />

permanence (objects will not simply<br />

disappear), object solidity (objects<br />

will not pass through one another),<br />

continuity (objects will have continuous<br />

paths and cannot teleport from one place<br />

to another), unchangeableness (objects<br />

retain their properties over time), and<br />

directional inertia (objects will stay in<br />

their path unless a force acts upon them).<br />

Every video that abided by a concept<br />

was paired with a visually similar one<br />

that violated that concept, both starting<br />

with identical scenes but deviating over<br />

the course of the video. The amount of<br />

'surprise' that a model exhibited was<br />

determined by the model’s prediction<br />

error—how different a future scene<br />

predicted by the model is compared to<br />

the real future scene in the accompanying<br />

video. Thus, the model’s understanding of<br />

a concept can be evaluated by examining<br />

the difference in the model’s surprise<br />

in response to physically plausible and<br />

implausible pairs of videos.<br />

This VoE paradigm is a departure<br />

from standard methods of evaluating<br />

AI’s performance on intuitive physics<br />

tasks. One common approach utilizes<br />

video prediction on physically plausible<br />

situations alone to evaluate learning<br />

progress. In the VoE paradigm, the<br />

model should, in theory, make incorrect<br />

predictions about physically implausible<br />

videos, enabling researchers to better<br />

understand whether a concept is truly<br />

being learned. Another common<br />

approach employs reinforcement learning<br />

tasks, whereby models plan actions to<br />

interact with the environment around<br />

them to receive a reward. However,<br />

the complexity of these tasks makes it<br />

difficult to isolate the true cause of failure<br />

because success requires intuitive physics<br />

knowledge and knowledge of how to<br />

navigate the given space.<br />

“If we want to evaluate intuitive physics<br />

knowledge, let's break it down into these<br />

different concepts, and let’s build stimuli<br />

that are really about the concepts…<br />

You can do well on benchmarks, but if<br />

they don't reflect the capabilities that<br />

you're actually trying to measure, then<br />

increasing your performance on those<br />

benchmarks doesn't necessarily get you<br />

closer to the capabilities that you want,”<br />

Piloto explained.<br />

The next key insight from developmental<br />

psychology incorporated by Piloto’s team<br />

was an object-based conception of physics.<br />

Infant intuitive physics behavior involves<br />

segmenting the visual field into distinct<br />

objects with their own properties (object<br />

individuation), tracking these objects<br />

across space and time (object tracking), and<br />

then processing how these objects interact<br />

with each other (relational processing).<br />

These three processes were implemented in<br />

a model called Physics Learning through<br />

Auto-encoding and Tracking Objects,<br />

nicknamed PLATO. Rather than only<br />

looking at patterns of pixels in a visual<br />

scene as other visual prediction models<br />

do, each frame that PLATO processes is<br />

broken down by masking specific parts<br />

of the scene so that the model can learn<br />

representations of individual objects.<br />

Indices assigned to each object enable<br />

them to be tracked through time. Lastly,<br />

a separate module is used to process how<br />

these objects interact with one another and<br />

predict future scenes.<br />

After just twenty-eight hours of visual<br />

training with physically plausible videos<br />

from the physical concepts dataset,<br />

PLATO demonstrated a grasp of all five<br />

concepts by exhibiting greater surprise<br />

in response to physically implausible<br />

videos. This result outperformed AI<br />

models that do not rely on object-based<br />

representations as PLATO does. The model<br />

also performed well on a different dataset<br />

developed independently by a team at the<br />

Massachusetts Institute of Technology,<br />

suggesting that PLATO’s understanding<br />

of intuitive physics is robust.<br />

The quest to build an AI system that<br />

can learn intuitive physics is far from<br />

over. While Piloto’s team at DeepMind<br />

has taken a great step forward, there is<br />

still much room for improvement. In<br />

particular, PLATO did not learn how<br />

to segment and label the visual field<br />

into distinct objects by itself. Instead,<br />

the researchers spoon-fed the model<br />

a series of masks that told it where<br />

each object was. Other recent work has<br />

successfully tackled this challenge,<br />

introducing methods for object<br />

discovery in an unsegmented visual<br />

field. Integrating this research with the<br />

relational processing module of PLATO<br />

would result in a seamless model that<br />

can understand intuitive physics with<br />

nothing but a video.<br />

PLATO’s success as a machine learning<br />

model inspired by biological brains speaks<br />

to artificial intelligence’s close relationship<br />

with neuroscience and psychology. “AI<br />

and neuroscience are attacking the same<br />

problem from different sides,” Piloto said.<br />

“The analogy that I like to use is that AI<br />

is building intelligence from scratch,<br />

and neuroscientists are saying, ‘Wait,<br />

hold on, we’ve got this intelligent system<br />

right here, why don’t we try and reverseengineer<br />

what’s going on?’”<br />

Although PLATO is far from being<br />

an accurate model of intuitive physics<br />

learning in children, the study still<br />

presents important implications for<br />

developmental psychology. PLATO’s<br />

success proves that intuitive physics<br />

knowledge is not necessarily innate—it<br />

can be rapidly acquired through visual<br />

learning. Additionally, Piloto’s team<br />

proposes using models like PLATO to<br />

investigate the order in which different<br />

intuitive physics concepts are acquired<br />

throughout development. This study<br />

demonstrates that the brain sciences<br />

and artificial intelligence have much to<br />

gain through work at the intersection of<br />

the two fields. ■<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 29


FEATURE<br />

Biomedical Engineering<br />

A LIFE-SAVING<br />

