YSM Issue 92.1

Yale Scientific 

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MARCH 2019 VOL. 92 NO. 1 | $6.99 

12 

PREYING ON 

POLLUTANTS 

EVADING THE 

IMMUNE SYSTEM15 

SEQUENCING 

HALF A CELL18 

LEARNING TO 

REMEMBER20 

ESSENTIAL 

ERRORS22

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TABLE OF CONTENTS 

VOL. 92 ISSUE NO. 1 

More articles available online at www.yalescientific.org. 

12 

15 

18 

20 

22 

PREYING ON POLLUTANTS 

COVER ARTICLE: A collaboration between researchers at Yale and Peking University has led to a nanocoagulant that mimics 

the sea anemone Actinia. It can remove multiple types of contaminants simultaneously and outperforms conventional 

coagulants in multiple classes, thereby offering a cost-effective solution to water purification challenges. 

EVADING THE IMMUNE SYSTEM 

With the discovery of the immunological role of fibrinogen-like protein 1 (FGL-1) and its potential to aid the growth of cancerous 

cells, Yale researchers have solved a mystery that has baffled cancer immunologists for years. 

SEQUENCING HALF A CELL 

Researchers at Yale have developed a method to sequence both mRNA and microRNA in a single cell, leading to new insights into 

non-genetic variability at the single-cell level. 

LEARNING TO REMEMBER 

When do we start remembering? A new study conducted at the Yale School of Medicine probes this question and reveals 

the developmental timeline of memory formation. 

ESSENTIAL ERRORS 

The accurate translation of genetic material into proteins is essential to life. For parasitic bacteria with mutated genomes, 

however, errors in translation are important for their life cycles and could be therapeutic targets, Yale researchers report. 

www.yalescientific.org 

March 2019 

Yale Scientific Magazine 

3

CAN 

WE ENGI- 

NEER SPICY 

TOMATOES? 

By Serena Thaw-Poon 

Chili peppers, often conjuring both tears of pain and 

pleasure, serve an important role in the culinary exploits of 

many cultures. Less well known, however, are the medicinal 

properties of the compound responsible for the distinct heat 

of chilis. Peppers make a molecule called capsaicin, which has 

anti-inflammatory and weight-loss properties. But what if other 

plants could be modified to produce capsaicin as well? Could we 

make spicy tomatoes? Augustin Zsögön and his team have recently 

discovered genes in tomatoes that encode for capsaicin, suggesting 

that the “spicy tomato” might become a reality. Not only 

would chefs reap the benefits of a culinary marvel, but scientists 

would also have an easier time producing capsaicin to research as 

tomatoes are easier to breed and cultivate than typical Capsicum 

plants. The process of genetically engineering tomatoes, however, 

presents certain challenges. Many cellular components combine 

forces to make the process possible. “Enzymes that are acting in 

the mitochondrion, cytosol, and chloroplast all need to work 

together in sequence,” Zsögön said. Consequently, the production 

of capsaicin involves the manipulation of multiple 

genes and an understanding of how each gene affects the 

overall pathway. Zsögön makes it clear that any commercial 

opportunities would be unintentional, though 

welcome, consequences of his team’s research. “We 

don’t really care about the money, we just really 

like the ideas and get carried away,” he said, 

laughing. Whether for monetary or gastronomical 

purposes, spicy tomatoes 

are sure to appease everyone’s 

appetite. 

Q&A 

. 

CAN TETRIS 

HELP TREAT 

PTSD? 

By Nadean Alnajjar 

Tetris is the best-selling videogame of all time, but 

what if this simple computer game could relieve symptoms 

of an even more prevalent psychiatric disorder? Professor 

Henrik Kessler and Aram Kehyayan from Ruhr-Universität 

Bochum in Germany studied possible links between 

Tetris and post-traumatic stress disorder (PTSD), an anxiety 

disorder induced by stressful, recurrent memories called 

intrusions. “Our study is the first worldwide study to apply this 

Tetris paradigm in real patients with complex PTSD,” Kessler 

said. His study involved twenty patients undergoing a six-toeight-week 

period of regular inpatient treatment. The treatment 

involved playing Tetris after writing about an intrusion. Sixteen 

of the twenty patients responded well to the treatment–reporting 

a sixty-four percent decrease in intrusions on average. Further 

studies with more patients and better controls are now under way 

to replicate these results. PTSD intrusions use visuospatial regions 

of the brain, which are also activated while playing Tetris. 

“You supposedly need the same working memory resources 

and capacity that an intrusion would require,” Kessler said. 

“Tetris could lock the processing of intrusions.” Another 

theory proposes that if you reactivate an old memory, it 

becomes vulnerable, and interference through Tetris can 

be performed to weaken the memory. While professional 

treatment is available for PTSD, few people 

utilize it. “The implications of this research are 

huge because this would mean that people 

who had traumatic experiences could 

mend their intrusions by themselves 

without needing professional 

help,” Kessler said. 

4 Yale Scientific Magazine March 2019 www.yalescientific.org

SPIRIT OF CREATIVITY 

Great scientific discoveries begin with a pinch of curiosity and a dash of creativity. Our 

world faces complex problems which require scientists to work together to compose outof-the-box 

solutions. This issue features the work of incredible teams of investigators who 

have pushed the limits of human understanding of life in the universe (pg. 28), the immune 

system (pg. 15), memory formation (pg. 18), and Earth’s old supercontinents (pg. 34). 

Employing unique approaches to solve intricate problems, researchers have grown 

artificial brains from stem cells to better understand neurological disorders (pg. 10), 

developed a method to sequence two types of RNA in the same cell to learn how they 

regulate each other (pg. 22), and designed microscopes mounted on top of the heads 

of mice to collect real-time data on hundreds of thousands of neurons (pg. 35). 

As the human population explodes, and clean, drinkable water becomes less abundant, 

scientists are looking to nature for solutions. In our cover article, researchers 

have designed a water purification technology inspired from the feeding process of 

a sea anemone known as the “flower of the sea” (pg. 12). Based on the principles 

of coagulation, this system could lead to a more 

THE 

cost-effective approach to making cleaner water. 

Researchers have also sequenced the genome 

of a giant tortoise named Lonesome George, 

whose death at age 100 marked the last of his 

kind (pg. 8). Not only has Lonesome George’s 

venerable story inspired new conservation efforts 

in the Galapagos, but his genome might 

EDITORalso 

reveal the secrets to living a long life. 

All of us want to live long, full lives, but equally 

important is ensuring our quality of life doesn’t 

decline as we age. One study explains how a 

promising new compound restores memories and 

neural connections in the brains of mice afflicted 

with Alzheimer’s disease (pg. 10). 

With a new year comes a new masthead. Each 

IN-CHIEF 

year we grow as a community of writers, artists, 

and designers. We are excited to continue the 

work of our predecessors in celebrating compelling, 

new research being done at Yale and 

around the world. The stories we have chosen 

to share this issue have the potential to lead to 

a brighter future for our planet, our health, and 

SPEAKS 

our well-being. One of our goals is to build a 

conversation surrounding this research so that, 

one day, these visions become reality. 

William Burns, Editor-in-Chief 

ABOUT THE ART 

The cover art for this issue is inspired by the 

incredible breakthrough in water purification 

technology, modeling the molecular “tentacle” 

nano-coagulants of a novel system after 

a beautiful organism: the sea anemone. It’s 

an elegant and inspiring solution, reminding 

us that we need not look farther than natural 

forms to develop solutions. 

Ivory Fu, Arts Editor 

MASTHEAD 

MARCH 2019 VOL. 92 NO. 1 

EDITORIAL BOARD 

Editor-in-Chief 

Managing Editors 

News Editor 

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OUTREACH 

Synapse Presidents 

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Social Media Coordinator 

Outreach Coordinators 

STAFF 

Sophia Sanchez-Maes 

Ameera Billings 

Rami Rajjoub 

Viola Lee 

Miriam Ross 

James Han 

Ashwin Chetty 

Megan He 

Isaac Wendler 

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ADVISORY BOARD 

Priyamvada Natarajan 

Sandy Chang 

Kurt Zilm, Chair 

Fred Volkmar 

Stanley Eisenstat 

James Duncan 

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Jakub Szefer 

Werner Wolf 

John Wettlaufer 

William Summers 

Scott Strobel 

Robert Bazell 

Craig Crews 

Ayaska Fernando 

Robert Cordova 

Serena Thaw-Poon 

Nadean Alnajjar 

Katie Schlick 

Khue Mai Tran 

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William Burns 

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Andrea Ouyang 

Christie Yu 

Carli Roush 

Astronomy 

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Child Study Center 

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SELECTING 

FOR CANCER 

Using evolution to explain the 

spread of cancer 

BY AMEERA BILLINGS 

In 2018, the 

International Agency for 

Research on Cancer estimated 

seventeen million new cancer diagnoses 

and 9.5 million cancer-related deaths worldwide. 

Though the numbers are grim, researchers have made 

great strides in explaining what causes and promotes cancer 

through an unexpected lens: evolution. 

The Townsend Lab at the Yale School of Public Health has 

developed a model to predict the evolutionary progression of 

cancerous cells. Now, we can quantify the relative importance 

of different gene mutations in stimulating cancer growth–the 

so-called ‘cancer effect size’ of a gene. By applying evolutionary 

principles, scientists can help analyze what mutations are driven 

by natural selection in a cancer lineage. “Selection is what drives 

[cancer] once you get a mutation…[causing cells to] replicate 

more,” explained Professor Jeffrey Townsend. 

Townsend and his team were able to calculate the mutation 

rate of cancer cells using tumor DNA sequencing. While some 

mutations may actually lead to cancer, others may have just 

happened to occur in those tumors. “If we see more [mutations] 

than expected by random mutation, then…it was more likely 

to lead to a tumor when you had those mutations in that gene,” 

Townsend said. 

What does this mean for the future of cancer medicine? “The 

cure for various cancers will be therapies that manage to corner 

all of the evolutionary avenues of an evolving tumor and make 

it impossible for it to find a new way to grow,” Townsend said. 

Being able to determine the cancer effect size of gene mutations 

will provide insight into the development of cancer cells, and 

thus, improve treatments for cancer patients in the future. 

Paleontology has long been regarded as the domain of dinosaur 

bones, teeth, and shells. During fossilization, these hard, 

organic scaffolds behave like a rough cast, providing structure 

for the assembly of minerals that will endure after the organics 

degrade. In this paradigm, soft tissues degrade too quickly 

for fossilization timescales, but perplexingly, structures which 

morphologically resemble them are common. 

A team led by Yale graduate student Jasmina Wiemann investigated 

the nature of these structures using a sample of vertebrate 

fossils from the Peabody Museum of Natural History 

collection. The researchers removed hard material from the 

fossils in a process called decalcification to isolate potential 

organic matter. Curiously, all the organic samples were brown 

in color, suggesting they had a common chemical composition. 

To explore this further, the team took fresh tissues rich 

in protein and subjected them to accelerated conditions for 

fossilization. Remarkably, the transformed tissues exhibited 

a brown color and composition reminiscent of the Peabody 

specimens. These findings suggest that the organic proteins 

in the Peabody specimens survived and metamorphized into 

a more stable, discolored polymer, visible to the unaided eye 

as the dark tinge on some fossils. The study shows that not 

only are organic structures, like cells and even organelles, preserved, 

but also that their preservation is surprisingly common 

in fossils formed under oxidative conditions. 

Scientists often use DNA testing to determine how living 

species are related, but DNA, which degrades easily, does not 

survive long in fossils. For long-extinct species, preserved 

proteins could be the next widely-used bio-informed 

molecule to more accurately 

reconstruct the tree of life. 

DINOSAUR 

SECRETS 

Preserved proteins reveal a 

more accurate tree of life 

BY SOPHIA S´ANCHEZ-MAES 

6 Yale Scientific Magazine March 2019

We are all familiar with the sensation of pain, but have 

you ever wondered why some people experience pain more 

vividly than others? For years, perplexed researchers have 

documented individual differences in pain tolerance to no 

avail. In a paper recently published in the Journal of Neuroscience, 

Malgorzata Mis, a postdoctoral associate in the 

Department of Neurology at Yale University, working with 

a team of researchers from the Yale School of Medicine 

and Veterans Affairs Connecticut Healthcare System, has 

taken the first steps towards identifying the genes involved 

in pain perception. 

The researchers analyzed a mother and son with inherited 

erythromelalgia, a disease caused by a mutation 

within a gene that kindles pain and burning sensations 

when expressed in the nervous system. Despite having 

the same mutation, the mother and son reported different 

levels of pains in a previous study. “The son reported 

over one-hundred nightly awakenings due to his mutation 

within a fifteen-day period, while the mother reported 

only one awakening,” Mis said. 

To further study this disparity, the research team grew 

sensory neurons derived from the mother’s and son’s 

stem cells in a laboratory dish. Using whole exome sequencing 

coupled with computer-aided dynamic clamp, 

a method that merges the visualization of live neurons 

with computational models, the researchers were able to 

identify a variation in the mother’s potassium channel 

encoded by the KCNQ2 gene, which ultimately led to 

her resilience to pain. The team is optimistic about 

implementing these new genetic methods 

that will guide them toward better 

treatments for pain. 

RETHINKING 

PAIN 

Uncovering the genes for 

pain resilience 

BY RAMI RAJJOUB 

THE BRAIN 

ON A DISH 

Organoids in the Age of 

Big Data 

BY VIOLA KYOUNG A LEE 

Yale neurobiologists 

are growing brain organoids to 

better understand the causes of neurological 

disorders. Brain organoids are artificial 

organs which are grown by differentiating pluripotent 

stem cells into neuronal tissues. 

Researchers in professor Flora Vaccarino’s lab at the Yale School of 

Medicine recently verified brain organoids’ ability to closely model fetal 

brain development. This project analyzed large-scale gene expression 

data from organoids’ RNA transcripts on Yale’s supercomputing clusters. 

“An extensive verification of the ability of brain organoids to serve 

as a model for the human brain has not been done before,” first author 

Anahita Amiri remarks. For years, professor Vaccarino has grown thousands 

of organoids to observe the correlation between gene expression 

and time-dependent cell differentiation. These brain organoids have 

many advantages over traditional neurobiological techniques. “[We 

have] the ability to observe the development of human neurons in a living 

system, in a time-dependent manner, and in 3D,” Vaccarino said. 

With the fidelity of their model system confirmed, the lab can grow 

hundreds of organoids and get massive amounts of data, including enhancer 

networks–which control which genes will be transcribed at each 

specific stage of brain development–and potential interactions with 

their target genes. 

Vaccarino and her lab are currently using organoids grown from the 

cells of patients with Autism Spectrum Disorder (ASD) to gain insights 

into how specific enhancers might contribute to ASD. “Once we can 

identify ASD biomarkers, the next steps could include developing therapies 

to target genes and enhancers involved through gene therapy or 

drugs,” Vaccarino said. With her brain organoid research, we are closer 

to understanding the mechanisms and causes of some neurodevelopmental 

diseases. 

March 2019 


7

NEWS 

genetics 

LONESOME 

GEORGE’S 

LEGACY 

Genetic markers 

of longevity 

in giant tortoises 

BY MIRIAM ROSS 

IMAGE COURTESY OF FLICKR 

“Gone but not forgotten;” an epithet that applies to Lonesome George, 

the giant tortoise, and his newly-extinct species. In 2012, Lonesome 

George died as the last member of Chelonoidis abingdonii, at the ripe 

old age of 100. Galapagos tortoises are among the longest-lived vertebrate 

organisms, and researchers have long been curious about which 

specific factors contribute to their long lives. In Lonesome George’s 

case, the main research to examine tortoise longevity began after his 

death. “We were at the point in which it would have been very useful for 

us to have a whole genome, [to give] better information of how polymorphisms 

of different species are distributed,” said Adalgisa Caccone, 

a senior research scientist in Yale’s Ecology and Evolutionary Biology 

Department and director of the Center for Genetic Analysis of Biodiversity. 