STICKER<br />

DEVELOPING<br />

A BIOADHESIVE<br />

ULTRASOUND<br />

DEVICE<br />

BY XIMENA<br />

LEYVA PERALTA<br />

ART BY KIERA SUH<br />

Diagnosing diseases can be tricky. How<br />

can doctors tell if a headache stems<br />

from a lack of sleep or something more<br />

serious? How can they see what is happening<br />

inside a patient? Peering inside the body can<br />

provide valuable, life-saving information<br />

for clinicians. Among the different imaging<br />

techniques, ultrasound—a non-invasive, riskfree<br />

diagnostic tool—stands out as a leading<br />

option. Researchers at the Massachusetts<br />

Institute of Technology (MIT)<br />

have developed a small, adhesive<br />

device that may revolutionize<br />

ultrasound technology.<br />

Ultrasound devices use sound<br />

waves to create a picture of<br />

internal organs and tissues. An ultrasound<br />

probe emits high-frequency waves, which<br />

can travel through soft tissues but bounce off<br />

harder structures. An image is then created<br />

by a computer using these echoes. Thanks to<br />

its lack of radiation, ultrasound is the safest<br />

imaging tool, making it an ideal choice for<br />

continuous monitoring. However, current<br />

ultrasound devices are bulky and require an<br />

experienced clinician to operate the handheld<br />

probe. The clinician can only obtain a few<br />

images or videos in a regular ultrasound<br />

appointment, which typically lasts less than<br />

thirty minutes. Continuous imaging to<br />

monitor internal changes as the body moves<br />

on a day-to-day basis is not an option.<br />

The team at MIT was able to transform the<br />

standard bulky, handheld ultrasound into a<br />

simple sticker by developing a brand-new<br />

bioadhesive that can comfortably attach<br />

a small ultrasound probe to the skin. The<br />

resulting bioadhesive ultrasound (BAUS)<br />

device can be attached to the body for up<br />

to forty-eight hours at a time to take highquality<br />

images and videos of our body’s<br />

activities—blood vessels contracting, lungs<br />

expanding, stomachs digesting, and hearts<br />

pumping. The BAUS device can comfortably<br />

move with the person and capture the<br />

human body’s natural dynamism.<br />

“Wearable ultrasound equipment can<br />

potentially revolutionize medical imaging,”<br />

said Xuanhe Zhao, professor of mechanical<br />

engineering and civil and environmental<br />

engineering at MIT, who co-authored the<br />

Science paper that describes the BAUS<br />

device. “Medical imaging is very important<br />

for diagnostic purposes. However,<br />

with existing medical imaging,<br />

the timescale is short. It’s usually<br />

a few seconds or minutes—just a<br />

snapshot.” Continuous and frequent<br />

imaging of internal organs, over<br />

days or even months, could help<br />

clinicians more effectively monitor the<br />

health of patients and observe how diseases<br />

progress. It could also provide invaluable<br />

new data about the human body and lead to<br />

discoveries in medicine and biology.<br />

The biggest challenge has been comfortably<br />

attaching an ultrasound probe to the body.<br />

“It’s really [about] how you can integrate the<br />

ultrasound device with the body so it can give<br />

you long-term continuous imaging over days<br />

even under dynamic body motion,” Zhao said.<br />

Previous wearable ultrasound devices were<br />

designed to be stretchable and move with the<br />

skin. However, this design sacrificed image<br />

quality and resolution despite the improved<br />

wearability. Moreover, sound transmission is<br />

vital to reach deep organs, such as the heart<br />

or stomach, and accurately image them.<br />

When using traditional ultrasound devices,<br />

clinicians apply a gel layer to prevent air<br />

pockets that can block the transmission of<br />

sound waves through the skin. However,<br />

these gels are not designed for prolonged<br />

use. “The liquid gel, if you put it in contact<br />

with the body, it can potentially cause<br />

acidification in a few hours,”<br />

Zhao explained. Wearable<br />

ultrasound devices have used<br />

hydrogels—a water-rich, goo-like<br />

substance—in the past to solve<br />

30 Yale Scientific Magazine October 2022 www.yalescientific.org


Biomedical Engineering<br />

FEATURE<br />

this problem, but they<br />

get dehydrated and detach<br />

after only a couple of hours.<br />

Other devices use a rubbery<br />

material called an elastomer<br />

to attach the device to the<br />

skin. However, pure elastomer adhesives<br />

dampen sound waves, preventing them from<br />

reaching deep organs.<br />

The beauty of the BAUS device comes from<br />

a newly developed bioadhesive that combines<br />

the adhesion capabilities of an elastomer with<br />

the sound transmission abilities of a hydrogel.<br />

“For the bioadhesive part, we really spent<br />

lots of effort to develop a hydrogel-elastomer<br />

hybrid. It’s very different from existing liquid<br />

hydrogels that can easily flow away,” Zhao<br />

said. The new material consists of a hydrogel<br />

encapsulated by an elastomer to form a soft<br />

solid that can adhere robustly and comfortably<br />

to the skin, doubling as an adhesive and<br />

a gel to improve sound transmission. The<br />

researchers then embedded a thin highperformance<br />

probe in the hydrogel-elastomer<br />

to complete the BAUS.<br />

They tested its performance over fortyeight<br />

hours by imaging the various organs<br />

and tissues of fifteen test subjects. The BAUS<br />

device showed everything from how blood<br />

vessels’ diameter increased as a subject stood<br />

up to how blood flow rate increased after<br />

thirty minutes of exercise to how the stomach<br />

emptied over two hours after a subject drank<br />

a glass of juice. It can also image the heart’s<br />

four chambers and show how they change<br />

in size under continuous body motion.<br />

Furthermore, its success in imaging the<br />

lungs and the diaphragm means that the<br />

BAUS could potentially be used to monitor<br />

respiratory diseases, including COVID-19,<br />

and prevent further complications.<br />

IMAGE COURTESY OF FELICE FRANKEL<br />

The bioadhesive ultrasound device.<br />

IMAGES COURTESY OF WANG ET AL.<br />

A bioadhesive ultrasound device adhered to the skin (left) and being detached from the skin (right).<br />

“I would say it’d be easier for clinicians<br />

and maybe even patients to [use] this. It’s<br />

like [adhering] a bandaid on the skin.<br />

And our lab is currently working to<br />

further simplify this process,” Zhao said.<br />

Traditional handheld ultrasound requires<br />

qualified personnel and can be relatively<br />

expensive. Apart from continuous<br />

imaging, the BAUS device provides a<br />

simplified imaging process that could<br />

eliminate the need for an experienced<br />

operator and possibly even give patients<br />

the option of adhering the device by<br />

themselves. Hence, the BAUS could help<br />

increase the accessibility of ultrasounds.<br />

Clinicians and healthcare professionals<br />

alike are excited about the broad<br />

medical potential of the BAUS device.<br />

Continuous imaging is essential for<br />

monitoring and tracking tumor growth<br />

and for early detection and treatment<br />

of cancer. Diagnoses for conditions<br />

that involve muscles, joints, and<br />

bones often require dynamic tests that<br />

cannot be performed using traditional<br />

ultrasound techniques. Cardiovascular<br />

diseases, which affect the performance<br />

of blood vessels and the heart, can lead<br />

to dangerous heart attacks that require<br />

ultrasound technology for diagnosis. A<br />

wearable ultrasound device could help<br />

alert those at higher risk for heart attacks<br />

of changes in their blood pressure<br />

in time to save lives. Ultimately,<br />

the BAUS opens up a world of<br />

possibilities in diagnostic<br />

practices and<br />

the continuous<br />

monitoring<br />

of patient health.<br />

However, more steps must be taken<br />

before the BAUS device can be widely used<br />

and implemented. The existing device still<br />

needs to plug into a computer that<br />

collects and analyzes data.<br />

Zhao’s team is working on<br />

making a portable wireless<br />

version that can truly<br />

move with a patient and<br />

be used even when<br />

there is no access<br />

to a computer. Zhao<br />

a l s o<br />

describes that while the image<br />

quality of the BAUS probes is superior<br />

to other wearable devices, his team is<br />

still working on obtaining higher image<br />

resolution to match traditional ultrasound<br />

devices. Clinical trials must also be<br />

conducted before FDA approval. “In the<br />

first paper, we only tested healthy people.<br />

Now, we are applying this system to patients<br />

to study various diseases,” Zhao said.<br />

The development of the BAUS device<br />

is only the latest project that Zhao’s team<br />

at MIT has been working on as part of<br />

their mission to advance science and<br />

technology at the interface of humans and<br />

machines. The team’s expertise centers<br />

around materials science, mechanics,<br />

and biotechnology, but they regularly<br />

collaborate with experts in other fields<br />

and engage in intersectional projects.<br />

“We are really focused on addressing<br />

multidisciplinary challenges in health and<br />

sustainability. I believe we are solving some<br />

of the most important questions facing<br />

society, and I hope we can contribute to<br />

their solution,” Zhao said. ■<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 31