After Lonesome George’s death in 2012, Caccone worked with 

colleagues at the Galapagos National Park Service, the Galapagos Conservancy, 

and the University of Oviedo to sequence his entire genome 

from a blood sample. With the full code of Lonesome George’s genome, 

the research team could begin making cross-species comparisons with 

smaller DNA sequences coded from several related tortoise species. 

In particular, Caccone and her research colleagues wanted to investigate 

variants linked to longevity in other species, which affected 

functions such as DNA repair, inflammation, and cancer development. 

The team had previously identified nine major “hallmarks 

of aging” in humans, and found variants affecting six of these “hallmarks” 

in the elderly tortoise’s genome–variants which are not found 

in the DNA of shorter-lived tortoise species. Of particular interest 

were a group of enzyme variants that seemed to offer protection 

against the sequence of protein activation which causes Parkinson’s 

disease. However, interpreting the meaning of variant changes within 

DNA is difficult. “It’s one thing to produce a genome, [and another] 

to annotate it, [and to] to know the function of a particular gene,” 

Caccone said. Traits are controlled by multiple genes which interact 

in multifaceted ways, and isolating the effect of a single variant can 

prove especially challenging. Although genome analysis reveals many 

variants, there is no easy way to map their functions; what is found 

are potential associations. And even in forming these associations, 

it is not clear from one genome alone whether a change is associated 

with longevity more broadly or effects in an individual organism. 

The first step towards identifying a variant’s function comes through 

cross-species comparisons. The research team had partial DNA samples 

of multiple individuals from related species of long-lived tortoises, 

which they compared to the full genome of Lonesome George. “Using 

this comparative approach, we can identify the hallmarks among all 

these genes, [and] eventually carry out functional studies on other organisms...to 

see if the [variants] have any associations with disease [or] 

longevity,” Caccone explained. Additionally, cross-species comparisons 

can allow the researchers to rule out the importance of changes 

which are not shared between species to longevity. The variants most 

likely to have functional significance should be those disproportionately 

present within the genomes of both Lonesome George and other 

Giant Galapagos tortoise species, all of which are long-lived. 

In addition to studying longevity, Lonesome George’s genome could 

also help with tortoise conservation. An effort is already underway to 

bring back extinct Galapagos tortoise species. “The Lonesome George 

genome is helping us is to identify molecular markers that are diagnostic 

for each species,” Caccone said. In previous research using DNA 

analysis, she discovered tortoises living on Galapagos islands that were 

actually genetic hybrids between the local species and an extinct one. 

The hybrids arose when early mariners brought tortoises with them 

for meat, and occasionally dropped them at random islands if the ship’s 

hold was too full. Caccone is helping the Galapagos National Park to 

start a breeding program that crosses these hybrids with each other to 

produce offspring more closely related to the original extinct species, 

the first breeding program of this type. The eventual goal is to release 

the tortoises’ offspring back onto the islands of their species’ origins. 

The sequencing of Lonesome George’s genome has given rise to 

many exciting potential associations, but the search for which variants 

actively contributed to his long life has just begun. With a group of 

potential associations and the sequences of other species, the secret to 

tortoises’ longevity will become clearer over time. Lonesome George 

may have died as the last member of his species, but discoveries from 

his genes can help us both to understand his long life, and perhaps 

even bring another extinct species back to their home island. 


cell biology 

NEWS 

HOPS 

INTO 

THE CELL 

IMAGE COURTESY OF WIKIMEDIA COMMONS 

When we take a drug, it flows through our bloodstream before 

entering the cells in our bodies–where the action happens. Most 

drugs that are currently used are small organic molecules that 

perform specific functions according to their chemical composition 

and shape. However, there is also substantial interest in using 

larger proteins and peptides as therapies for diseases. Unlike 

most small organic molecules, which are small enough to cross 

cell membranes, larger proteins or enzymes–molecular machines 

which have many more functions than small organic molecules– 

are tougher to shuttle across membranes inside cells. In a recent 

study published in the Proceedings of the National Academy of 

Sciences, a team led by Yale professor Alanna Schepartz uncovered 

new pathways and mechanisms that help proteins enter cells. 

Schepartz focused on two classes of proteins–cell-penetrating peptides 

(CPPs) and cell-permeant miniature proteins (CPMPs)–and the 

mechanism they use to enter the cell. In the study, Schepartz hoped to 

shed light on some of the unknown mechanisms employed by CPPs 

and CPMPs to enter cells. Both CPPs and CPMPs use what is called an 

endocytic pathway, taking advantage of the built-in cellular machinery 

for bringing larger molecules into the cell. During endocytosis, the cellular 

membrane surrounds the target molecule, pinches off, and creates 

an endosome inside the cell. This process is like the surface of a 

bubble pinching off inwards to become a new bubble inside the original 

bubble. Though scientists knew CPPs and CPMPs used the endocytic 

pathway, they were still unsure how CPPs and CPMPs are able to 

escape the endosome and enter the cellular fluid to fulfill their roles. 

Schepartz first tested the hypothesis that CPPs and CPMPs 

simply rupture the endosome to escape. The researchers used 

fluorescent tags to look for signs of endosome damage in the 

cell and locate ruptured endosomes. They discovered that the 

endosomes in cells that had taken in CPPs and CPMPs were relatively 

unharmed. The researchers then tested for signs of leakage 

from the endosome, which came back negative. Based on 

these results, the researchers were certain that endosomes are 

not harmed when the CPPs and CPMPs are released into cells. 

The team then decided to look for genes that could be regulating 

Uncovering 

how proteins 

enter cells 

BY JAMES HAN 

this release of proteins into the cell. They implemented a technique using 

small interfering RNAs (siRNAs), which allow researchers to “turn 

off” certain genes and observe the effects. After testing genes across 

the genome, Schepartz found that if VPS39, a gene that codes for a 

piece of the homotypic fusion and protein-sorting (HOPS) complex, 

was turned off, CPPs and CPMPs could not leave the endosome and 

enter the cell. They compared HOPS to similar complexes, but only 

turning off HOPS prevented proteins from leaving the endosome. 

Schepartz and her team then decided to look at the effects of 

CPPs and CPMPs on the function of HOPS. Using a fluorescence 

technique that looks for the products of HOPS’s reactions, 

Schepartz found that HOPS remained active even with delivery 

of CPPs and CPMPs. Finally, using fluorescent microscopy, the 

researchers found that HOPS functions by acting as a guide for 

CPPs and CPMPs, directing them to a class of endosome, called 

Lamp1, which has factors which facilitate the escape of proteins. 

Though the confirmation of HOPS as a key player in cell entry 

for proteins is a major breakthrough, further research is needed 

to understand the final steps of entry into the cell–particularly, 

how CPMPs escape from Lamp1 endosomes. Nevertheless, 

Schepartz’s research has great therapeutic potential and furthers 

our understanding of movement into and out of cells. As researchers 

learn more about these mechanisms, intricate molecular 

machines may replace small organic chemicals in medicine. 

SCHEPARTZ’S RESEARCH HAS GREAT 

THERAPEUTIC POTENTIAL AND 

FURTHERS OUR UNDERSTANDING OF 

MOVEMENT INTO AND OUT OF CELLS. 


March 2019 


9

NEWS 

neuroscience 

PIONEERING 

ALZHEIMER’S 

TREATMENT 

A compound that 

can reverse neural 

connection loss 

BY MIRIAM ROSS 

Alzheimer’s disease (AD), which currently affects more that 5.7 

million people in the US, is a neurodegenerative disease that greatly 

impairs memory. Despite the vast field of research dedicated toward 

tackling Alzheimer’s, there is still no cure. Erik Gunther, along with 

a team of Yale researchers in Professor Stephen Strittmatter’s lab, has 

discovered a promising drug to reverse the progression of AD. After 

screening over 60,000 compounds at the Yale Small Molecule 

Discovery Center, they developed a new compound that, instead of 

simply treating AD symptoms like currently approved drugs, can reverse 

neural connection loss and memory defects in mice. 

To better unravel the mechanism of the drug, it is important to 

understand AD development. AD results from an accumulation of 

β-amyloid peptides, which are small proteins present only in low concentrations 

in non-Alzheimer’s patients. In AD patients, β-amyloid 

peptides clump together to form β-amyloid oligomers, which then 

further combine to form β-amyloid plaques that look like “rocks in the 

brain,” according to Strittmatter. β-amyloid oligomers are problematic 

because they interact with neurons to set off a cascade of molecular 

events that damages synapses–the connections between neurons–and 

thus lead to memory impairment. Ten years ago, Strittmatter demonstrated 

that β-amyloid peptide binds strongly to cellular prion protein 

(PrP), a protein on the surface of neurons, so he began to investigate 

how to block this damaging interaction from occurring. 

Strittmatter’s lab initially screened over 12,000 compounds, hoping 

to find one that would inhibit the β-amyloid oligomer interaction 

with PrP. They first identified the antibiotic cefixime as a potential 

candidate, which, unusually, was only effective after it had degraded–since 

most drugs are effective before they start to degrade. If cefixime 

had not degraded by the time the research team screened it, 

Strittmatter believes, “We might still be searching [for a compound].” 

Other antibiotics with analogous structures to cefixime’s yielded similar 

results. After further testing, the team switched their focus toward 

the degraded product of the antibiotic ceftazidime because it was 

more effective than the degraded product of cefixime. Through further 

analysis, the research team learned that ceftazidime decomposes 

and reacts with itself to create a different polymer, referred to as 


Compound Z, that inhibits β-amyloid oligomer interaction with PrP. 

Although the researchers knew Compound Z has inhibitory activity, 

they were uncertain whether it binds to PrP. Using antibodies constructed 

to bind to specific regions of PrP, they found that Compound 

Z binds to two regions of PrP that interact with the β-amyloid oligomer, 

preventing any interaction between β-amyloid oligomers and PrP. 

Once the researchers elucidated this pathway, they tested Compound 

Z’s effect on neurons. Even in a petri dish, neurons exposed to β-amyloid 

oligomers have damaged synapses, but Strittmatter’s lab found that Compound 

Z reduces β-amyloid oligomer binding to neurons by over eighty 

percent and reduces the loss of dendritic spines–an essential component 

of neuron signaling–by eight-fold. With these promising results, they administered 

Compound Z to mice engineered with Alzheimer’s-like disease. 

The researchers knew they had discovered a potential treatment for 

AD when the mice recovered learning and memory function. 

This compound, however, was unable to bypass the brain’s filtration 

system, the blood-brain barrier, rendering it difficult to 

use as a potential therapeutic. Strittmatter’s lab needed to find a 

compound that could cross the blood-brain barrier. They tested 

over 56,000 molecules until they landed on a synthetic compound 

poly(4-styrenesulfonnic acid-co-maleic acid), abbreviated as PSC- 

MA. Similar to Compound Z, PSCMA has inhibitory properties, 

but unlike Compound Z it can be administered orally and thus is 

considerably more practical as a potential drug. 

Though the mice in this study were able to complete memory tasks 

with the remaining β-amyloid oligomers in the brain, the results will 

not necessarily translate in human subjects. “[The mice models] are 

not a complete picture of human AD.” Strittmatter acknowledged. 

There are numerous steps before human trials can begin, but the 

researchers’ main goal now is to find the ideal balance between maintaining 

the drug’s inhibitory activity while optimizing the drug’s access 

to the brain. Strittmatter hopes to eventually test whether a drug 

from his lab might prove effective in treating AD in humans. “My 

optimism is high because I really believe we have a molecular basis 

for its effectiveness, and while these animal models are not perfect, 

they are the best predictors we have at this time,” he said. 


ecology 

NEWS 

SOURCES 

AND 

SINKS 

IMAGE COURTESY OF WIKIMEDIA COMMONS 

The global carbon cycle is an essential aspect of life on Earth, 

and there has been extensive scientific research concerning 

how the movement and exchange of carbon compounds can 

help manage atmospheric carbon dioxide (CO2) concentrations 

and predict climate change. Contemporary carbon cycle 

models largely look at carbon that is involved in live plant biomass 

and organic matter and the relationship between plants 

across landscapes and the atmosphere. Yet, these models ignore 

the effects of animals in higher trophic levels of ecosystems. 

An interdisciplinary team of researchers led by professor 

Oswald Schmitz at Yale sought to dispel the notion that animals 

have little or no impact on the carbon cycle. The researchers 

argue that wild animal populations are key players 

in shaping how ecosystems mitigate climate change and 

should be considered when making carbon measurements. 

Their paper, published in Science, found that the direct and 

indirect effects of animals can control the magnitude of carbon 

exchange in various global reservoirs. This can consequently 

influence carbon turnover rates, or the time it takes 

for carbon fixed in a plant by photosynthesis to be released 

back into the atmosphere. 

The animals in question are a diverse group spread across 

varying locations, including both large and small herbivores, 

carnivores, vertebrates, and invertebrates. Herbivores consume 

plant biomass and assimilate carbon into their own 

animal biomass after digestion, releasing additional carbon 

through defecation and respiration. With less plant biomass 

comes a decrease in photosynthesis and an increase in respiration, 

which reduces the chemical energy created by an ecosystem. 

Additionally, the heavy trampling of soil and sediment by 

larger animals can change surface temperatures that increase 

either carbon retention or release. 

These animals can even have conflicting positive and negative 

effects on the carbon cycle. For example, in some cases, 

grazing and browsing herbivores such as muskox and geese 

enhance carbon uptake and storage from the atmosphere into 

How animals 

shape the 

carbon cycle 

BY MEGAN HE 

organic compounds by twenty to twenty-five percent. In other 

cases, these grazing animals cause a fifteen to seventy percent decrease 

in CO2 uptake. The predators of these herbivores, on the 

other hand, can reverse these effects. In grassland ecosystems, 

grasshoppers cause a seventeen percent reduction in CO2 uptake, 

but the spiders that forage on these grasshoppers “reverse” the effect 

by increasing CO2 uptake by forty-six percent. In freshwater, 

stickleback fish that feed on macroinvertebrate stonefly insects, 

increase algal CO2 uptake, which in turn decreases concentrations 

of dissolved inorganic carbon in the water, enhancing carbon 

capture by around ninety percent. 

Other underlooked factors in ecosystem models are animal 

movement and migration. “Since large animals roam widely 

across landscapes, being able to monitor their movements and 

quantify the amount of material that is moved along with them 

is crucial to understanding their impact,” Schmitz said. Schmitz 

outlined a one instrument–named LIDAR–able to provide 3D 

portraits of habitat structure, but these methods still are limited 

in their ability to quantify the impacts of animals. On-the-ground 

sampling is often coupled with remote sensing to produce a more 

comprehensive analysis of carbon distribution. For example, the 

impact of African elephant populations on densities of woody 

vegetation can be monitored through both methods. 

An interesting challenge faced by the team was the pushback 

from skeptical reviewers, who were not convinced of the 

importance of incorporating animals into these models. Ultimately, 

however, Schmitz thinks that the data speaks for itself. 

“In some cases, you can triple how much carbon you take up if 

you protect these animals,” Schmitz said. 

What about the role of humans? “We have to protect the 

food chains–the animals and plants–that drive carbon dynamics. 

Nature provides all these services for our survival benefit 

and for other species, so we have to reimagine ourselves as being 

part of nature,” Schmitz said. At the end of the day, wildlife 

conservation proves to be an essential strategy for creating 

carbon storage capacity, and that task is up to the people. 


March 2019 


11

cell biology 

FOCUS 

The sea anemone Actinia is a deceptive organism, in 

both name and appearance. For one, it is known as the 

“flower of the sea” for its colorful ring of tentacles. It also 

adopts a sessile lifestyle, preferring to lie and wait for food 

rather than go looking for it. When an unassuming plankton 

or fish passes by and stimulates its tentacles, the marine 

predator stuns it, abruptly retracts its tentacles, and 

gracefully encapsulates its catch. 

In a classic example of biomimetics–the imitation of 

natural systems for the purpose of solving human problems–a 

team of researchers from Yale and Peking University 

has designed a coagulant that can capture contaminants 

in water via a shape eversion process reminiscent 

of Actinia’s feeding process. Due to its unique structure, 

the innovative technology can trap many different types 

of contaminants in a single step. This versatile feature can 

potentially enable tremendous increases in water purification 

efficiency. 

Water and Energy: A Modern Compromise 

This innovation comes at a crucial time, as it promises 

to revolutionize the way we treat water. One in nine people 

worldwide do not have access to potable water. Water scarcity 

is a multifaceted problem without a clear solution, and cleaning 

up water with modern water purification systems has a 

high energetic and economic cost. Water and wastewater facilities 

are responsible for approximately thirty-five percent 

of a typical US municipal energy budget. Today, in order to 

supply consumers with clean water, facilities release over forty-five 

million tons of greenhouse gases annually–an output 

equivalent to that of more than six million cars. 

Current water treatment systems feature an extensive 

number of steps to ensure complete purification, because 

each step cannot remove all contaminants at once. Water 

contains many types of contaminants, each with drastically 

different chemical properties–think bacteria, 

harmful chemicals, and organic matter. 

One popular purification method is coagulation, 

in which positively charged 

coagulants, when added into water, 

bind to negatively charged 

dissolved organic carbon 

(DOC) and carbon-based 

remains 

of organisms. The 

added coagulants 

and 

organic 

mat- 

by HANNAH RO 

art by ANUSHA BISHOP 

PREYING 

ON POLLUTANTS 

technology imitates life 

to generate cleaner water 


March 2019 


12

FOCUS 

cell biology 

ter clump together into larger particles, then settle by gravity 

to the bottom of the basin so they can be more easily removed 

from the water. Another common step, sedimentation, allows 

heavier particles to settle, and a further chlorination step kills 

remaining microorganisms. Each of these methods requires 

specific technologies and tools, and the entire package together 

accounts for the high energy costs incurred today. 

The newly developed technology developed at Yale and Peking 

University, aptly named Actinia-like micellar nanocoagulant 

(AMC), streamlines water purification in two ways: 

one, it decreases the number of steps; two, it maximizes energy 

efficiency. If AMC enters the water purification industry, 

it could well eliminate multiple types of contaminants in one 

step, an optimal solution to lowering both the time and cost 

of cleaning water. 

Form Follows Function 

Last month, the collaborative project published results 

demonstrating that AMC could capture a spectrum of different 

contaminants in a single step. Conventional coagulants, 

such as aluminum sulfate, can typically only remove bulky 

organic matter. AMC inherits its special properties from Actinia. 

Like the sea anemone, the coagulant features a flexible 

outer shell that can be everted–turned outward/inside-out– 

to reveal an inner core, which has contrasting chemical properties. 

The positively charged outer shell binds to DOCs and 

other organic substances, while the negatively charged inner 

core contains organic micelles that capture smaller micropollutants. 

Notably, AMC can also extract nitrates, an excess 

of which can be harmful to humans. 

Both inner and outer surfaces can be accessed 

by altering the pH–a scale 

from zero to fourteen that 

corresponds to a 

solution’s acidity–of 

the surrounding solution. When stored in acidic conditions 

with a pH lower than four, the coagulant maintains its stable 

form, with the inorganic shell completely shielding the 

organic core. Raising the pH around AMC is akin to stimulating 

the tentacles of the Actinia–in wastewater above pH 

four, AMC changes its configuration to reveal the organic 

core. “Shape eversion of the coagulant adds additional functionality. 

Coagulants neutralize the charges on the organic 

matter and cause them to clump together so they can settle. 

But when the core is exposed, it absorbs additional contaminants 

that other coagulants would not be able to,” said Ryan 

DuChanois, a graduate student in the Elimelech group, who 

worked on the project. 

Another unique characteristic of the AMC is its ability 

to self-assemble. Much like the phospholipid bilayers that 

make up cell membranes, the AMC contains both hydrophobic 

and hydrophilic elements that rearrange in an aqueous 

solution. During the synthesis of AMC, hydrophobic 

carbon chains gather inwards, driven away from water, to 

form the organic core, and hydrophilic ionic complexes, 

comprising ammonium, silicon, and aluminum, form the 

outer shell. The researchers closely regulated the ratios of 

the reactants to achieve the product’s desired shape. Thanks 

to AMC’s optimized and stable build, it does not aggregate 

in solution and instead maintains its size and shape even after 

one year of storage. 

Having synthesized the particles, the researchers had 

to perform characterization to confirm and optimize its 

structure. However, one significant challenge of this project 

was the nanoscale of the coagulant; specialized equipment 

was required to observe the structure and function 

of the miniscule AMC particles. Researchers confirmed 

the spherical shape of AMC using transmission electron 

microscope (TEM) images and approximated its size with 

dynamic light scattering (DLS) measurements. For both 

types of technology, a beam of electrons, or light, is transmitted 

through the molecule to map out its structure. The 

caveat is that these methods only work when the molecule 

being observed is stationary. This is not the natural 

working state of the AMC. As such, the 

researchers had to turn to other technologies 

to learn about AMC’s mobile 

functionality. 

To observe how 

AMC self-as- 

sem- 

THE AMC RESEMBLES THE STRUCTURE OF SEA ANEMONE, WITH AN OUTER SHELL AND AN INNER CORE THAT TARGET

cell biology 

FOCUS 

bles, researchers conducted molecular dynamics 

simulations. These computational 

simulations, among other visualization 

techniques, predict and explain how a coagulant 

will behave when exposed to different 

types of wastewater. “[Simulations] show 

why the shell is removing certain contaminants 

and why the core is removing certain 

[other] contaminants. You can pinpoint the 

exact mechanisms, like electrostatic and hydrophobic 

interactions,” DuChanois said. 

Comparing Coagulants 

Once the structure and function of AMC 

were confirmed and better understood, researchers 

progressed to the field research 

portion of the project. Jar tests–in which 

treatment parameters, such as dosage, mixing 

rate, and aeration time, are altered to determine 

how a coagulant will behave with 

specific contaminants–were used to simulate 

full-scale water purification processes. 

These were performed to compare the 

efficiency of AMC and conventional coagulants. 

Efficiency was determined by two 

factors: the resulting contaminant concentration, 

as well as turbidity, a quantitative 

measurement of a liquid’s murkiness. 

AMC edged out other commercially 

used coagulants tested in the study–including 

a polymer called polyDADMAC, 

aluminum sulfate, and iron(III) chloride– 

with an average efficiency of over ninety 

percent. While all of the coagulants exhibited 

similar efficiency in removing turbidity, 

AMC was more successful at lowering 

DOC, phosphorous, and nitrate concentrations. 

Furthermore, while traditional coagulants 

demonstrated negligible removal of 

nitrate, AMC’s nitrate removal efficiency 

exceeded ninety percent. 

Other key contaminants the researchers 

considered were organic micropollutants 

and certain pharmaceuticals. 

Commonly, water is contaminated by 

micropollutants from residue left behind 

by personal care products, hormones, 

and pesticides. Because these particles 

are nonbiodegradable, they persist in 

wastewater treatment discharges 

and enter the environment. 

Conventional coagulants 

perform 

poorly 

in this category. Instead, the existing methods 

of removing micropollutants are ozonation 

and ultrasound. These approaches are energy-expensive, 

time-consuming, and work for 

only their specific class of contaminants. 

In this study, the conventional coagulants 

demonstrated removal efficiencies between 

zero and sixty percent. AMC outshone all of 

them, achieving removal efficiencies of over 

ninety percent for all tested micropollutants. 

This makes AMC all the more promising as a 

future water purification technique because 

it offers an entire functional package. “The 

real benefit is that if you can remove many 

different types of contaminants in one step 

instead of using many steps, you can simplify 

the process, use less money, and take up 

less land. Overall, the process becomes more 

efficient,” DuChanois said. 

The Big Picture 

Ultimately, this project demonstrates 

how adaptations which species develop 

to face problems in nature can inspire 

technological innovations to solve human 

problems. Encouraged by the success of 

AMC, the researchers hope to continue 

applying their novel ideas to other areas 

of water treatment and materials science. 

“Coagulation has been in use for centuries 

and nothing has really changed. You 

would think at this point in time, after 

thousands of people have thought about 

this, that we would have perfected the water 

treatment process. But there’s always 

opportunity to innovate,” DuChanois 

said. Perhaps more innovations, building 

on the success of the AMC, will lead to effective 

solutions to the abiding challenge 

of energy-efficient water purification. 

ABOUT THE AUTHOR 

IMAGE COURTESY OF RYAN DUCHANOIS 

HANNAH RO 

HANNAH RO is a first-year in Trumbull from Orange County, California. In addition to writing for the 

Yale Scientific, she volunteers with Synapse, researches in the Bergwitz lab, and plans events for Korean 

American Students at Yale. 

THE AUTHOR WOULD LIKE TO THANK Ryan DuChanois for his time and enthusiasm to share their 

research. 

FURTHER READING 

Jinwei Liu, Shihan Cheng, Na Cao, Chunxiang Geng, Chen He, Quan Shi, Chunming Xu, Jinren Ni, Ryan 

M. DuChanois, Menachem Elimelech, Huazhang Zhao. Actinia-like multifunctional nanocoagulant for singlestep 

removal of water contaminants. Nature Nanotechnology, 2018; DOI: 10.1038/s41565-018-0307-8 

T TARGETS DIFFERENT TYPES OF CONTAMINANTS. IMAGE COURTESY OF RYAN DUCHANOIS 


March 2019 


14

THE DEFENSES CANCERS RAISE AGAINST 

US, AND HOW WE DEFEAT THEM 

RESCUING 

the 

IMMUNE 

SYSTEM 

BY SAMI ELRAZKY 

ART BY ELISSA MARTIN

FOCUS 

medicine 

The process of drug development is enigmatic 

to most of us. Several groups, labs, 

and industries contribute considerable 

time and resources to producing the medicines 

which keep us healthy. The key to a 

drug’s success is the interplay between industry, 

which ultimately produces the drug, 

and academic research, where the “next big 

drug” is usually discovered. Research can 

be a slow and uncertain process–years pass 

seamlessly between major discoveries. In 

contrast, the companies that translate these 

discoveries into the clinic follow a strict, 

fast-moving timeline. 

In rapidly expanding fields of science like 

cancer immunotherapy, the disconnect between 

academic research and industry can 

sometimes lead to problems. A recent study 

in the Chen group at the Yale School of Medicine 

has overturned our traditional understanding 

of a certain immunological mechanism–brining 

under scrutiny the use of 

certain drugs which have been used by pharmaceutical 

industry for years. In the study, 

the researchers characterized and examined 

the interaction between fibrinogen-like protein 

1 (FGL-1) and the LAG-3 receptor on 

immune T cells. The results of this study 

could lead to the development of better treatments 

in the field of cancer immunotherapy. 

The immune system 

The human immune system is an intricate 

machine because of the amazing variety 

of threats it has to recognize and deal with, 

from bacteria, to viruses, to even fungi. Its 

operation is centered around innate immunity, 

which involves recognizing interactions 

between molecular sensors attached 

to immune cells and common types of molecules 

on foreign cells. But some invaders, 

such as viruses, cannot be recognized in this 

way. In response, every non-immune human 

cell has evolved antibodies and the major 

histocompatibility complex ligands class 

I or II (MHC I/II), which are attached to the 

cell surface and serve as a diagnostic tool for 

immune T cells. 

The MHC ligand samples protein fragments 

from inside the cell and presents it 

for inspection by the T cells, which roam 

around like policemen. When a virus invades 

and forces the cell to produce abnormal 

proteins, these proteins will appear on 

the MHC-I, and the T cell responsible for 

identifying it will be activated. In many cases, 

the T cell will kill the infected cell and 

stop widespread infection. 

In a pinch, this process also allows T cells 

to detect and kill cancer cells. Cancer cells 

originate from accumulated random mutations 

that endow them with an abnormally 

high proliferation rate, allowing these cancer 

cells to grow unchecked in the body. 

These mutations often result in abnormal 

protein production, which are sampled and 

presented on the MHC-I ligand on the cell’s 

surface. T cells can recognize this abnormality 

and act as necessary. 

I GOT TO THINKING, 

MAYBE MHC-II ISN’T 

THE MAJOR LIGAND. 

MAYBE THE LIGAND 

IS SOMEWHERE ELSE. 

What is cancer immunology? 

This study was supervised by Lieping 

Chen, United Technologies Corporation 

professor in cancer research and professor 

of Immunobiology, Dermatology, and Medicine 

at Yale. He had previously revolutionized 

cancer treatment with his discovery 

and characterization of the PD-L1 ligand, a 

cell-death pathway that cancer cells hijack to 

prevent an immune response. His research 

group works to use the human body’s natural 

immune system to fight cancer. To do so, 

the team faces a number of challenges. Cancer 

cells proliferate rapidly and can thereby 

rapidly evolve defenses against T cells. One 

such defense is misdirection–when binding 

between an abnormal MHC-I ligand and a 

T cell receptor sends off an alarm signal, the 

cancer cell can induce other interactions that 

cancel out that signal, or even kill the T cell. 

For example, a cancer cell under attack 

by the immune system can evolve the PD- 

L1 ligand. The next time a T cell binds to 

the MHC-I, the cancer cell will attach its 

PD-L1 ligand to the PD-1 receptor on the 

T cell. This binding sends a signal to the T 

cell to both stop attacking and to self-ter- 


medicine 

FOCUS 

minate through apoptosis. The PD-L1 ligand 

is, in essence, the cancer cell’s “get 

out of jail free” card. 

To mitigate the cancer cell’s defenses, cancer 

immunologists can introduce antibodies 

that block the T cell’s PD-1 receptor. The 

T cell regains the ability to bind to the MHC 

ligand and sound the alarm. This, of course, 

prompts the cancer cell line to either find another 

way to suppress immune cells or die 

out. What results is a game of cat-and-mouse 

between the cancer cell and the T cell. Clearly, 

an understanding of the various interactions 

between cancer cells and immune system receptors, 

as well as the cellular responses they 

induce, is critical to controlling cancer. 

Signals of an issue 

IMAGE COURTSEY OF FLICKR 

Another receptor that caught the eye of 

the Chen group was LAG-3 on T cells. LAG- 

3, like PD-1, is an inhibitory receptor on T 

cells. That is, if a suitable molecule binds in 

a complementary manner to LAG-3, the T 

cell loses its ability to attack foreign and cancerous 

cells. Discovered before PD-1, the 

MHC-II ligand–the version of MHC ligand 

on specialized immune cells–was commonly 

thought to be the complementary ligand to 

the LAG-3 receptor for decades. As a result, 

numerous pharmaceutical companies produced 

drugs to block LAG-3 from binding 

to MHC-II. The rationale was that introducing 

molecules that crowd out the MHC-II 

ligands will allow LAG-3 will be unbound, 

allowing T cells to remain active. 

However, evidence had been mounting 

that MHC-II is not the major ligand that 

pairs with LAG-3. A number of research 

studies demonstrated that other kinds of 

molecules that prevent LAG-3-mediated inactivation 

without blocking MHC-II were 

effective at amplifying T-cell responses and 

managing tumors, indicating that the MHC- 

II/LAG-3 interaction may not be as important 

as researchers thought. 

Unfortunately, the majority of LAG-3 targeting 

drugs pushed to clinical trials are still 

MHC-II blockers. Jun Wang, an associate 

research scientist in the Chen lab and first 

author on the paper, is acutely aware of this 

issue. “This phenomenon has been in this 

field for more than fifteen years…people 

know the issue is there, but they don’t know 

the biology and so they continue to produce 

MHC-II blockers,” Wang said. It was this 

widespread issue that drew Wang to investigate. 

“I got to thinking, ‘maybe MHC-II isn’t 

the major ligand. Maybe the ligand is somewhere 

else,” Wang said. 

Dispelling an old misunderstanding 

Wang began experimenting by growing T 

cells and cancer cells together in a medium 

lacking serum, a slurry of the different proteins 

and fluids typically used to help cells 

remain healthy in laboratory dishes. In this 

case, using MHC-II blocking antibodies induced 

no therapeutic response whatsoever, 

whereas use of the same antibodies on 

cells grown on regular serum medium had 


a small effect on cancer cell growth. This 

experiment indicated that the antibodies 

weren’t blocking MHC-II, but rather something 

in the serum that was responsible for 

binding to LAG-3. 