FEATURE<br />

Biotechnology<br />

BY RISHA<br />

CHAKRABORTY<br />

ELECTRONIC<br />

SKIN<br />

Our world is being increasingly defined<br />

by a series of ones and zeroes.<br />

From the smallest phone gyroscope<br />

capable of detecting body movement to metal<br />

detectors at the airport to automatic PCR<br />

machines that test for the SARS-COV-2 virus<br />

in a matter of hours, the technology that<br />

acquires and transmits this data has made<br />

human lives much easier. Over the last two<br />

decades, practical artificial intelligence (AI)<br />

usage has led to expanding roles for computers<br />

in detecting danger, predicting scores,<br />

and advising outcomes in fields ranging<br />

from security to medicine—often beyond<br />

the scope of its original creation and with<br />

limited human intervention. Of course, popular<br />

debate and science fiction warns about<br />

how AI may eventually replace humans<br />

across many fields and make human effort<br />

obsolete. However, Wei Gao, a professor of<br />

medical engineering at the California Institute<br />

of Technology, sees the advancement of<br />

AI as an opportunity rather than a threat.<br />

Gao received his bachelor’s degree in mechanical<br />

engineering and his master’s degree<br />

in chemical engineering at the University of<br />

California, San Diego. He completed a postdoctoral<br />

fellowship in electrical engineering<br />

at the University of California, Berkeley. Because<br />

of his diverse educational background,<br />

he pursued the creation of robots imbued<br />

with functionalities beyond traditional ones.<br />

“In our minds, robots are industrial-level, capable<br />

of doing dangerous tasks in agriculture,<br />

defense, and space exploration because they<br />

can move and perform repetitive tasks, but<br />

we are thinking about the future. How can<br />

we build a better robot [by giving it] better<br />

functionalities and making it smarter? How<br />

can we give it more powerful sensing capabilities?”<br />

Gao pondered.<br />

Inspired by human skin’s ability to detect<br />

temperature, touch, texture, and even certain<br />

chemicals, for example, an allergic skin<br />

response after rolling around in the grass,<br />

Gao set out to develop ‘electronic skin.’ In<br />

the past, researchers have developed robots<br />

to detect and respond to physical parameters<br />

such as temperature and pressure.<br />

However, they were unwieldy and impractical—not<br />

much more than a thermometer<br />

on a remote-controllable stick. Moreover,<br />

Gao wanted to diversify the sensors in his<br />

robot so that the electronic skin could have<br />

an even greater range of sensory capabilities<br />

than human skin. In particular, he hoped to<br />

detect infectious pathogens for medical applications,<br />

neurotoxins or bomb debris for<br />

security purposes, and chemical pesticides<br />

for agricultural uses—all harmful or dangerous<br />

for humans to handle.<br />

The main problem was designing a method<br />

to make electronic skin emulate human<br />

skin. Scientists are only beginning to understand<br />

how human 'sensors' such as mechanoreceptors<br />

and thermoreceptors work. In<br />

fact, the 2020 Nobel Prize in Medicine and<br />

Physiology was awarded to two scientists<br />

for discovering the neural mechanisms behind<br />

human sensations. What would be the<br />

technological equivalent of millions of nerve<br />

endings in human skin conferring incredible<br />

sensitivity and a wide range of detecting<br />

abilities, and how could such a system be<br />

built in a reproducible, scalable way?<br />

With the help of colleagues with expertise<br />

in materials science and nano-engineering,<br />

Gao developed electronic skin, which he<br />

called E-skin-H. “My primary inspiration<br />

comes from human skin,” Gao said. Touch<br />

and pressure cause electrical changes that<br />

can then be converted to computer signals.<br />

To mimic the vast nerve network of human<br />

skin, Gao created sensor arrays with microscopic<br />

radii of detection, increasing both the<br />

sensitivity and strength of a signal compared<br />

to using a single large sensor. These properties<br />

are helpful in complex applications like<br />

detecting the presence of a specific chemical<br />

out of a large mixture.<br />

Embedding such minuscule sensor arrays<br />

in a highly flexible matrix is a technically<br />

easier way to create a bridge between sensors<br />

and robots than integrating the existing<br />

large chemical sensors meant for analysis<br />

of dry particles on robots. The flexibility of<br />

the sensor array material enables E-skin-H<br />

to retain its sensing capabilities regardless<br />

of how the actual robotic hand or arm on<br />

which it is mounted moves. Moreover, by<br />

using a hydrogel underneath the e-skin interface,<br />

the robotic skin can test for chemicals<br />

like they are in solution even though<br />

the sensor array is technically in a solid state.<br />

For example, biochemical tests like ELISAs<br />

can detect specific proteins, like those marking<br />

the surfaces of a SARS-COV-2 virus, in<br />

a solution. But now, with the hydrogel, the<br />

sensor array can detect proteins from a solid<br />

surface. Perhaps the most brilliant facet of<br />

Gao’s e-skin is that it can be printed with an<br />

inkjet printer. It requires only a series of nano-material<br />

metal inks such as gold, silver,<br />

and platinum to decorate graphene electrodes<br />

and a 3D-hydrogel printer. The ease<br />

of production vastly increases the scalability,<br />

adaptability, and replaceability of the sensor<br />

32 Yale Scientific Magazine October 2022 www.yalescientific.org


Biotechnology<br />

FEATURE<br />

How robots are gaining<br />

human-like sensing abilities<br />

ART BY CHARLOTTE LEAKEY<br />

arrays. It also decreases production costs,<br />

allowing for the creation of larger sensor arrays<br />

that can be modified to test for various<br />

new compounds.<br />

In his article published in Science Robotics,<br />

Gao built a robot called M-bot, which<br />

used machine learning to learn how human<br />

muscles, specifically hand and arm muscles,<br />

move in response to detecting certain tactile<br />

or chemical threats. Gao evaluated E-skin-H<br />

to see how the skin’s sensing capabilities<br />

could assist robots in making AI-based decisions<br />

the same way a human would. He concluded<br />

that M-bot could be used to detect<br />

compounds in a contaminated environment<br />

and track the source of trace amounts of<br />

hazardous compounds. In an early demonstration,<br />

M-bot tracked a nerve agent leak in<br />

an open field by detecting a gradient of the<br />