To find the molecule responsible in the serum, 

the team scanned the human genome 

for proteins that would bind to LAG-3. Using 

what is termed a GSRA assay, they found 

that fibrinogen-like protein 1 (FGL-1), a 

protein normally produced in the liver, had 

a very high binding affinity for LAG-3. “We 

generate antibodies as therapeutic drugs because 

they have very high affinity for receptors…but 

[the FGL-1/LAG-3 interaction] 

has a very high affinity, just like on the antibody 

level,” Wang said. 

Further experimentation confirmed the 

importance of this interaction towards cancer 

research. A biophysical study found that 

FGL-1 binds to the area of LAG-3 that is 

blocked by the non-MHC-II blockers often 

used in laboratory studies, finally explaining 

the effectiveness of these blockers 

in years of studies. Furthermore, knocking 

out the FGL-1 gene reduced T cell deactivation 

at a comparable level to LAG-3, further 

strengthening the connection between 

the two. Finally, just like PD-L1, the team 

found that FGL-1 was greatly upregulated 

in humans with solid tumor cancers, indicating 

that the protein acts as a defensive 

measure used by cancer cells against T cells 

and could serve as a helpful biomarker for 

cancer immunotherapy. 

This research demonstrates that FGL- 

1 is the complementary ligand to LAG-3, 

meaning that the numerous drugs produced 

to target MHC-II are relying on biological 

assumptions proven to be false. 

Chen hopes that his team’s research will 

lead to the creation of new treatments 

which take advantage of this newly discovered 

FGL-1/LAG-3 interaction. 

SAMI ELRAZKY 

SAMI ELRAZKY is a first-year prospective Molecular, Cellular and Developmental Biology major 

in Saybrook College. Hailing from Tacoma, Washington, he also writes for the Yale Journal of 

Medicine and Law. 

THE AUTHOR WOULD LIKE TO THANK Dr. Jun Wang for his extensive explanation of the work, and 

Dr. Lieping Chen for his insights into the world of cancer immunology. 


Wang, Jun, Miguel F. Sanmamed, Ila Datar, Tina Tianjiao Su, Lan Ji, Jingwei Sun, Ling Chen et al. 

“Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.” Cell 176, no. 1-2 (2019): 

334-347. 


March 2019 


17

FOCUS 

neuroscience 

Can you remember when you started to remember? 

At what point in time, and by what 

mechanism, does our brain gain the ability to 

form memories? A recently published study 

conducted by Usman Farooq and George 

Dragoi, assistant professor of psychiatry and 

neuroscience at the Yale School of Medicine, 

has probed the developmental timeline of 

memory formation and extracted key information 

about this process. This study aimed to uncover 

the mechanism through which animals 

like us develop the ability to form memories 

that link our past experiences with our present 

and future selves. 

Untangling 

the formation 

ofmemories 

LEARNING 

to 

REMEMBER 

B Y I S A A C W E N D L E R 

Conventional views of memory development 

The scientific community has long 

known that memories are established, 

stored, and maintained in the brain. Broadly 

speaking, there are three types of memory: 

sensory, which lasts only a few seconds; 

working, which lasts from a few seconds 

to a minute; and long-term, which can last 

for years. Different parts of the brain, such 

as the hippocampus or amygdala, serve 

as mediators for these different types of 

memory. These brain regions house the 

networks and ‘bundles’ of interconnected 

neurons whose interplay forms the physiological 

foundation of memory. 

Moreover, it is known that newborns 

are not able to form long-lasting memories 

immediately post-birth; for their first 

weeks to months, they are consciously 

in the present, after which they gain the 

ability to form memories. Although much 

is known about the anatomical and neurological 

support of new memory formation 

in adulthood, scientists know far less 

about the exact mechanisms that prompt 

the genesis of memory in early animal development. 

The present study fills this gap 

in knowledge, looking specifically at the 

neurological changes during the development 

of episodic memory–a type of longterm 

memory dealing with first-hand experiences–in 

rats. 

Stages of memory formation 

Farooq and Dragoi wanted to study the 

developmental timeline of memory formation 

in real time, so they monitored the 

electrophysiological activity of different 

“neuronal ensembles”–bundles of functionally 

connected neurons–in the hippocampi 

of rats over the third and fourth 

weeks after birth. They chose to monitor 

the hippocampi because they are known 

to be critical for the formation of new 

memories in adulthood. These rats were 

placed onto a linear track and allowed to 

move freely while their neuronal activity 

was recorded and decoded to display 

spatial information. “Particular neurons 

in the hippocampus ‘code’ or ‘fire’ for discrete 

locations; together, a population of 

these so-called ‘place cells’ can represent a 

whole arena composed of many locations,” 

Farooq said. In other words, each instantaneous 

location along the track was rep- 


neuroscience 

FOCUS 

IMAGE COURTESY OF FLIKR 

Much of the structure and function of the 

animal brain is conserved across different 

species; this allows the use of rats as model 

organisms for investigating phenomena that 

affect even humans 

resented by a specific pattern of neuronal 

activity. Furthermore, the neural activity 

of the rats was recorded during periods of 

sleep and “awake rest,” where the rats were 

awake but resting on the track. 

The goal of the study was to see how 

the activity of these neuronal ensembles 

changes over time, as the rats gain the ability 

to remember their previous experiences 

on the track. This experimental design allowed 

for direct investigation of the development 

of episodic memory. 

The researchers observed that episodic 

memory development occurs in three separate 

stages. In the first stage, around two 

weeks after birth, rats displayed neural 

activity characterized only by discrete, instantaneous 

locations represented by single 

neurons, lacking any pattern of activity 

characteristic of memory. “These young animals 

are completely ‘stuck’ in the present 

and cannot form memories,” Farooq said. 

In the second stage, around the middle of 

week three, the rats began to display signals 

that functionally connected different neurons 

to one another. Although these signals 

were not yet characteristic of full-fledged 

memories, the neural patterns of the rats at 

this stage gradually started to organize into 

sequential motifs that “preplay” the patterns 

expressed during memory encoding, 

a kind of memory storage practice intrinsic 

to the adult animal brain. Interestingly, 

these preconfigured patterns were expressed 

during sleep, independently of any 

external stimuli. 

By the onset of stage three–about three 

and a half weeks after birth–the rats had 

developed an ability to modify their preconfigured 

neural network of activity in 

response to a new experience. With this 

in place, the rats were now able to develop 

episodic memories. These memories were 

characterized by the strengthening and manipulation 

of the preexisting sequential patterns. 

Crucially, the rats in this final stage 

had developed the ability to use “replay”, 

wherein the preconfigured neural connections 

are used to relate different neurons– 

and thus, different locations on the track–in 

a sequential, long-lasting temporal manner. 

In other words, these rats had developed 

the ability to form memories. 

Learning about memory 

“Prior to our study, there was essentially a 

gap in our understanding of how and when 

these sequential patterns develop,” Dragoi 

said. Having observed these three stages of 

memory formation, the researchers were 

able to identify two interdependent prerequisites 

for memory development. First, the 

preconfigured patterns of sequential neural 

activity must form; next, the external 

world must impose some changes to these 

neural patterns of the brain. These steps 

must occur in that order, otherwise the 

brain has an insufficient foundation upon 

which to build a memory. 

These distinct stages of memory development 

might have evolutionary roots. In 

the same time it takes for a newborn experimental 

rat to progress through the developmental 

steps in the confines of the linear 

track, a wild newborn would leave its nest 

to explore the surrounding environment. 

The emergence of an episodic memory is 


almost certainly essential for these animals 

to navigate an unforgiving external environment 

and stay alive. 

The results of this study provide interesting 

insights into the animal mind. They bring us 

closer to elucidating the system by which the 

brain makes and stores memories. “This is an 

important question which has attracted the 

attention of philosophers for centuries. Now 

we’re able to directly test some of their hypotheses,” 

Farooq said. 

Experimental challenges and future plans 

Aside from valuable scientific contributions 

made by this study, it is also an archetypal 

developmental study. A tremendous 

amount of time and preparation was necessary 

to lay the groundwork and design the 

right approach to the problem. “For this 

developmental study, it took close to four 

years from the start of the experiments until 

its publication,” Dragoi explained. 

As for the future, Dragoi and Farooq are 

looking to pursue a few different routes. 

One possible effort might focus on dissecting 

the factors, mechanisms, and neuronal 

circuits underlying the developmental processes 

investigated in this study. Another 

potential direction involves studying the 

development of neural patterns in animal 

models of neurodevelopmental disorders, 

potentially allowing comparisons to the 

current findings, to elucidate any deficits in 

the developmental system associated with 

the disorders. 

In any case, this study has managed to 

provide some answers to the fundamental 

question of memory formation. This understanding 

will prove crucial to support 

further exploration of the miracle that is the 

animal brain. 

A R T B Y S U N N I E L I U 

Isaac Wendler 

Isaac Wendler is a junior in Berkeley College, majoring in Chemistry and MCDB. When he’s not 

putting in hours on his chemistry research project, he can be found at Payne Whitney playing 

pick-up basketball or representing the Thundercoqs in intramurals. 

THE AUTHOR WOULD LIKE TO THANK Dr. George Dragoi and Usman Farooq for their time and 

enthusiasm about their research. 


Farooq, U., and G. Dragoi. "Emergence of preconfigured and plastic time-compressed sequences in 

early postnatal development." Science 363, no. 6423 (2019): 168-173. 


March 2019 


19

FOCUS 

cell biology 

E S S E 

In the average adult human, half a pound 

of proteins is turned over daily–destroyed 

and rebuilt from scratch. Among the many 

biological processes that occupy an organism 

throughout its lifetime, protein production 

ranks among the most intensive. Most forms of 

life therefore depend on accurate protein production. 

For instance, in humans, single base 

pair mutations in DNA blueprints, leading to 

a change in one amino acid building block, are 

known to cause diseases ranging from sickle 

cell anemia to cancer. However, a recent study 

at Yale has found an exception. Researchers in 

professor Dieter Soll’s group, working in collaboration 

with Antonia van den Elzen from 

professor Carson Thoreen’s group, examined 

the genomes–the complete set of genetic material 

in an organism–of thousands of bacterial 

species and found that parasitic bacteria with 

reduced genomes lack protein proofreading 

organisms do not face the same evolutionary 

pressures as free-living organisms. They do 

not have to be the best in their habitat to survive 

and reproduce. They merely need to be 

good enough. 

As a result, parasites can tolerate mutations 

and genomic deletions that weaken their survival 

ability. As free-living organisms transfer 

to parasitic lifestyles, they lose small pieces of 

their DNA over time due to the imperfect nature 

of DNA replication. Unlike in free-living 

organisms, these small losses of functionality 

are not important in the relatively noncompetitive 

host environment, so the bacteria survive 

and continue replicating, eventually losing up 

to ninety-five percent of their DNA. This process, 

known as “erosive evolution” or “Muller’s 

Ratchet,” explains why the genomes of parasitic 

organisms are much smaller than those of the 

free-living organisms from which they evolved. 

This erosion of the genome has consequences 

for the cellular machinery. During 

this reduction of genetic code, certain features 

typically thought to be essential for 

life can be lost, such as the ability of the 

protein production machinery to proofread 

the amino acid sequence being generated. 

After studying 10,423 genomes of 2,277 

bacterial species, Melnikov and his colleagues 

determined that parasitic bacteria 

with reduced genomes lose mechanisms responsible 

for protein quality control. “Parasitic 

life eradicates one important property 

of cells: accurate processing of genetic information,” 

Melkinov said. 

According to their research, an unusually 

large percentage of the parasitic bacteria 

studied had mutations in their protein 

synthesis quality control system. One 

such system identified was the aaRSs editing 

site of tRNA, where messenger RNAs 

coming from the organism's DNA are 

converted to protein. Seventeen percent 

of the bacteria had multiple mutations in 

one synthetase, an enzyme that links two 

amino acids together, and five percent had 

multiple mutations in several synthetases. 

Mutations were more common in species 

with reduced genomes. For instance, only 

6.3 percent of species with genome sizes 

greater than three million base pairs had 

editing-site mutations, while 83.8 percent 

of species with genome sizes less than one 

million base pairs had percent editing-site 

mutations. These mutations indicate that 

these species do not correct erroneous amino 

acids incorporated into the produced 

protein. 

ADVANTAGEOUS ERROR- 

mechanisms. How is it that these bacteria survive–and 

even thrive–with chunks of faulty 

protein production machinery? 

Parasites only have to be “good enough” 

The parasitic lifestyle may provide an answer. 

Organisms can be divided into two major 

lifestyles: free-living or parasitic. Free-living 

organisms live in open environments–air, 

soil, water, or ground–while parasitic organisms 

live inside other organisms. “These 

lifestyles are fundamentally different because 

of the difference in competition,” said Sergey 

Melnikov, a postdoctoral associate who led 

the project. While a free-living organism 

competes with others for environmental resources, 

a parasitic organism does not; the 

resources available inside its host are plentiful. 

Without intense competition, parasitic 

Loss of quality control 

Surviving and thriving with mutations 

Although their amino acid sequences may 

be incorrect, these parasites somehow still 

survive. To explain this, Melnikov uses an 

analogy between headphone cords and proteins. 

“Think of headphones. It is very easy for 

them to form knots and fold incorrectly, but 

only one form of the untangled headphones 

cord is useful to you,” Melnikov said. Just like 

headphone cords, proteins can misfold into 

incorrect structures that prevent them from 

executing their intended function. 

To offset the increased possibility of protein 

misfolding, parasites have elevated amounts 

of chaperone proteins. These chaperone proteins 

help guide the folding of the protein into 

its biologically active form. Consequently, 

parasitic proteins are still functional despite 

defects in their sequence. Moreover, protein 

E R R 


cell biology 

FOCUS 

N T I A L 


Helicobacter pylori, a common bacterium that can 

lead to stomach ulcers and eventually stomach 

cancer. Its protein production mechanism is 

characteristic of a parasite, making it a potential 

target for amino acid therapy. 

clumping, a common and catastrophic consequence 

of misfolding, is less likely. 

All of the errors in protein synthesis proofreading 

actually help the bacteria survive the 

host’s immune defenses. This is because the 

errors result in incredible protein diversity. 

Leveraging the errors 

of the parasite could be suppressed without 

affecting the growth of the host. 

The reliance of parasites on chaperone proteins 

can also be targeted with small molecules 

that inactivate chaperones. Although 

this therapeutic approach could impact the 

chaperone proteins of the host as well, it likely 

will affect the parasites much more than it 

will the host, meaning that even a low dose 

could disrupt the growth of parasites without 

significantly impacting host growth and survival. 

Potential targets for these approaches 

include the parasites responsible for ulcers 

(Helicobacteri pylori), sexually transmitted 

diseases (Ureaplasma parvum), and Lyme disease 

(Borrelia afzelii). 

Studying genomes of over 10,000 bacteria 

has shown that a parasitic lifestyle leads to 

the degeneration of the genome, severely diminishing 

quality control systems in protein 

PRONE DNA TRANSLATION 

While typical proteins are constructed from 

twenty stock amino acids, these bacterial 

proteins were found to have over a hundred 

additional amino acid variants. The erroneous 

use of these unnatural amino acids 

would typically be prevented by the tRNA 

proofreading system, which is mutated in 

these bacteria. The result is that every “copy” 

of a protein produced is slightly different 

from the next. 

The constant flux in protein structure allows 

the parasite to evade the host immune 

system. As soon as the host develops immunity–that 

is, learns to recognize and destroy 

certain parasite proteins–the parasite changes 

its identity. These organisms have evolved 

to perfect their role as parasites. 

Researchers are devising novel approaches 

to fight parasite infection that exploit precisely 

this property. “What we are doing here 

is developing a treatment not based on what 

the parasite has, but based on what the parasite 

does not have: the ability to proofread 

amino acids when building proteins,” Melnikov 

said. 

Traditionally, therapeutics target a feature 

that is present in a specific parasite, but not 

in the host, in order to selectively destroy the 

specific parasite. But this knowledge of faulty 

protein synthesis can now be exploited to create 

a therapeutic that targets parasites in general. 

By increasing the availability of unnatural 

amino acids, the protein synthesis of the parasite 

could be disrupted without disrupting 

the protein synthesis of the host, whose proofreading 

mechanisms would prevent the use of 

these erroneous amino acids. If the amino acid 

sequence is sufficiently disrupted so that the 

proteins can no longer properly fold and perform 

functions necessary for life, the growth 


synthesis. These errors are a parasite’s greatest 

strength, as its ever-changing composition 

ensures it avoids the host’s immune response, 

but they also present a key weakness to be exploited 

by future therapeutic approaches. 

KELLY FARLEY 

KELLY FARLEY is a first-year in Morse College interested in science communication. She is the Yale 

Scientific Magazine's Special Sections Editor, teaches a bilingual 3rd grade science class through 

Demos, and leads dance classes for children at Yale-New Haven Hospital through Peristalsis. 

THE AUTHOR WOULD LIKE TO THANK Dr. Sergey Melnikov for his time, knowledge, and enthusiasm 

while explaining his work. 


Melnikov, Sergey et al. 2018. “Loss of protein synthesis quality control in host-restricted organisms.” 

Proc Natl Acad Sci USA. 

A R T B Y S U N N I E L I U 

O R S21 


March 2019 

Yale Scientific Magazine

FOCUS 

molecular biology 

CONQUER 

DIVIDE & 

Sequencing Two 

Types of RNA in 

a Single Cell 

BY MATT TU 

ART BY SUNNIE LIU


FOCUS 

Imagine a police officer chasing two suspects 

down a narrow alleyway. He almost 

catches up to them, when suddenly, the 

alleyway splits into two paths going in opposite 

directions. One of the suspects takes 

the left path while the accomplice takes 

the right path. No matter which choice he 

makes, one convict will go behind bars, 

and the other will remain at large. 

This might seem a far-fetched scenario 

for scientists, but they in fact face a similar 

dilemma when genetically sequencing 

a single cell. Conventionally, much like the 

one policeman, researchers can sequence 

either the messenger RNA (mRNA) or 

micro RNA (microRNA) of a single cell, 

but never both simultaneously. Therefore, 

it remains poorly understood how both 

types of RNA affect and regulate each 

other within a single cell. Recently, a collaborative 

study involving the Lu and Fan 

labs at Yale has led to a method that allows 

both types of RNA from the same cell to 

be sequenced. This method could prove 

useful in a variety of fields, ranging from 

epigenetics to cancer research. 

A look inside the protein factory 

RNA is generally known to serve as a 

template and regulator in protein synthesis, 

but the true complexity of the specific 

roles played by various types of RNAs 

and how they interact with each other is 

less well-known. Each RNA type is like a 

worker with a unique job on an assembly 

line, and each of these workers coordinates 

with every other component in the overall 

production pipeline. The three main types 

are large messenger RNAs (mRNA), the 

intermediate between DNA and protein, 

transfer RNAs (tRNA), and ribosomal 

RNAs (rRNA), both of which are involved 

in the translation of mRNA into functional 

proteins. Less commonly known is microRNA, 

a small RNA composed of only 

twenty-two nucleotides that inhibits gene 

expression by attaching itself to specific 

strands of mRNA, physically blocking 

translation. MicroRNA, alongside a myriad 

of other RNA types, is crucial in gene 

expression regulation. For instance, abnormal 

activities of some microRNAs have 

been linked to the development of cancer 

and the onset of Alzheimer’s disease. 

Divide and conquer 

As a result, many researchers are interested 

in better understanding microRNA 

and other types of small RNA, especially 

at the single-cell level. For Jun Lu, associate 

professor of Genetics and co-principal 

investigator of the study, studying microRNA’s 

role in gene expression can help 

explain slight variations in functionally 

similar cells. “Looking at many genes in a 

single cell at a time has allowed us to detect 

variations of gene expression in cells 

of the same tissue…We are interested in 

understanding microRNA in single cells 

and their relationship to this variability,” 

Lu said. 

The only way to exactly determine the 

effects of microRNA on a cell’s genetic 

variability would be to also simultaneously 

sequence its messenger RNA, since the two 

regulate each other. Although it has long 

been possible to sequence both large RNA 

and small RNA in a group of cells, no previous 

methodology has proven successful 

at sequencing both large and small RNA 

types in a single cell. Directly combining 

current approaches does not work. “Just 

like how certain cooking ingredients cannot 

be added together, any technique to sequence 

large RNA, such as mRNA, cannot 

be combined with techniques to sequence 

small RNA like microRNA,” Lu explained. 

Therefore, in the first part of their 

study, Lu and his collaborator Rong Fan, 

associate professor of Biomedical Engineering, 

worked together to develop their 

own methodology that could co-sequence 

both types of RNA. “If we could somehow 

split the single cell in half, then we could 

sequence the microRNA and mRNA separately,” 

Lu said. In other words, what if 

the police officer in the beginning of this 

story had a partner to catch the other suspect? 

Initially, the team thought about 

engineering an extremely precise tool to 

cut the cell in half like a microscopic cake 

cutter. However, they eventually realized 

that this approach was nearly impossible 

to implement in practice, due to physical 

constraints and the inevitability of damaging 

the genetic material inside the cell. 

Instead, they decided to divide the cell using 

an approach called half-cell genomics. 

In this method, the membranes of single 

PHOTOGRAPHY BY KATE KELLY 

Professor Jun Lu holds a component of the 

laboratory robotics system the team used in 

their methodology. 

cells were first broken. The resulting lysate 

was split into two “half-cell lysates” where 

one was sequenced for its microRNA while 

the other was sequenced for its mRNA. To 

account for the smaller amount of genetic 

material in a half cell compared to a group 

of cells, the researchers chose sensitive sequencing 

techniques. 

Perfecting the “cell-splitting” methodology 

was difficult. For instance, when the 

researchers realized that each “half-cell” 

didn’t have equal amounts of microRNA, 

they had to tinker with freezing and heating 

processes in the cell lysis protocol to 

produce lysates that had equal amounts of 

mRNA and microRNA. With the kinks sorted 

out, the technique proved to be remarkably 

successful–even to the surprise of the 

researchers. Out of twenty trials with single 

cells, nineteen of them passed the quality 

check for both microRNA and mRNAs. 

Insights from the new method 

In addition to verifying their methodology 

on single cell RNA samples, the researchers 

also analyzed the resulting sequencing 

data to determine the degree to 

which variations in microRNA expression 

related to mRNA expression in a single 

cell. As predicted, the variation of abundantly 

expressed microRNAs was significantly 

anti-correlated with the mRNAs 

that those microRNAs targeted, suggesting 

that differences in cell-specific microRNA 

expression alone can lead to non-genetic 

variation between cells. Furthermore, the 

researchers found evidence suggesting that 

some large RNAs could also regulate small 


March 2019 


23

FOCUS 


LU AND FAN BELIEVE 

THAT THEIR "HALF- 

CELL GENOMICS" 

METHOD CAN SERVE 

AS A POWERFUL 

MOLECULAR TOOL 

TO UNDERSTAND 

GENOMICS ON A 

CELL-BY-CELL BASIS. 

of thousands and even millions. To further 

advance this technology and broaden its 

impact, designs of higher throughput is the 

direction to go.” Chen said. Another foreseeable 

direction is to automate and enhance 

the microRNA sequencing process 

using tools like microfluidics. 

A large part of this project’s success was 

attributed to the close collaboration between 

the Lu and Fan labs, and a shared 

interest in developing single-cell techniques 

to study microRNA. “It was natural 

for us. We had expertise on the molecular 

aspects of small RNA research, while Dr. 

Fan had expertise in developing single-cell 

technologies,” Lu said. Zhuo Chen, a graduate 

student in the Fan lab who was part of 

the project team, spoke to the contrasting 

strengths of the collaborators. “Engineers 

are more results-driven and are always trying 

to build things that work. Biologists 

are more detail-oriented and curious about 

why things happen,” he said. 

The collaboration between the Lu and 

Fan labs has led to the creation of a new 

and important method in single-cell gene 

sequencing and will likely continue to reap 

benefits given the multiple promising directions 

in sight. As in the case of co-sequencing, 

it often takes two collaborators 

to divide and conquer. 

RNAs like microRNAs, suggesting an interdependent 

relationship rather than conventional 

one-way regulation of microR- 

NAs inhibiting mRNAs. 

Lu and Fan believe that their “half-cell 

genomics” method can serve as a powerful 

molecular tool to understand genomics on 

a cell-by-cell basis. Specifically, this tool 

could help researchers study the relationship 

between the expression of cancer-initiating 

microRNAs and differences in individual 

cells in cancer tissue. “If we can 

continue improving this methodology, we 

could look at cancer tissue in high definition…and 

extensively study one cell’s 

gene expression patterns in a manner unlike 

other techniques,” Lu said. Moreover, 

this methodology opens the door to other 

methods that can further examine the underlying 

molecular “wiring” between small 

RNAs and large RNAs. “Since we can now 

sequence both small and large RNAs in a 

single cell, we can start to use computational 

tools to figure out the logic behind 

how they regulate each other,” Lu said. Ultimately, 

however, the researchers hope to 

have their new method adopted by others, 

who can apply it to solve a wide variety of 

specific problems. 

Collaboration and continuation 

Despite this recent success, both labs 

acknowledge the limitations of their current 

implementation of “half-cell genomics” 

and seek to improve the speed and 

scalability of this technique. “If you take 

a look at other single-cell measurements, 

you will be amazed at how many single 

cells they can measure in a single run–tens 


PHOTOGRAPHY BY KATE KELLY 

Professor Jun Lu demonstrates operation of the 

automatic pipetting machine in the Lu and Fan 

labs at Yale. 

MATT TU 

MATT TU is a first-year and a prospective Statistics and Data Science major. He is the Webmaster of 

Yale Scientific and is planning to work in Ty Cannon’s psychology lab over the summer. 

THE AUTHOR WOULD LIKE TO THANK Professor Jun Lu and Zhuo Chen for time taken to explain 

their research. 


Wang, Nayi, Ji Zheng, et al. "Single-cell microRNA-mRNA co-sequencing reveals non-genetic heterogeneity 

and mechanisms of microRNA regulation." Nature Communications 10, no. 1 (2019): 95. 


ROBOT 

biotechnology 

SELF-ORGANIZING ABILITY OF ROBOTS WITH- 

OUT CENTRAL CONTROL 

BY ANTALIQUE TRAN 

IMAGE COURTESY OF WIKIMEDIA 

A swarm of kilobots, cheap robots that the research team used 

for modeling, demonstrate the morphogenetic capability of a 

true robot swarm. 

Can technology develop a mind of its own? The robot 

apocalypse is not yet upon us, but the Sharpe group from 

European Molecular Biology Laboratory (EMBL) in Barcelona 

has recently demonstrated the capability of a group of 

robots to self-organize into a swarm without a central control. 

Modeled after morphogenesis, the spatial organization 

of biological systems during embryonic development, the 

spatial behavior of the robot swarm works through feedback 

loops rather than through top-down control. Since 

self-organizing systems have the advantage of adaptability 

in size and shapes and can function despite the unreliability 

of an individual, replicating this biological process in human 

technology could pave the way to innovations in machinery, 

architecture, and pharmaceuticals. 

Previous morphogenetic engineering studies had only 

addressed robotic swarms in small scale simulations or 

through top-down control, but could a true robot swarm 

self-organize on a larger scale? The group addressed this 

question by programming kilobots–cheap robots that allowed 

for large-scale testing of the functioning of a whole 

despite the imperfections of the individual–to follow Turing 

patterns, or patterns derived from feedback mechanisms 

rather than from positional information. 

Combined with robot migration, a Turing pattern determined 

by virtual molecules allowed the swarm to generate 

a pattern without relying on individuals’ precise distances 

and angles from one another. Robots moved only if they 

were on the edge of the swarm and if they were in a region 

of low virtual molecular concentration; they were to stop 

once they reached an area of high molecular concentration 

called a “Turing spot.” LED lights on the robots represented 

molecular gradients that allowed the team to observe the 

spatial patterns formed. 

After the team decided that spots, as opposed to stripes 

or inverted spots, were the best pattern for exploring morphological 

development, a larger-scale study tested the 

swarm’s ability to produce more complex morphological 

shapes. This showed that the swarm could create organic 

shapes just as biological cells are able to. Test trials without 

the programmed Turing patterns did not organize to make 

the same shapes, confirming that the results were indeed a 

result of patterning rather than simple robot movement. In 

line with the adaptability of local self-organized systems, 

the robotic swarm could also reproduce Turing spots no 

matter what the shape or size of the original swarm was, 

and if the swarm was damaged; the swarm could still recover 

the general pattern even if it was split if half. 

This robot swarm thus provides all the advantages of an 

organic, self-organizing system–as the patterns that formed 

were dynamically adaptable. The morphological patterns 

persisted throughout the trials despite varying the size of 

the swarm–ranging from 110 to 300 robots–or varying the 

initial shape of the swarm–circular or rectangular. “Tissue 

healing” also occurred with any inflicted damage. These 

characteristics could be especially useful for applications in 

nanoengineering, such as drug targeting via a nanoparticle 

swarm, or in dynamic machinery and structures, such as a 

bridge that adapts to its river. 

There is a still a long way to go before applications like 

that. Although this proof-of-concept has been achieved 

here using Turing patterns and feedback mechanisms, the 

team hopes for a more sophisticated control system in the 

future able to achieve more complicated shapes. 

THIS ROBOT SWARM THUS PROVIDES ALL 

THE ADVANTAGES OF AN ORGANIC, SELF- 

ORGANIZING SYSTEM—AS THE PATTERNS THAT 

FORMED WERE DYNAMICALLY ADAPTABLE. 

FEATURE 


March 2019 


25

GO WITH 

MODELING FLEXIBLE MICROSCOPIC SHEETS THAT 

FEATURE materials science 

SCULPT THEMSELVES 

The Swiss Army Knife is a necessity for survivalists and 

the outdoorsy, providing tools for any situation you might 

encounter. Researchers at the University of Pittsburgh’s Department 

of Chemical Engineering have created a computational 

model for just that—on a microscopic scale. Researchers 

Abhrajit Laskar, Oleg Shklyaev, and Anna Balazs 

have developed a model for flexible, chemically-active 

sheets capable of interacting with a fluid environment to 

create fluid flow, which in turn moves and alters the shape 

of the sheet. Each sheet is composed of a network of flexible 

chemical bonds connecting nodes coated with catalysts, 

chemical compounds that speed up chemical reactions. 

This potential for autonomous deformation and locomotion 

opens up new opportunities for mechanical and biomedical 

engineering on the microscopic scale. 

A key of the model is a chemical reaction that has reactants 

and products of different volume. “Think of the reactants as 

being little balloons and the products as being big balloons,” 

Balazs said. “The big balloon and little balloon displace different 

amounts of fluid in the container, and so they make 

these local density gradients in the fluid.” This phenomenon, 

known as solutal buoyancy, is the crux of the model. 

The reaction occurs through catalysts which break down 

reactants introduced into the fluid. An example reaction is 

the decomposition of hydrogen peroxide (H2O2) into water 

(H2O) and oxygen (O2). This reaction is sped up with an enzyme, 

called catalase, coated onto a sheet in the shape of a petaled 

flower. The less-dense products rise upward in the fluid, 

changing the direction of fluid flow and causing the petals to 

rise. As the amount of H2O2 remaining in solution decreases, 

the sheet flattens again due to the drop in products made. 

By intermittently introducing H2O2 into the system, the catalyst-coated 

petals can be made to open and close cyclically. 

Coating the petals with different catalysts and setting up a 

chain of catalytic reactions allow for further control over the 

sheet’s shape. However, differing reactions’ rates sometimes 

pose a challenge if the reaction rate of one is significantly slower 

than another’s. This can be compensated for by coating the 

walls of the container with an appropriate catalyst to increase 

the surface area catalyzing the reaction, or by changing the areal 

density of catalyst on the surface of the sheet. 