compound across the sensor array. By tracking<br />

the location of the highest concentration<br />

www.yalescientific.org<br />

of the compound, the AI algorithm within<br />

M-bot was able to signal to the motors<br />

within the robot arms and fingers to extend<br />

towards the location of the highest concentration<br />

to grasp objects and collect samples.<br />

“It was pretty impressive since it was fully<br />

automatic,” Gao said.<br />

Gao sees E-skin-H being used in medical<br />

and defense applications within the next five<br />

to ten years. “You don’t want to send a human<br />

into a danger zone to detect explosives<br />

or biohazards. Electronic skin can be used in<br />

military, environmental, and agricultural applications.<br />

We just have to make the robots<br />

[that use e-skin] smarter and more automatic—with<br />

the help of materials science, chemistry,<br />

and data processing.” Gao said.<br />

With the foreseeable future wrought by<br />

AI applications and robotic sensing technologies,<br />

Gao encourages anyone interested in<br />

robotics and technology to nurture this interest<br />

by identifying a problem, understanding<br />

where there is a gap in current technologies<br />

that attempt to address this problem,<br />

and imagining potential solutions. “Becoming<br />

involved in engineering or robotics is not<br />

a problem about technology, but more about<br />

developing a pattern of thinking. Trying<br />

competitions like FIRST Lego League and<br />

VEX Robotics inspires young students to<br />

imagine the fullest potential of robots,” Gao<br />

said. With this principle in mind, Gao combines<br />

chemical, medical, electrical, and mechanical<br />

principles to create solutions to the<br />

problems that fascinate him. As he expands<br />

his projects, from robots that use electronic<br />

skin in defense applications to nano-robots<br />

that deliver drugs to cells in the body, Gao<br />

is convinced of their increasing necessity in<br />

the future. “I’m excited to see how we interact<br />

with robots in our daily lives going forward,”<br />

Gao concluded. ■<br />

October 2022 Yale Scientific Magazine 33


UNDERGRADUATE PROFILE<br />

Shervin Dehmoubed—sophomore at Yale and stellar<br />

tennis player—is also a CEO, starting his entrepreneurial<br />

journey when he was just fifteen. He launched a children’s<br />

toy company specializing in products for kids diagnosed with<br />

ADHD/ADD, making a six-figure revenue within the first three<br />

years. This success fueled his following projects, Pik ‘le’ Ball, a<br />

pickleball accessory and clothing line, and a software company<br />

that built iOS apps for health and fitness. These experiences gave<br />

him the unique perspective and required expertise to launch his<br />

latest and most successful company, EcoPackables.<br />

Dehmoubed was shocked to discover how much plastic waste<br />

even a small brand could produce when working on Pik ‘le’ Ball.<br />

Thus, he launched a sustainable packaging company that sells<br />

packaging films made from recycled or compostable materials,<br />

aiming to find solutions to promote sustainability within the private<br />

sector. “This was during Covid, and e-commerce was booming, so<br />

I decided I wanted to do something about this,” Dehmoubed said.<br />

The key technology is a compostable film made from a<br />

blend of polylactic acid (PLA) and a bio-based polymer<br />

(PBAT). These films could eliminate “greenwashing” when an<br />

organization spends more time and money marketing itself as<br />

environmentally friendly than minimizing its environmental<br />

impact. PLA and PBAT are already used in biodegradable<br />

plastics such as waste bags. However, to make the films more<br />

suitable for packaging, Dehmoubed made them thicker and<br />

added certain proportions of different renewable elements<br />

to make them more sustainable. Now, their compostable<br />

film, called D42, is certified to degrade in home compost<br />

environments within one-hundred eighty days and industrial<br />

compost environments within ninety days. Dehmoubed claims<br />

that EcoPackables is the most sustainable packaging company<br />

because they have the highest proportion of renewable<br />

resources (organic materials) to PBAT while still breaking<br />

down into organic biomass, water, and CO 2<br />

, leaving behind<br />

zero plastic waste. “I’ve been very passionate about reducing<br />

BY SHERRY WANG<br />

plastic waste and stopping climate change. Specifically, how<br />

you can reduce your carbon footprints based on how you<br />

produce packaging material and handle proper end-of-life<br />

disposal,” Dehmoubed said.<br />

Historically, the packaging industry has been one of the<br />

most commoditized—no company owns more than five<br />

percent of the market share. For a younger entrepreneur like<br />

Dehmoubed, building a brand in such an environment was<br />

challenging. Thus, he built a brand focused on sustainability<br />

instead of being a direct competitor of packaging companies.<br />

He was not interested in cutting costs or taking shortcuts<br />

to increase the bottom line, or the company’s net profit,<br />

but rather wanted to hit the triple bottom line: good for the<br />

customer, good for the planet, and good for the company. His<br />

biggest challenge was selling his vision to traditionally archaic<br />

buyers hyper-focused on net profits. However, by convincing<br />

companies to look towards the younger generations for future<br />

sustainable operations, Ecopackables is being used by brands<br />

such as Ivory Ella, Beats, and Bud Light.<br />

Dehmoubed envisions that EcoPackables will become a<br />

globally recognized brand for its sustainable practices. He<br />

hopes to become a one-stop shop for brand-oriented companies<br />

looking to clean up their operations. Currently, they have two<br />

more products in the works: food-safe packaging developed<br />

using post-consumer recycled content and curbside recyclable<br />

Ocea brand polythene bags. The thin Ocea plastic bags are<br />

made from Forest Stewardship Council certified mixed paper,<br />

ensuring that products come from responsibly managed forests<br />

that provide environmental, social, and economic benefits.<br />

Ocea launched their product earlier this year to eliminate<br />

plastic from accumulating in our oceans. “Packaging is<br />

extremely important because it’s the first part of your product<br />

the customer interacts with. And we know how important first<br />

impressions are,” Dehmoubed said. ■<br />

SHERVIN<br />

DEHMOUBED<br />

IMAGE COURTESY OF SHERVIN DEHMOUBED<br />

34 Yale Scientific Magazine October 2022 www.yalescientific.org