The sheets can be made to move through the chamber 

by two primary methods. One is modeled by small bumps 

representing unevenness along the bottom surface of the 

container. A catalase-coated sheet would tumble over each 

bump because of its flexibility and chemical activity generating 

upward local fluid flow. In this way, an active sheet 

can be made to move through the channel over obstacles at 

BY MICHAEL ADEYI 


If a chemical reaction involving reactants and products of different 

volumes are symbolized as small balloons and large balloons, the two 

balloons would displace different amounts of fluid in the container. 

the bottom until there is no more reactant to be consumed. 

The second method is to have a catalyst-coated sheet with 

edges heavier than the interior of the sheet, allowing the sheet 

to move like an inchworm—the products flow upward and create 

a bulge in the lighter center. After the reactant is consumed, 

the sheet flattens out, displaced to a new position. Addition of 

more H2O2 can repeat the process and propel the sheet further. 

Another method to induce inchworm locomotion would be to 

coat the sheet with an uneven concentration of catalyst. “You’d 

have more of the catalyst in one region than the other, and you 

could potentially achieve the same thing,” Balazs said. 

The researchers think the sheets could be used to identify 

diseased cells and, acting as claws, remove them from 

the bloodstream for examination. “The gripper itself has 

to be on the same size scale as the cell and also has to be 

very flexible and gentle,” Balazs said. Another use of the 

sheets would be for construction. “You can have these little 

hands that can pick up things in the microfluidic device 

and then do construction.” This could pave the way 

for what could be thought of as microscopic foundries. 

“It’s still challenging to make the sheet sufficiently flexible 

and compliant that it will fold and bend nicely without 

crumpling,” Balazs said. Coating flexible sheets with 

catalyst is not a technology most are familiar with, so 

bringing the model to life in a wet lab may be difficult. 

Balazs and her collaborators have certainly put us on the 

right track, and, regardless of the challenges, this technology 

is sure to do more than open cans and bottles. 

THE FLOW 


PESTS OR 

ecology 

HOW TERMITES HELP MITIGATE THE EFFECTS 

OF RAINFOREST DROUGHT 

BY MAKAYLA CONLEY 


Termites move soil from deep down towards the surface, contributing 

to increased soil moisture and nutrient heterogeneity in rainforests 

during droughts. 

When termites come up in everyday conversation, horror 

stories of tented houses and damaged house foundations 

usually soon follow. However, of all the termite species in 

the world, only four percent are actually pests. Rather, most 

termites help maintain healthy ecosystems and soil integrity. 

This is what led researcher Louise Ashton of the University 

of Hong Kong and a group of scientists from around 

the world to fly to Borneo and study the effects of termite 

populations on tropical rainforest ecosystems. 

The researchers set about creating a large-scale experiment 

to test how native termite species interact with the ecosystem. 

In order to see the difference between environments with 

and without termite populations, the scientists killed off termite 

populations in several controlled plots of land. First, they 

set up four eighty-by-eighty-meter plots in the rainforest and 

physically removed all termite mounds within those areas. 

They then placed toilet paper dipped in low concentrations 

of insecticide across the plots. Since toilet paper is an appealing 

meal for termites, the insects ate the paper with insecticide 

and brought it back to their nests, thus effectively suppressing 

most of the termite population in the experimental zones. 

Ready to watch for an effect on the ecosystem, the timing 

of their experiment proved serendipitous. “We had 

originally intended to understand termites and ecological 

processes, but inadvertently we had data on termites 

during a major drought,” Aston said. The researchers soon 

realized that they had set up an experiment to collect data 

right in time for the 2015 El Niño drought, one of the 

strongest and most damaging droughts in recent history. 

The initial results shocked the researchers. During the 

drought, termite numbers doubled. “Everything else in 

the forest slows down in the drought, but the termites 

thrived,” Ashton explained. According to Aston, the termites 

acted as soil engineers. “They bring clay from underneath 

the soil to the surface to make the sheeting that 

they move around,” Ashton said. This results in greater 

soil heterogeneity and more soil moisture compared to the 

plots where termites were suppressed. 

Soil moisture and heterogeneity are key features of rainforest 

ecosystems intricately tied to biodiversity. Previous 

research shows that seedlings in the rainforest usually start 

growing around five centimeters under the soil surface, 

where researchers in this study noted that termites had a direct 

impact. To study the effect of termites on seedling survival, 

they conducted a transplantation experiment using 

liana seedlings in both the control and termite suppression 

plots. They quantified the number of seedlings that survived 

in soil with and without termite suppression and found that 

the control plots with termites had a significantly higher 

seedling survival rate during the drought compared to termite 

suppression plots. In this way, termites help the rainforest 

maintain a healthy ecosystem even during dry spells. 

In order to confirm that the differences in the initial experiment 

were due to the drought and not some other potential 

factor, the scientists conducted a second experiment the following 

year when the Borneo rainforests experienced normal 

rainfall. The findings of this second study confirmed the results 

of the drought experiment. There was no significant difference 

in the seedling survival rate of the control plots versus 

termite suppression plots during non-drought conditions, 

suggesting it was the doubled termite population that benefitted 

seedling growth during the drought. While it is not yet 

known exactly why termites thrive in drought conditions, tunneling 

and foraging ability in drier ground might play a role. 

This was the first large-scale termite suppression experiment 

ever to be conducted, serving as a model for future 

work in discovering the profound impact little critters 

have on entire ecosystems. While this study focused on the 

rainforests of Borneo, there is further research to be done. 

“There’s significant remaining work on other parts of the 

landscape, like agricultural systems or other disturbed areas, 

to see if they have lost this insurance policy that the termites 

confer,” Ashton said. Understanding how organisms contribute 

to an ecosystem’s response to extreme weather conditions 

has the potential to affect environmental policy and shape 

the way we interact with rainforests in the years to come. 

FEATURE 


ENGINEERS? 

27 

March 2019 

Yale Scientific Magazine

STARING 

by || ELLIE GABRIEL 

art by || ELISSA MARTIN 

AT THE 

SKY 

NASA satellite finds new exoplanets 

just months after launch 

Many of us wonder what lies beyond 

Earth and our solar system. Star Wars, The 

Martian, and other science fiction works 

have helped to quench our imaginations, 

but perhaps it need not all be fiction. NA- 

SA’s recently retired Kepler satellite lasted 

approximately one decade on a mission to 

discover Earth-sized planets in habitable regions 

of stars. The Kepler satellite looked at 

one part of the Milky Way for years, whereas 

a promising new satellite is currently 

exploring the entire sky utilizing similar 

technology. NASA launched the Transiting 

Exoplanet Survey Satellite (TESS) in April 

2018 for a two-year mission. In its first four 

months of surveying, it has already successfully 

identified eight exoplanets, planets 

that lie beyond our solar system, and 

observed more than three hundred others 

for follow-ups. These are of great interest to 

scientists, as the data collected by satellites 

like Kepler and TESS can help answer questions 

about life in the universe and the suitability 

of other planets to sustain life. 

Transiting—the science behind satellites 

Kepler and TESS are able to determine 

the presence of exoplanets by monitoring 

the brightness of a particular star over 

time and detecting dips in brightness due 

to transiting, the movement of a planet in 

front of the star. A planetary transit reduces 

the brightness of a star as it passes across. 

The planet’s orbit can be deduced from the 

time between dips in brightness. 

TESS is expected to be a more effective 

planet hunter than Kepler, because TESS 

surveys a new patch of sky each month. It 

will take just two years for TESS to scan all 

360 degrees of sky seen from Earth. Since 

TESS spends a short amount of time scanning 

each sky segment, scientists do not expect 

it to find many planets with periods, 

the time it takes for a planet to make one 

full orbit, longer than one Earth month. 

Longer-period planets transit less frequently; 

therefore, TESS is expected to primarily 

detect planets with periods less than ten 

Earth days. 

Nevertheless, TESS has already proudly 

confirmed the existence of HD 21749b, an 

exoplanet with a period of 35.61 Earth days. 

The density of HD 21749b suggests a rather 

gaseous atmosphere. “The density is really 

valuable. It gives a sense of the composition 

of the planet,” said Diana Dragomir, postdoctoral 

researcher at the MIT Kavli Institute 

for Astrophysics and Space Research 

and member of the TESS team. Calculations 

like density, mass, temperature, and planet 

size are made possible by TESS technology, 

specifically through measuring how big of a 

dip in brightness occurs during transit. Furthermore, 

the magnitude of the dimming is 

related to the planet’s mass and diameter 


astronomy 

FOCUS 

relative to the star’s size. The star’s size can 

be determined using asteroseismological 

data from TESS. Additionally, the orbital 

size of the planet and the temperature of the 

star can be used to calculate the temperature 

of the planet. Evidently, planets cannot 

be considered isolated bodies, but part of a 

larger celestial system, particularly dependent 

on the stars they orbit. 

TESS and the life question 

IMAGE COURTESY OF WIKIMEDIA 

Researchers are able to explore the totality of the 

milky way galaxy with TESS, which they previously 

could not do. 

TESS is about the size of a big fridge and 

has four telescopes, each about ten centimeters 

in diameter, rather small compared to 

the Hubble Telescope. “It has a pretty funky 

orbital; it approaches Earth once per orbit 

and then swings out to avoid light reflected 

from Earth on the camera,” Dragomir said. 

Such light from Earth would be considered 

as contaminating measurements of light 

from distant stars. “We are looking in the 

inhabitable zone of stars for planets able to 

store water,” Dragomir explained. Earth is 

the perfect distance from the sun, making it 

able to hold water and sustain the immense 

diversity of life that it does. TESS attempts 

to find exoplanets that, like Earth, are located 

in what is known as the Goldilocks zone. 

“We think the results will answer the life 

question,” Dragomir said. 

Outlandish new worlds 

Of the over three hundred exoplanets 

that TESS has observed in its first four 

segments of the galaxy, many are already 

wondering what remains to be found. One 

strange finding was Pi Mensae c, reported 

in September 2018. Pi Mensae c has a 6.27- 

day orbit and is 2.14 times the diameter of 

Earth, with 4.8 times Earth’s mass, such that 

its density is close to that of water. Another 

planet, Pi Mensae b, orbits the same star 

but much more slowly, with a period of 5.7 

years, and has 3170 times Earth’s mass. It 

is rather unusual that Pi Mensae c is able 

to survive the eccentric orbital swinging 

caused by Pi Mensae b. 

TESS has also discovered a planet covered 

in lava known as LHS 3844b. It is 1.3 times 

the size of Earth but maintains an orbit of 

eleven Earth days. Its surface temperature 

of 540 degrees Celsius makes it interesting– 

but unfortunately, not a viable alternative to 

Earth for human life. 

The TESS mission goes beyond simply 

finding exoplanets. The information collected 

by TESS is continuing the space 

revolution with more rigor than any satellite 

before. “We will have 

the means to detect things 

like oxygen on other planets,” 

Dragomir said. Every 

detail discovered about 

other planets will help scientists 

understand Earth 

more thoroughly, as well 

as help improve TESS to 

plan future missions. Processes 

like planet formation 

can be more clearly 

understood by collecting a 

large amount of data from 

TESS’s search. For instance, 

planetary composition 

is key information 

that can help researchers 

discern the chemical reactions 

able to take place on 

individual planets–some 

of which are essential for 

sustaining life. 

Infinite promise 

“We’re working to extend the mission 

from two years,” Dragomir said. She believes 

that TESS will be in space for a while. In an 

effort to make full use of the TESS mission, 

NASA plans to launch the James Webb Space 

Telescope in 2020 to follow up on some of 

TESS’s most prominent discoveries. Besides 

directly hunting for planets and analyzing 

their physical characteristics, TESS is able 

to indirectly learn about planets through 

asteroseismology, a technique where stellar 

sound wave vibrations in stars are used 

to determine the composition of stars, their 

ages, and their sizes. Such sound waves result 

from temperature changes inside the star’s 

convection zone, an area between the core 

and visible surface where hot plasma rises, 

cools, and falls on repeat. When the plasma 

falls toward the core, it releases an energy 

wave that makes the star expand and contract, 

essentially making the star comparable 

to a bell. This bell rings through space. TESS 

is capable of sensing the star sounds while in 

space by seeking changes in star brightness, 

which is indicative of star “ringing.” Knowing 

more about stars can do much to shed 

light on the planets that orbit them. 

TESS has shown incredible promise in a 

rather short time frame. The conclusions of 

the mission are impossible to predict but exciting 

to imagine. TESS has proven that it is 

capable of turning science fiction into reality. 

Visual of Venus transiting across the sun. 

IMAGE COURTESY OF GBPHOTODIDACTICAL 


March 2019 


29

FOCUS 

applied physics 

LIGHT 

READINGBY XIAOYING 

Lights on, lights off 

ral magnetization of the signal. In the past 

decade, since its discovery in gadolinium/ 

As technology continues to evolve, data iron/cobalt alloys, AOS technology has 

writing is growing as an area of interest. seen an influx of attention and a boom in 

Simultaneously, the emerging field of spintronics 

studies how the spin and magneting 

the speed and energy efficiency of data 

research, as it shows potential in increasic 

properties of an electron can be used writing in spintronic memory devices. 

for information processing. All Optical This type of data memory relies on setting 

Switching (AOS) is a related technique the spin of electrons. Each electron can assume 

two states: up and down. These can 

that reverses magnetization of a magnetic 

material with short laser pulses. It allows 

one optical signal to 

patterns of spin can represent bits of infor- 

be utilized to represent data, as different 

control another optical 

mation. Because AOS allows information 

signal through interfering 

with the natu- 

appeal in its efficiency if possible. 

to travel at near light speed, it has wide 

The AOS mechanism still has 

ZHENG 

ART BY 

ANTALIQUE TRAN 

flaws, causing it to lose some speed and energy 

efficiency, but researchers have begun 

to solve some of the issues. 

In the past decade, researchers discovered 

that AOS in Rare Earth-Transition 

Metals (RE-TM) alloys can be performed 

in a single pulse process driven by heat. 

AOS mechanisms in rare earth transition 

metal alloys, as well as their existence in 

ferromagnetic thin films and multilayers, 

were shown. Additionally, AOS has been 

connected to two promising spintronics 

research areas, namely racetrack memory 

and next-generation magnetic random-access 

memory. Racetrack stores magnetic 

signals in regions of nanowires that are oppositely 

oriented, called racetracks. Electric 

pulses are then applied to the nanowires, 

which create so-called domain walls 

between them. The magnetic orientation 

of each region is then used to store bits of 

data. If AOS is integrated successfully in 

racetrack memory, it has the potential to 

store a high volume of information compared 

to existing storage devices such as 

flash drives. However, even though AOS 

was found to be possible in these methods, 

it requires many pulses to switch memory 

states, which bars this type of AOS from 

being used in fast spintronic devices. Only 

a thermal single-pulse AOS mechanism 

can be successfully integrated into spintronic 

devices. 

Searching for new AOS materials 

In recent work done by a team at Eindhoven 

University of Technology, it was 

found that the thermal single-pulse AOS 

mechanism needed for spintronic integration 

existed in multilayers made of a platinum/cobalt/gadolinium 

(Pt/Co/Gd) synthetic-ferrimagnetic 

stack, stacks of alloys 

that display weak permanent magnetism. 

www.yalescientific.org


IMAGE COURTESY OF V3 NEWSDESK 

With continued application of AOS to spintronic 

memory devices, methods for memory storage 

are becoming more efficient. 

A member of the team, professor M. L. M. 

Lalieu, has led research demonstrating that 

this Pt/Co/Gd stack is ideal for integrating 

AOS with spintronics and racetrack memory. 

In this study, Lalieu shows that clear 

single-pulse AOS in Pt/Co/Gd racetracks 

is possible, suggesting that the domain 

walls (which separate magnetic domains) 

of the optically written domains are chiral 

Neél walls, meaning they can be moved 

along the racetrack with the Spin Hall Effect 

(SHE), a means of transport that relies 

on the accumulation of homogeneity 

in spin direction. Additionally, the SHE 

efficiency in this Pt/Co/Gd racetrack and 

domain wall velocities are both predicted 

to be high. Domain wall velocity can be 

used to predict speed of memory devices, 

making its value integral to gaining insight 

regarding the mechanism of AOS in spintronics. 