PHOTO COURTESY OF ALEX DONG<br />

TYLER MYERS<br />

Organic Chemistry is one of the most notoriously difficult<br />

classes at Yale. Pre-med hopefuls and chemistry whizzes<br />

alike spend long nights learning reaction mechanisms<br />

and drawing energy-level diagrams. But last year, one Yale teaching<br />

fellow (TF) went above and beyond by making Organic Chemistry<br />

a much more manageable, even enjoyable experience. Tyler Myers,<br />

a Chemistry Ph.D. candidate in the Miller Lab, is making an impact<br />

on his students through his palpable passion for chemistry.<br />

Myers discovered his love for the subject in high school, spending<br />

three years learning chemistry with a phenomenal teacher named Ms.<br />

Bell. His interest brought him to the University of Wyoming, where he<br />

was a chemistry major. After one of his general chemistry exams, his<br />

professor, David Anderson, passed him a note which read: Big-T, you<br />

should talk to me about research! “Research was completely foreign to<br />

me — but it was one of the best experiences I’ve ever had,” Myers said.<br />

In Anderson’s lab, Myers synthesized complexes to help construct<br />

hydrogen-based fuel cells. After taking Organic Chemistry with<br />

Robert Corcoran and loving it, Myers switched to Michael Taylor’s lab,<br />

where he worked on selective modifications of the amino acid residue<br />

tryptophan in peptides and proteins.<br />

The next stop for Myers was Yale—as a graduate student in Scott<br />

Miller’s lab. He remembers sitting in the airport before flying to New<br />

Haven for an admitted students visit when he saw that the Miller<br />

Lab had recently published a paper on the selective modification<br />

of Geldanamycin, a biologically active natural product. “Late-stage<br />

diversification of natural products was fascinating to me,” Myers<br />

said. While at Yale, he attended a meeting with Miller and heard<br />

more about his research. “All I remember was that my chest got<br />

really fuzzy,” Myers said, “I knew that this was the place for me.”<br />

Now, Myers researches asymmetric catalysis—working to<br />

preferentially synthesize one enantiomer of a chemical compound<br />

over the other. Enantiomers are chemical structures that are<br />

non-superimposable mirror images of each other, and it can<br />

be challenging to selectively synthesize one enantiomer of a<br />

compound. “The most common example we use is our hands,”<br />

www.yalescientific.org<br />

GRADUATE PROFILE<br />

BY SOPHIA BURICK<br />

Myers said, “Just how you can write better with one hand, drugs<br />

experience a very similar phenomenon with biological activity,<br />

where one enantiomer of a drug is often more biologically active<br />

than the other.” Myers, now a third-year Ph.D. candidate, recently<br />

received the prestigious NSF Graduate Research Fellowship for his<br />

potential to contribute to the field of chemistry and broaden access<br />

to science and research.<br />

Myers is equally excellent in his work as a teaching fellow. As<br />

students in First-year Organic Chemistry, CHEM 174, last fall will tell<br />

you, Myers was a saving grace. He has loved teaching since he was<br />

an undergraduate, working as a tutor, a teaching assistant, and even<br />

traveling across Wyoming to deliver engaging scientific demonstrations<br />

to students to encourage them to pursue a STEM education.<br />

“I thought being a teaching fellow would be great practice since I<br />

want to go into academia, and it was another opportunity to interact<br />

with students. It was really fun. I met some phenomenal students that<br />

are really passionate,” Myers said. His work as a TF won him a Yale<br />

Prize Teaching Fellowship—one of the highest honors a graduate<br />

student at Yale can receive. He was nominated for the award by the<br />

many appreciative students in CHEM 174. “Tyler was a great TF and<br />

also such a great mentor. He encouraged me to pursue chemistry<br />

research and was a friendly face this summer when I was in a lab<br />

near his,” said Lizbeth Lozano, one of Myers’s past students.<br />

“I got to read the reviews that students wrote,” Myers said,<br />

“I remember leaving work just ecstatic.” Knowing his students<br />

truly enjoyed his work as a teaching fellow was the most<br />

rewarding thing for Myers.<br />

After graduating, Myers hopes to become a professor at a<br />

primarily undergraduate institution. His goal is to dismantle the<br />

reputation of organic chemistry as an intimidating, inaccessible<br />

science and help others appreciate the beauty and potential it holds.<br />

“I am fortunate to have so many great opportunities and supportive<br />

people in my life,” Myers said, “I think teaching at a primarily<br />

undergraduate institution would be an excellent opportunity to<br />

give back to the community.” ■<br />

October 2022 Yale Scientific Magazine 35


BY<br />

KELLY<br />

CHEN<br />

THE WORLDS WE<br />

DON'T REALIZE<br />

Close your eyes and take a deep breath. Imagine that you<br />

SCIENCE I N<br />

can suddenly hear the hum of two insects communicating,<br />

smell every scent trail, or even feel the Earth’s magnetic<br />

field. Supersonic hearing, enhanced smell, or an internal sense<br />

of direction—traits we think of as superpowers have long been<br />

possessed by animals.<br />

IMAGE COURTESY OF FLICKR<br />

Join Ed Yong in his book An Immense World: How Animal Senses<br />

Reveal the Hidden Realms Around Us as he takes you on journeys<br />

you may literally never be able to see. For example, most animals<br />

can see ultraviolet (UV) light. With UV vision, rodents are better<br />

able to see birds in the sky, fish can easily identify plankton in<br />

water, and reindeer can comfortably find mosses and lichens to<br />

eat, all because of UV light detection. Yong’s curiosity will pull<br />

you in as he shows you discoveries made by scientists over the<br />

years, as well as his own encounters with the animal world; his<br />

easy-going language yet detailed imagery transports you right to<br />

the middle of other animals’ worlds while also teaching you about<br />

the science behind it all.<br />

As you dive into the book, you’ll learn about different Umwelts—a<br />

German term popularized by the Baltic-German zoologist Jakob<br />

von Uexküll—defined as “the part of [the animal’s] surroundings<br />

that an animal can sense and experience—its perceptual world.”<br />

Yong writes, “Nothing can sense everything, and nothing needs<br />

to.” From hearing about everything from snakes and elephants<br />

to mosquitoes and dogs, you'll realize that the sensory skill sets<br />

between animals are widely different, and for good reason. If we<br />

were to sense everything, Yong said, “[we] would be overwhelmed<br />

by the flood of stimuli, most of which would be irrelevant.” The<br />

things we perceive are special to our Umwelt with unnecessary<br />

information filtered from our senses as we evolve.<br />

And though we might wish for some of the senses other animals<br />

possess, human senses have advantages. For example, humans are<br />

one of the most visually adept species. While we may not be able<br />

to track scents with our noses, we are one of the best species at<br />

differentiating between scents.<br />

However, most of all, we have the technology to explore the<br />

Umwelts of the world. “This ability to dip into other Umwelten<br />

is our greatest sensory skill,” says Yong. Though we may never<br />

be able to truly experience the Umwelts of other animals, our<br />

growing knowledge enables us to understand and choose to see<br />

the world from realms that are not our own. By reading Yong’s<br />

engrossing novel, the world as we know it suddenly becomes<br />

much more vibrant. As Yong puts it, “It is not a blessing we<br />

have earned, but it is one we must cherish." ■<br />

36 Yale Scientific Magazine October 2022 www.yalescientific.org


THE SKY IS FOR<br />

EVERYONE<br />

BY<br />

CELINA ZHAO<br />

The Sky is for Everyone: Women Astronomers in<br />

Their Own Words is a newly published collection of<br />

autobiographical excerpts from renowned women<br />

in astronomy, detailing their challenges and triumphs in this<br />

historically male-dominated field. It features two prominent<br />

Yale astrophysicists: Meg Urry, Israel Munson Professor of<br />

Physics and Director of the Yale Center for Astronomy and<br />

Astrophysics, and Priyamvada Natarajan, Joseph C. and Sofia<br />

C. Futon Professor of Astronomy and Physics and Director of<br />

Yale’s Franke Program in Science and the Humanities.<br />

In her chapter titled “The Gentlemen and Me,” Dr. Urry<br />

speaks about the few times this field felt unwelcoming. As one<br />

of two women in her graduate astronomy program, she was<br />

never invited to weekly study sessions and was cruelly pranked<br />

with a Playgirl magazine by her male classmates. Dr. Natarajan’s<br />

chapter focuses on her background, work, and personal journey<br />

through academia and how her love for science developed.<br />

What was your reaction when asked to contribute to this book?<br />

Urry: I actually told them I couldn’t do it at first, but then<br />

shortly after Covid hit, while I was sitting at home, I was<br />

reflecting about where I was and how I’d gotten there and<br />

thought, “Wow, this is really something I’d like to do.”<br />

Natarajan: I was very honored but also kind of surprised<br />

and intrigued because they made it explicit that they wanted<br />

something about my personal experience and journey, and I didn’t<br />

think that would be something of interest.<br />

What was your writing process?<br />

Urry: In two days, I’d actually written eighteen thousand<br />

words while the editors had only wanted three thousand. So, I<br />

spent time cutting it down—the whole process actually inspired<br />

T H E<br />

SPOTLIGHT<br />

me to write and tell more of my stories.<br />

Natarajan: I like writing, and I do a lot of different kinds of it,<br />

but it was very challenging because I don’t ever write explicitly<br />

about myself… It was also interesting to go over my path and<br />

look back—I tend not to reminisce much as there is so much<br />

more science that I want to do.<br />

Why do you think these stories are important?<br />

Urry: Sadly, I think it’s because there hasn’t been enough<br />

change. When I came to Yale in 2001, I was the only woman in<br />

the physics department faculty. Now we have six so there’s been<br />

Professor Urry next to her book.<br />

PHOTO COURTESY OF JENNY WONG<br />

a positive change there, but I still hear younger women talking<br />

about similar experiences [that I talk about in the book].<br />

Natarajan: It was quite amazing to hear about how others<br />

had found their way into academia and what motivates them.<br />

It’s so important for people to see that there’s no one way to<br />

be a scientist…. But what’s really sobering is that you can see<br />

that a lot of women have had more challenging paths through<br />

intellectual life [than men], and it’s important to see all the<br />

different kinds of struggles and how they persevered for the<br />

love of the subject. ■<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 37


IMAGE COURTESY OF NIH PHOTO LIBRARY<br />

COUNTERPOINT<br />

A New Way of<br />

Detecting Alzheimer’s<br />

BY ABIGAIL JOLTEUS<br />

Imagine progressively losing the memories you<br />

cherish deeply, eventually no longer being able<br />

to learn new things, read and write with ease,<br />

or recognize loved ones. People with Alzheimer’s, a<br />

form of dementia, lead lives with these worsening<br />

symptoms. With no cure and a short lifespan after<br />

diagnosis, Alzheimer’s is a devastating, progressive<br />

neurological disorder that affects memory, behavior,<br />

motor skills and thought processes.<br />

Initially, scientists could only diagnose Alzheimer’s<br />

by performing an autopsy after death. Since then,<br />

many advances have been made. Clinicians can now<br />

detect early signs using remarkable technology, such<br />

as positron emission tomography (PET), a type of diagnostic<br />

technology used to show the metabolic activity<br />

of the brain, and various tests on cerebrospinal fluid<br />

(CSF)—the clear, watery fluid around the spinal cord<br />

and brain. Some hallmarks include decreased glucose<br />

uptake and the accumulation of beta-amyloid plaques,<br />

proteins that aggregate between neurons and disrupt<br />

their normal function. However, these methods can be<br />

quite invasive. For example, a PET scan requires the<br />

injection of radioactive material into the bloodstream,<br />

and the extraction of CSF involves inserting a needle<br />

into someone’s back. These diagnostic tools are uncomfortable<br />

and expensive, making these procedures<br />

inaccessible to many people.<br />

Alzheimer’s is characterized by plaques of beta-amyloid<br />

in the brain, yet new evidence suggests these<br />

plaques also accumulate in the retina. The retina, which<br />

is closely related to brain tissue, is routinely examined<br />

to detect eye diseases through a process called fundus<br />

photography or digital retinal imaging. A similar technique<br />

may soon provide a non-invasive and cost-efficient<br />

method of identifying early signs of Alzheimer’s.<br />

Robert Vince, Swati More, and their colleagues at<br />

the University of Minnesota discovered a technique<br />

called hyperspectral imaging. They used the technique<br />