In order to affirm that single-pulse AOS 

can be found in Pt/Co/Gd wires, tantalum/ 

platinum/cobalt/gadolinium/platinum 

stacks were deposited on silicon substrates 

coated with silicon dioxide (SiO2) at room 

temperature and formed into wires. Each 

wire had a structure called a Hall Cross. 

The magnetization in a Hall Cross is measured 

in order to investigate AOS in these 

wires. The Anomalous Hall Effect (AHE), 

a phenomenon that occurs in ferromagnetic 

solids that measures magnetization, was 

used in order to do this. To identify single 

pulses in the AHE measurement, the team 

utilized slow, repeated laser-pulses. It was 

shown that the magnetization in the Hall 

Cross region oscillates between positive 

and negative states of spin. When measurements 

with AOS were repeated for a longer 

time, a one-hundred percent success rate of 

the AOS was shown, which means that single-pulse 

AOS of magnetization is, indeed, 

present in the Pt/Co/Gd wires. 

It was expected that the domain walls in 

the Pt/Co/Gd were chiral Neél walls, which 

means that the two domain walls were 

symmetrical with respect to spin organization. 

These domain walls could move 

through the wire by means of electrical 

current through SHE and the accumulation 

of a common spin. The direction of motion 

experienced by these domain walls could 

be determined by the sign of magnetization 

and chirality of domain walls. In the top 

layer of the wire, the Pt layer, this motion 

was reported to go against the direction of 

electron flow. 

Spintronics on the fly 

On-the-fly data writing, which is data 

writing that is changed as the process of 

writing data is being carried out, has been 

established through a combination of 

SHE-driven transport of optically written 

domains, or domains that are coded with 

optical signals, and single pulse AOS in 

racetrack memory. In this type of measurement, 

AOS is used for writing a domain in a 

Pt/Co/Gd wire with two Hall Crosses while 

a current is also flowing through the wire. 

Because both the domain walls that have 

the written domains share the same chirality, 

they move in the same direction, along 

the direction of the current, immediately as 

they are written. In this, the full domain is 

transported through the wire. It is then recorded 

using AHE. 

SHE efficiency and domain wall chirality 

in optically written domains were also 

analyzed quantitatively through performing 

field-driven SHE-assisted domain wall 

velocity measurements. In this method, an 

out-of-plane field is applied while a current 

is sent through the wire. Depending on the 

polarity of the current, domain wall motion 

is affected by SHE (either assisted or hindered), 

so an increase or decrease in velocity 

is seen. The wires used for these measurements 

have two Hall Crosses that are 

exposed to gallium ion irradiation. When 

the measurement is started, the applied 

March 2019 

applied physics 

FOCUS 

field causes the domain to expand through 

the wire and pass the two Hall Crosses. This 

is recorded by a switch in the AHE signal. 

It has been demonstrated that thermal single-pulse 

AOS- and SHE-induced domain 

wall motion can be combined in a racetrack 

to utilize the chiral Neél nature of domain 

walls for efficient and smooth motion of optically 

written domains. Because of this, the 

Pt/Co/Gd racetrack is an ideal mechanism 

for integrating AOS into spintronics. The 

integration of AOS with racetrack memory 

could potentially pave the way for integrated 

photonic memory devices. 

IMAGE COURTESY OF CNRS NEWS 

Depiction of electron spin, one of the foundational 

principles of spintronics. 

This discovery holds much power in the 

world of spintronics, as it seems that a potential 

mechanism for creating efficient 

photonic memory devices is finally plausible. 

However, many professionals in the 

field are still skeptical about the application 

of AOS to widely accessible memory devices. 

“I don’t think any of these ideas are reality 

yet,” stated a Yale electrical engineering 

professor who asked not to be named. 

“They have remained in the laboratory or 

on paper for now.” However, if perfected, 

AOS could alter the field of data writing 

and memory, offering society more efficient 

memory devices. 

Researchers use electron 

science to write data in 

photonic memory 


31

FOCUS 

medicine 

Take a Deep Breath 

of Fresh mRNA 

||| by Britt Bistis ||| art by Ellie Gabriel ||| 

converting cells into drug synthesizers 

A recently published study from the Koch 

Institute for Integrative Cancer Research at 

MIT gets glowing results, literally. Using a 

messenger RNA (mRNA) transcript that 

encodes for the bioluminescent, light-emitting 

protein, called luciferase, MIT researchers 

were able to track the expression of the 

aerosolized polymer-bound mRNA that had 

been delivered to mice epithelial cells via a 

nebulizer. The findings hold hope for more 

effective treatments of lung diseases. 

Tackling drug delivery 

Many believe that RNA drugs will be the 

next major achievement in drug development 

technology. These types of drugs either 

target RNA or use RNA directly as a therapy. 

Other types of commonly used drugs are 

small chemical treatments and protein drugs. 

Chemical drugs are generally non-specific 

and diffuse throughout the body. They are often 

not naturally degraded and can accrue to 

toxic levels–sometimes producing considerable 

side effects. The development of protein 

drugs addressed many of these limitations. 

Protein drugs are well-known, well-established, 

and well-funded, with the 2016 global 

market for protein drugs estimated at 172.5 

billion USD. However, protein drugs also 

have drawbacks—the largest arguably being 

that proteins are sometimes immunogenic, 

meaning that they are prone to induce an immune 

response from the body. 

However, DNA has received recent attention 

as a potential therapy. An inhalable 

lipid-DNA complex that contains the gene 

Cystic Fibrosis Transmembrane Conductance 

Regulator (CFTR), which can cause cystic 

The development of protein drugs addressed 

many of these limitations. Protein 

drugs are well-known, well-established, 

and well-funded, with the 2016 

global market for protein drugs estimated 

at 172.5 billion USD. However, protein 

drugs also have drawbacks–the largest 

arguably being that proteins are sometimes 

immunogenic, meaning that they 

are prone to induce an immune response 

from the body. 

fibrosis when mutated, is currently going 

through clinical trials. By delivering the correct 

copy of the CFTR gene, researchers had 

noted some improvement in patients' conditions. 

While researchers are working to op- 

32 Yale Scientific Magazine March 2019

medicine 

FOCUS 

timize the delivery system and enhance the 

delivery system of the DNA treatment, using 

DNA poses specific challenges. "One issue 

with DNA delivery is that a lot of the DNA 

vectors, or molecules used to carry DNA, are 

viral," reports Padmini Pillai, a current postdoctoral 

fellow doing immunoengineering research 

at MIT after receiving her PhD in immunobiology 

from Yale. “This is less favorable 

since it can induce an immune response. Secondly, 

DNA needs to enter the nucleus, which 

THE NEW DESIGN, NAMED 

THE S-HINGE, MAKES 

MATERIALS BETTER ABLE 

TO OVERCOME THE STRESS 

FROM APPLIED FORCES. 

is a big ask," Pillai said. These challenges have 

led MIT researchers and others to pioneer the 

investigation of using RNA instead of DNA in 

aerosolized treatments. 

The promise of RNA drugs 

Despite a deep understanding of how RNA 

can regulate gene expression, researchers 

discounted RNA as a viable therapeutic primarily 

due to how readily it is degraded. The 

experiments conducted in the MIT study employ 

the natural protein-building machinery 

of the cell. By introducing messenger RNA 

into the cell, the cell will use its own synthetic 

pathways to translate this mRNA into 

a functioning protein. Previous studies have 

examined the possibility of using nebulized 

nucleic acids to treat diseases and disorders in 

the lungs, while others have investigated the 

use of systemic delivery of mRNA to combat 

tumors. Both lines of study have yielded positive 

results. Injections of mRNA packaged 

in lipid nanoparticles, fat blobs designed to 

protect RNA from degradation, have shown 

potential in treating cancer in a mouse model 

of melanoma. An mRNA-based vaccine that 

would target tumor cells is currently in clinical 

trial. 

The mRNA transcript does not require delivery 

inside a viral vector like DNA. Furthermore, 

mRNA is more easily transported and 

only temporarily active as it is quickly degraded 

after it has been translated into protein, enabling 

researchers to control mRNA expression 

with precision through readministration. 

Additionally, mRNA only has to enter the cell 

membrane, rather than both the cell membrane 

and the nucleus. One limitation of most 

current forms of RNA delivery is that they are 

non-specific. For example, even if only certain 

cell-types in the lung are diseased or cancerous, 

an injection of mRNA transcript, and by 

extension the protein that it will encode, will 

result in mRNA expression systemically. 

Breathe easy 

The research team investigated two questions: 

Could aerosolized mRNA be administered 

effectively through a nebulizer, and 

what type of nanoparticle would better facilitate 

mRNA delivery? The inhalation of 

aerosolized nanoparticles is a noninvasive 

treatment that has enabled researchers to target 

the epithelial cells in the lungs with precision. 

Systemic drugs, which are injected or 

absorbed into the bloodstream, are expressed 

throughout the entire body. "The benefit of 

the nebulized delivery system of treatment 

is that it facilitates targeted delivery that is 

isolated to the lung. Further, the nebulizer is 

completely noninvasive; no needles or sharps 

[sharp objects] are needed," Pillai said. This 

technique initially showed that RNA was able 

to enter one-quarter of the target epithelial 

cells in mice, evenly distributed throughout 

all chambers of the lungs. 

The MIT team further engineered a 

polymer that more efficiently delivered 

nebulized mRNA to the epithelial cells of 

the lung. To deliver mRNA via inhalation 

through a nebulizer, researchers needed to 

first bind the mRNA to nanoparticles that 

would help facilitate delivery and protect 

the mRNA from degradation before they 

enter cells. The polymer the MIT research 

team used as their nanoparticle is hPbAE, 

which is positively charged, biodegradable, 

hyperbranched polymer. The positive 

charge on the polymer facilitates stronger 

binding between the nanoparticle and negatively 

charged mRNA. Additionally, the 

positively charged nanoparticle will more 

easily penetrate the negatively charged cell 

membrane. Studies cited by the MIT team 

indicate that a hyperbranched polymer is 

better suited to aerosolization than a linear 

polymer. Pillai explains that the branched 

polymers terminated with polar groups are 

more efficient due to their increased solubility. 

The increased solubility results in a 

nanoparticle that can be easily encased by 

water molecules and therefore nebulized 

into water breathable gaseous water particles 

more easily. Further, the nanoparticle 

needs to be biodegradable, as previous studies 

have indicated that non-biodegradable 

polymers can accumulate in toxic levels. 

An RNA future 

“While previous studies have used another 

biomaterial, PEI, to deliver nucleic acids, it is 

not biodegradable, and its accumulation in the 

body can lead to side effects,” Pillai said. Pillai 

is optimistic of the aerosolized-mRNA delivery 

method due to its ability to facilitate targeted 

delivery of mRNA to a specific cell type, 

the lung epithelial cells. She further projects 

that the aerosolized delivery of mRNA could 

have a variety of therapeutic applications, not 

only in cystic fibrosis, but also to a wide range 

of diseases affecting the epithelium of the 

lungs, perhaps even viral infections. The field 

of RNA research is developing therapeutics 

for a broad range of medical conditions, including 

cancer. Whatever the condition, this 

new potential treatment, breaking through a 

sea of criticism and doubt, is sure to provide a 

breath of fresh RNA. 

March 2019 


33

T R A C I N G A N C I E N T 

M O T I O N I N R O C K S 

Pangea is Earth’s most well-known and recent theory rests on geological evidence of a “ring of 

supercontinent. It began to break apart only fire” surrounding the Pacific, where plates in the 

around two hundred million years ago, but the deep Earth come together and drop downwards 

history of Earth’s continental movement starts like a carpet being pulled into a slit in the ground. 

many more hundreds of millions of years ago. As a result, continents, like the furniture on the 

David Evans, director of the Yale Paleomagnetic carpet, collide and can continue to move neither 

Laboratory, professor of geology and geophysics, forwards nor backwards. 

and head of Berkeley College, studies this ancient More recently, Evans has turned his attention 

movement. Recent developments in his research to Rodinia, a supercontinent that existed eight 

have uncovered a new hypothesis. 

hundred to nine hundred million years ago. His 

Unlike Pangea, whose geological record of lab is currently investigating a relatively novel 

breakup is still intact in the ocean floor, the older hypothesis of this supercontinent’s structure, 

supercontinents that Evans studies require a refuting the idea that California was once 

different arsenal of methods, as the oceanic records connected directly to Australia or South China 

of their motion have since descended back into as many other experts have suggested, and 

Earth’s interior. His lab uses paleomagnetism, in looking for other candidates. “People started 

which the magnetic signatures of certain minerals out looking at the big intact pieces of the Earth’s 

in ancient rock are analyzed to draw new insights. crust—Australia is one of those big pieces…For 

By associating the orientations of their magnetic all the pieces that have been suggested, we’ve 

fields with their ages, Evans can hypothesize the been able to refute them through a combination 

path of their movement. 

of magnetic studies or comparisons of geology,” 

Studying continental drift is complicated by the Evans said. Researchers realized that relying on 

fact that bodies of land tend to become deformed these “big pieces” might not work in places like 

as they move. Evans compares the gradual wear Central Asia, where its relatively recent collision 

and tear of continents to having multiple fenderbenders 

on a bumper car and trying to figure 

out what it looked like originally. “Or, using a 

puzzle piece analogy, someone snipping off all the 

interlocking bits and somebody else sanding away 

a bit of the picture of each piece. Of course, many 

pieces also get lost and you’re trying to figure this 

out without a picture on a box,” Evans said. 

Despite these obstacles, deducing a complete 

history of continental movement is important 

for finding patterns and predicting future 

supercontinents. There are three models for the 

assembly of new supercontinents: introversion, 

extroversion, and orthoversion. Introversion 

COU 

NTER 

PO 

BY 

INT 

GRACE 

CHEN 

hypothesizes that new supercontinents form in the 

same location as previous ones; a supercontinent 

breaks up, temporarily opens up an ocean, and 

drifts back together in the same place, perhaps 

in a different orientation. The extroversion 

model predicts exactly the opposite, that broken 

supercontinents rejoin on the opposite side of 

the Earth. The last theory of orthoversion is an 

intermediate theory which Evans’s lab coined 

several years ago. Orthoversion states that 

continents are instead confined to no more than 

ninety degrees from their point of origin. This 

with India has broken up the land into much 

smaller pieces. “What we’re recognizing now is 

there was a big piece there, but you can’t recognize 

it anymore,” Evans added. 

From analysis of field samples collected from 

the area, Evans’s data showed that part of China 

could not have been where people initially 

thought it was, on the side of Rodinia. Instead, 

his data directs it to a spot right in between 

California and Australia. “One of the things that 

really impressed me about the possibilities now is 

that we might need to look at some of these areas 

that have been chopped up by younger events 

and consider those as maybe once-larger intact 

blocks,” Evans said. 

“The ultimate goal is to finish the entire puzzle, 

which is actually a series of puzzles strung 

together across the vast reaches of time,” Evans 

started. Moving forward, Evans hopes to fill in 

another piece of the puzzle by leading his lab 

to Morocco, which used to be part of the West 

African Craton. “When you can play an entire 

movie back and forth of seeing three or four 

supercontinents assemble and break up and 

reassemble again, that is when we can start to find 

patterns,” Evans added. 


CURIOUS 

HEAD MOUNTED 

MICROSCOPES 

BY BRETT JENNINGS 

To study an animal’s brain in real-time as it 

navigates its surroundings, researchers typically 

implant electrodes into the animal’s brain. These 

electrodes track electrical changes in neurons, 

detecting when the neurons are activated. However, 

this method is limited in how many neurons can be 

analyzed simultaneously. “When you are looking at 

activity with electrodes, you are unsure if it is coming 

from one neuron or another area,” said Catherine 

Dulac, professor of molecular and cellular biology 

and researcher at Harvard University. 