to detect clumps of beta-amyloid in mouse retinas<br />

at the early stages of the disease. In hyperspectral<br />

imaging, standard eye examination equipment, like<br />

an autorefractor, is combined with a hyperspectral<br />

camera — a special camera that captures light from<br />

IMAGE COURTESY OF EMMAGARCIAMILLER<br />

across the electromagnetic spectrum.<br />

Then, artificial intelligence compares<br />

the data-rich images with other images<br />

with similar physical properties associated<br />

with Alzheimer’s disease.<br />

Clinical trials are currently underway<br />

across North America to test the efficacy of this technique,<br />

and there have already been promising results.<br />

In a cohort of 108 participants who were either at risk<br />

of Alzheimer’s or already had preclinical Alzheimer’s,<br />

the technique correctly identified people with beta-amyloid<br />

plaques in their brains eighty-six percent<br />

of the time. PET scans and CSF results validated these<br />

retinal screening tests. They also observed beta-amyloid<br />

clumps in the brain at later stages, suggesting that<br />

the presence of beta-amyloid plaques in<br />

the retina may also be an early detection<br />

marker in humans.<br />

Though these results are promising,<br />

more studies with diverse participants<br />

and larger cohorts are needed before phy- sicians<br />

can use this technique as an official diagnostic tool.<br />

Moreover, some researchers have noted that amyloids<br />

can be present in the retinas of people that do<br />

not develop signs of cognitive decline.<br />

While there are issues with this technique that<br />

need to be resolved, early detection of<br />

Alzheimer’s using retinal imaging has the<br />

potential to become a widely-used diagnostic<br />

tool. Other retinal signs may<br />

help with the early detection of Alzheimer’s,<br />

including retinal thickness and changes<br />

in blood vessels. A longitudinal trial called Atlas of<br />

Retinal Imaging in Alzheimer’s Study (ARIAS) is<br />

examining these retina-based biomarkers in hopes<br />

of improving the early diagnosis of Alzheimer’s.<br />

This project is still in the recruiting phase, but if<br />

proven successful, researchers may seek to develop<br />

more types of retinal-based tests. Earlier treatment<br />

of Alzheimer’s may alleviate many<br />

symptoms and help scientists better understand<br />

the pathogenesis of this condition<br />

with the hope of developing a cure. ■<br />

38 Yale Scientific Magazine October 2022 www.yalescientific.org


HIDDEN<br />

HISTORIES<br />

BESTIE BLOUNT GRIFFIN<br />

BY ILORA ROY<br />

ART BY NOORA SAID<br />

Bessie Blount Griffin was an inventor, nurse, physical<br />

therapist, forensic handwriting and document analyst,<br />

and avid public speaker. However, unlike many in her<br />

field, she was Black, left-handed, and a woman. Blount was born<br />

on November 24, 1914, in Hickory, now Chesapeake, Virginia,<br />

to parents George Woodard and Mary Elizabeth Griffin. In<br />

elementary school, her teachers constantly reprimanded her<br />

for writing with her left hand. After having her knuckles<br />

rapped countless times, Blount protested: if it was wrong for<br />

her to write with her left hand, then it must also be wrong to<br />

write with her right! She then taught herself how to write with<br />

her teeth and toes in response to her teacher’s disapproval.<br />

Blount studied nursing at Keney Memorial Hospital and<br />

physical therapy at Union Junior College and Panzer College<br />

of Physical Education and Hygiene. After obtaining her degree<br />

from Union, Blount became a licensed physiotherapist at the<br />

Bronx Hospital in New York, where she helped World War<br />

II veterans with amputated limbs. She was not your average<br />

nurse. In addition to supporting amputee patients in recovering<br />

their balance and mobility, she also helped them reclaim their<br />

independence. Blount took a page out of her own book and<br />

taught the veterans how to write with their teeth and toes.<br />

“You’re not crippled, only crippled in your mind,” she said.<br />

She continued to look for ways to give veterans autonomy<br />

over their bodies, for example, inventing a device called the<br />

Invalid Feeder to help. Patients would bite down on a tube that<br />

would activate a motor, and food would dispense through a<br />

mouthpiece in the shape of a spoon. The device shuts off after<br />

each cycle to ensure the patient would not choke. While Blount<br />

continued to work as a nurse during the day, she would work<br />

late hours in the night from 1:00 AM to 4:00 AM building her<br />

instruments. Blount did not have a degree in engineering, yet<br />

she was able to construct ingenious devices because of her<br />

passion for helping patients.<br />

Continuing to invent, Blount created more apparatuses, such<br />

as disposable kidney-shaped basins to dispose of bodily waste<br />

and the “portable receptacle support,” similar to the “invalid<br />

feeder,” with the addition of a neck brace with a bowl. The<br />

latter received a patent under her name on April 24, 1951,<br />

making Blount one of the first officially recognized inventors<br />

in physical therapy. She had many other accomplishments<br />

from becoming a handwriting analyst for several police<br />

departments— including Scotland Yard in England, where she<br />

was the first Black American woman to have trained there—to<br />

starting her own consulting business in her hometown.<br />

However, Blount’s accomplishments did not come without<br />

challenges. After inventing the “invalid feeder,” she wanted to<br />

bring relief to others around the country, but the US military<br />

refused to pay Blount a fair amount. She also tried to sell her<br />

devices to the American Veterans Association, but they did not<br />

want to support her due to her race and gender. Blount wanted<br />

to prove that her inventions<br />

themselves were impressive<br />

and did not want to tie<br />

her inventions to her<br />

identity as a Black<br />

woman. She was<br />

not driven<br />

by financial<br />

motivation<br />

but rather by<br />

the idea of<br />

helping society<br />

progress<br />

through her<br />

innovations.<br />

Even after being<br />

turned down<br />

by many different<br />

organizations, she<br />

eventually donated the<br />

“invalid feeder” to France,<br />

where the French<br />

used it in military<br />

hospitals. Belgium<br />

also bought<br />

her disposable<br />

basins. ■<br />

www.yalescientific.org<br />

October 2022 Yale Scientific Magazine 39


AD_Yale_SC_ENG_half_FALL_10_19qxp.qxp_8 10/7/19 12:05 PM Page 1<br />

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