To procure a broader view of the brain, Dulac 

and her team have begun to used microscopes 

mounted on top of the heads of mice. “Typically, 

a microscope is something on your desk and you 

put a slide under the lens to look at tissue or fats,” 

Dulac said. “[But] this microscope is a miniature 

version–light enough to sit on the head of a 

mouse.” Small and portable, these miniaturized 

versions of fluorescent microscopes can sit 

on the head of mice, collecting live data while 

the mice perform various activities. These 

microscopes are connected to the neurons in the 

brain through an endoscopic tube, or a camera 

that peers inside an organism. Instead of tracking 

the change in electrical charge between neurons, 

researchers can now view the fluorescence of 

calcium binding in neurons, for example, to 

show signaling between neurons in the brain. To 

pass on a message, one neuron releases calcium 

into the synapse to activate signal receptors 

on the next neuron. The movement of calcium 

produces a change in fluorescent intensity that 

can be observed by researchers. This method 

allows researchers to visualize the activity of 

hundreds of thousands of neurons all at once, 

rather than focusing on just a few. 


Dulac’s team has begun to use these portable 

microscopes to investigate the brain processes 

underlying the perception of social cues. The 

portability of these microscopes enables the research 

team to track the activity of the medial amygdala– 

the brain region that responds to social stimuli–of a 

mouse as it interacts with other mice. The scientists 

can then see how a mouse’s brain interprets the cues 

which determine its response. For example, the 

researchers compared the brain activity of a male 

mouse attempting to mate with a female mouse 

with an onlooking male mouse who decided to 

combat the mating mouse. These microscopes 

can also collect data to make predictions for other 

neurons. “You can take half of the neurons that 

you have recorded and model the form of activity 

mathematically to predict the activity in the other 

half,” Dulac said. “To some extent, you can simply 

look at neural activity and make a guess of what the 

animal is thinking and doing.” 

In the future, researchers hope to apply these 

microscopes to image multiple areas at once. 

This function would give researchers the ability 

to see the dialogue between multiple areas of the 

brain, investigating how brain signals travel and 

pass between different brain regions. 

Additionally, researchers are looking into a 

number of improvements, such as sharpening the 

spatial resolution of the microscope’s images to 

detect more fluorescent colors. Dulac’s team is also 

working on a smaller, potentially wireless version of 

the device as well as a multifunctional head-mounted 

microscope with an electrical probe to stimulate 

or inhibit neural activity. “For a neuroscientist, it’s 

a dream come true to have a window to what the 

brain does when an animal is looking around and 

making decisions,” Dulac added. 

March 2019 

METHODS 


35

UNDERGRADUATE PROFILE 

NICOLE ESKOW (PC ’19) 

LOOKING FORWARD IN CANCER BIOLOGY 

BY TONY LECHE 

PHOTOGRAPHY BY MEHANA DAFTARY 

Nicole Eskow (PC ’19) has always been asking questions. 

“After losing both of my grandmothers to cancer at a young 

age, I began to inquire about cancers and where these diseases 

originate,” Eskow said. Determined to find answers, 

she started to think critically about diseases such as HIV 

and cardiovascular disease. Eskow was not satisfied with the 

information she found on the internet. At fifteen, she began 

conducting research on leukemia treatments in her high 

school’s cell biology laboratory. Her passion for research has 

only blossomed since. Soon after, Eskow started shadowing a 

pediatric hematologist-oncologist at Hackensack University 

Medical Center. After that summer, Eskow knew she wanted 

to pursue both research and clinical medicine. 

Now a Molecular, Cellular, and Developmental Biology (MCDB) 

major, Eskow spends much of her time working in the Krause Lab, 

which is dedicated to researching the mechanism that regulates 

hematopoiesis, the formation of new blood cells, and how that 

process can go awry. Eskow has focused her time on understanding 

acute megakaryoblastic leukemia, a type of pediatric cancer 

that primarily affects newborns. This kind of cancer disrupts the 

development of megakaryocytes, cells that produce platelets, 

which are important in blood clotting. “Interestingly, previous research 

has suggested that this cancer begins to develop in the fetus, 

before a baby is born,” Eskow said. Her project investigates the 

role of a protein known to be mutated in many patients with acute 

megakaryoblastic leukemia. For her accomplishments and dedication 

to research, Eskow was selected for the Rosenfeld Science 

Scholar Program, which supports promising students conducting 

summer research under the supervision of a Yale faculty member. 

Eskow has also played an integral role in the Yale Undergraduate 

Research Association (YURA) since joining her freshman 

year. As the former co-president of YURA, she has helped give 

students easier access to research opportunities on campus. 

During her sophomore year, Eskow compiled a list of all the research 

labs at Yale, featuring descriptions of what the lab studied 

as well as the contact information and general interests of 

the head researcher. This program was released to the Yale community 

in 2016 and is now known as the YURA Research Database 

(RDB). “I find it incredible whenever I hear that first-years 

are finding research labs through the YURA RDB,” Eskow said. 

After graduating, Eskow hopes to pursue an MD-PhD to 

dedicate her time to both research and patient care. “While 

I haven’t completely decided what area of medicine I’d like to 

pursue, I know that I’m very passionate about oncology and 

cancer research,” Eskow said. “I’ve really enjoyed researching 

“I KNOW THAT 20 OR 30 YEARS 

DOWN THE ROAD I’M NOT GOING TO 

REMEMBER THE EXACT NUMBER OF 

PAPERS I PUBLISHED OR MY GPA.” 

hematologic malignancies like leukemia and lymphomas, and 

it’s definitely an area I can see myself pursuing in the future.” 

Looking back, Eskow has gained a better understanding of the 

relationship between her research and her life. “I know that 20 

or 30 years down the road I’m not going to remember the exact 

number of papers I published or my GPA,” Eskow said. “Over the 

past four years, I’ve learned that investing time in the people who 

love and support you is equally as important as building a career. I 

couldn’t imagine my life without the friends and family members 

who have stood by me and helped me get to where I am today.” 


ALUMNI PROFILE 

CHRISTINA AGAPAKIS (YC ’06) 

Being different has always been the norm for Christina 

Agapakis (YC ’06). After receiving her PhD in biological and 

biomedical sciences from Harvard University in 2011, she became 

the creative director in 2015 for Ginkgo Bioworks, an 

organism design company looking to apply biological methods 

to engineering challenges. As a member of the 2012 Forbes 30 

Under 30 list, Agapakis managed to combine her passions in 

art and biology to bring biotechnology to the greater public. 

Growing up, Agapakis has always loved art. “I was interested 

in art in high school and really enjoyed art classes and art making, 

especially drawing and making jewelry. I love the feeling 

of being able to translate something from inside my head into 

something real,” Agapakis said. However, she originally thought 

that she could not meld her interests in art and science together. 

“I used to think that liking art and science were sort of incompatible 

and totally separate. It was not until later in my life that I 

realized the power of the combination,” Agapakis said. 

At home, her parents, who both studied in STEM fields, have 

constantly supported her love of science, encouraging her to join 

programs like Science Olympiad and Odyssey of the Mind. In fact, 

Science Olympiad cemented her interest in biology. “I remember 

an event called ‘Science of Fitness’ where I learned about the Krebs 

cycle, and the biochemistry of it just blew my mind,” she said. 

However, an artist at heart, Agapakis craved a way to combine 

art and biology, but she did not believe that art could contribute 

to her education and career as a scientist until her senior year at 

Yale, when she took Intro to Architecture and Sculptures as Object. 

“These two courses really helped me rewire my brain and allowed 

me to approach problems differently,” Agapakis explained. 

While pursuing her PhD, she met Pam Silver, an RNA expert 

pioneering the field of synthetic biology, who became Agapakis’s 

mentor. During this time, Agapakis finally realized how art could 

be part of her scientific practice: artists ask questions, solve problems, 

and find different ways to see the world–missions also essential 

to scientists. “Art [has] helped me be a better scientist and totally 

shifted my perspective on what a scientist should be,” she said. 

Many of the questions she hoped to answer in synthetic biology 

required her to think beyond her laboratory work–towards 

more general scientific principles. Agapakis began blogging at 

Harvard, exploring the impact and implications of biotechnology. 

Her pieces range from discussing the social and political 

“ecologies” of producing cheese to the irony of design evolution. 

“I believe that the intersection of society and biotechnology is 

so powerful. By making scientists more engaged and aware of 

social issues, it makes us better scientists,” Agapakis explained. 

BRIDGING BIOLOGY AND ART 

BY TIFFANY LIAO 

IMAGE COURTESY OF ERIN CHIA 

More importantly, blogging enabled her to finally combine her 

interests in biology and art. “By writing, I was able to put out 

my thoughts, even if they were unfinished. Then, people would 

reach out, and that is how I started connecting with artists and 

designers working on synthetic biology,” she said. 

After finishing her postdoctoral studies at UCLA, Agapakis 

joined her interests in art, biology, and writing together at Ginkgo 

Bioworks, which shares her vision to make the world of biotechnology 

more approachable. She now leads a Ginkgo venture nicknamed 

Project Cretaceous, which works with multidisciplinary 

artist Daisy Ginsberg and scent researcher Sissel Tolaas to bring 

back the smell of extinct flowers. The resulting artwork will be presented 

at numerous galleries and exhibitions as an interactive piece 

in which individuals can smell the scents of ancient flowers such as 

the Hawaiian mountain hibiscus (Hibiscadelphus wilderianus) and 

the Falls of the Ohio scurfpea (Orbexilum stipulatum). “This project 

is the result after years of doubt, wondering how in the world 

would I combine these two interests of mine,” Agapakis explained. 

“The most important thing is to keep pushing and changing 

what you think of when you think ‘scientist,’” she said. “We 

need more political, artist, teacher, feminist scientists–individuals 

who have multiple interests and are willing to combine 

them to better the world.” 


March 2019 


37

SEX ON THE KITCHEN TABLE 

THE ROMANCE BETWEEN PLANTS AND YOUR FOOD 

B Y K H U E T R A N 

Vulgar, dirty, and exposed–these descriptors may come to mind upon reading the title of 

Norman Ellstrand’s new book. However, in Sex on the Kitchen Table: The Romance of Plants 

and Your Food, Ellstrand actually illustrates a much more demure topic: the importance of 

understanding the relationship we have with the food we consume. 

Each chapter highlights a specific crop, seamlessly melding its history, anatomy, and special 

reproduction system. Using humorous metaphors and a distinctly easygoing voice, Ellstrand 

discusses the reproduction, economics, and politics surrounding the future of each 

plant, culminating in a delectable homemade recipe. “I can’t pick just one to be called my 

favorite,” Ellstrand said. Ellstrand gives human-like sexuality and mechanisms to each plant: 

the bisexual tomato plant, for example, self-pollinates using its flowers. Though playful, each 

recipe demonstrates our exploitation of plant sexuality. 

Ellstrand explores the complex, twisted history of–as well as humanity’s influence behind–each 

plant’s reproduction system, revealing that the foods we eat evolved from very 

different looking plants thousands of years ago. Currently a professor at the University of 

California, Riverside, Ellstrand teaches a class called “California Cornucopia,” where he 

utilizes fruits mentioned in his book, such as the sterile banana, to teach plant biology. 


scie 

in 

spot 

“You can’t understand why sex is important without examining something without sex,” 

Ellstrand said. 

Additionally, Ellstrand illuminates the potential problems that may arise in these vegetable 

sexual reproduction systems. For instance, when a plant possesses only “female” or “male” 

reproductive parts, it runs into self-incompatibility issues and thus, cannot reproduce. 

While Ellstrand wrote Sex on the Kitchen Table, his second book, to be humorous and casual 

pleasure reading, his first book, Dangerous Liaisons, was a scholarly science book directed 

at policy makers, selling less than nine hundred copies in fifteen years. Although he feared 

that his colleagues would criticize Sex on the Kitchen Table for being unscientific, the general 

public loved the simple, beautiful analogies he employed to describe biological functions 

of plants in this book. For example, Ellstrand said, “Tomatoes are self-fertile individuals 

[that] have the potential to serve as both mother and father to one or more of their kids.” 

This book will not only change your perspective on tomatoes, bananas, avocados, beets, 

and squash, but it will also morph your view of vegetables into the erotic plants that they 

truly are, opening your eyes to observe the nature around you as perhaps a bit spicier. 


nce 

the 

light 


Ian Cheney’s (YC ’02) 2018 film The Most Unknown takes a different approach than most science documentaries. 

Although his film explores how people study organisms, space, quantum physics, geobiology, 

and the human mind, Cheney, a graduate of Yale College and the Yale School of Forestry and Environmental 

Studies, ultimately tells a story about the field of science itself–one about what it means to think, question, 

experiment, and live as a scientist. 

The Most Unknown’s opening credits acknowledge that the documentary itself is an experiment. The film 

takes viewers around the globe, from ocean floors to mountain peaks, to meet nine accomplished scientists. 

As the quirky stories of those researchers intertwine and each travels to learn about the work of another, 

Cheney showcases the excruciatingly detailed and thoughtful processes behind scientific discoveries. The 

film highlights the passion that these scientists throw into their work and the joy that comes with contributing 

even a bit more to both the “answered” and “yet-to-be-understood” piles within their respective fields. 

A microbiologist obsessed with slime visits a physicist who enthusiastically explains how his “simple” dark 

matter-detecting machine works. Sardonically, the physicist refuses to speak on the whereabouts of dark 

matter because he believes that scientists should not speculate without substantial reasoning and experimentation. 

Later, we travel to the peaks of Hawaii with an astrophysicist and an astrobiologist: macro- and 

micro-scales of science align when the astrobiologist, who spends most of his time looking through microscopes, 

saw how similar the speckled night sky through a telescope looks to the cosmos-like arrangement of 

archaea under a microscope. Finally, we meet a cognitive psychologist, Yale professor and Silliman Head of 

College Laurie Santos, on an island near Puerto Rico inhabited by monkeys. As some of the last images taken 

before Hurricane Maria hit just three weeks later, the beautiful footage from the island resonates especially 

deeply with audiences. 

Regardless of the various scientific fields and special environments in which they work, these nine scientists 

all have stories that beautifully stitch together to shed light on universal unknowns. Santos, whose work 

has centered on applying scientific answers in ways that directly help people, hypothesized that most scientists 

do not have what psychologists refer to as a need for certainty. Scientists are comfortable admitting the 

extents of their knowledge. Thus, The Most Unknown illuminates the human face of science–a particularly 

important feat given how the field often seems so distant, sterile, and daunting. “How I think about science 

in just the last few years has expanded–not just answering these questions in ivory tower pursuits but finding 

ways to bring the science back to people,” Santos said. 

The Most Unknown humbly reminds us that even scientists lack all of the answers. After all, questions are 

what perpetuate the grand scientific experiment of uncovering the unknowns. 

CHENEY’S REVOLUTIONARY SCIENCE DOCUMENTARY 

B Y K A T I E S H L I C K 

THE MOST UNKNOWN 


March 2019 


39

Interested in writing for 

Contact us at 

yalescientific@yale.edu 

AD_Yale_SC_ENG_half Winter Issue_2019.qxp_8 2/11/19 1:05 PM Page 1 

Kudos to the YSEA Award Winners! 

Your achievements inspire all of us in the Yale STEM community. 

Advancement of Basic and Applied 

Science Award: 

Daniel Prober, Ph.D. 

Professor of Applied Physics, Physics and 

Electrical Engineering 

Experimental solid state physics and 

superconductivity 

Distinguished Service to Industry, 

Commerce or Education: 

Michael Gold ’60 BS, M.Eng 

Founder & President, Gold 

Metallurgical Services, LLC 

Former Principle Engineer, Babcock & 

Wilcox Power Generation 

Meritorious Service to Yale: 

Brian Scassellati, Ph.D. 

Professor of Computer Science, Cognitive 

Science & Mechanical Engineering 

Director of the NSF Expedition on Socially 

Assistive Robotics 

Thank you for continuing Yale's rich tradition in STEM. 

Awards shall be presented at the YSEA Annual Dinner, April 12, 2019. 

For more information visit: ysea.org

YSM Issue 92.1

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