Shawn Je - engineering breakthroughs in neuroscience | MEDICUS 2024 Issue 1

Shawn Je: engineering breakthroughs in neuroscience
By Nicole Lim, Senior editor

Assoc Prof Shawn Je, pictured here with Research Fellow Dr Yu Weon Jin, brings an engineer's perspective to neuroscience // Credit: Norfaezah Abdullah, Duke-NUS

Neuroscientist Shawn Je is the first to admit that he has a sweet tooth.

“When I lived in the US, I tried all the candies in the supermarket to find the best one,” said the associate professor with Duke-NUS’ Neuroscience and Behavioural Disorders Programme.

Quirky as that may be, few who know him are surprised.

Professor Patrick Casey, a professor with Duke-NUS’ Cancer and Stem Cell Biology Programme and the School’s former Senior Vice-Dean for Research, said: “For some, seeing is believing. For Shawn, testing is believing. He’s not going to take anything on faith.”

This extends to Je’s approach to science too. His colleague and fellow neuroscientist Assistant Professor Alfred Sun added: “Shawn is very fundamental in the sense that he will not cherry-pick or go after best guesses. He is extremely rigorous.”

And that rigour is evident in throughout the lab of engineer-turned-scientist: Pipettes hang next to electrodes; new model systems are built to answer otherwise unanswerable questions; and experiments are conducted with custom-built solutions that range from bespoke-built microscopes to constructs that allow him to measure brain activity without interference or artefacts.

“Intellectual growth should commence at birth and cease only at death.” – Albert Einstein

Born in South Korea, Je was a very good child, who never talked back to his parents. In fact, he didn’t speak at all. His parents were on the verge of enrolling their four-year-old son in a school that catered to mute children, when he surprised them by starting to talk. A voracious reading habit followed, which soon led him to Albert Einstein.

“I became a scientist after reading the biography of Dr Albert Einstein,” said Je.

Combining his interest in the sciences with a photographic memory, he excelled at studying and aced the knowledge-based exams required of Korean students. And was quick to work out how to maximise his scores in national exams.

“In these standardised tests, there’s always an answer, so I developed a skill for giving the best answer,” he said.

He was placed on a fast-track programme in high school, from which he graduated aged just 17. During that time, he clinched the top spot in the national exams twice and regularly competed in national science challenges.

“It was then that I realised there was no point in being number one on a standardised test. I was going into a field where nobody really knew the answer.”
Assoc Prof Shawn Je

“Tuition centres wanted me to be their student—for free,” he recalled with a shrug.

But as he followed in the footsteps of Einstein, Je felt increasingly inadequate. Surrounded by equally talented peers, he “kind of freaked out”: “I couldn’t even make it into the international Olympiad, but my friends were competing and getting gold and silver medals.”

Outcompeted by his friends in math and computer science, Je searched for his niche, enrolling first in mechanical engineering and two years later, chemical engineering and biotechnology.

In the end, he chanced upon his calling during his volunteering work. Ever since he had been in high school, he accompanied his mother to spend a few hours every week volunteering at his church, playing with children with different needs.

“Among the children, there was this boy, he didn’t respond to anything,” recalled Je. “But whenever the Gatorade commercial came on, he would bang his head. At that time in Korea, people didn’t really know about autism.”

Unable to forget the encounter, Je knew he wanted to help: “In my grad school application, I wrote that I want to find a cure for autism, for that boy,” said Je.

To do that, he had to switch fields.

“Falling in love is not at all the most stupid thing that people do, but gravitation cannot be held responsible for it.”—Albert Einstein

For the logically minded engineer, the switch was at first “one of the biggest mistakes”.

“Engineering is all about solving math problems, which I’m good at,” he said.

“But when I started grad school in Michigan, it was all about presentations and essays, I suddenly had to convince people, the science alone wasn’t enough.”

And he had to embrace biology, a subject that until then he’d detested for its comparable messiness.

Adopting the same approach he takes with candy, Je started over, relearning everything from textbooks, the most valuable of which—Human Molecular Genetics, Histology, Developmental Biology and Molecular Biology of the Cell—today have the honour of acting as his monitor stand.

A photo of a monitor elevated on four biology textbooks

Assoc Prof Shawn Je uses the four textbooks to lift his monitor // Credit: Nicole Lim, Duke-NUS

“It was then that I realised there was no point in being number one on a standardised test. I was going into a field where nobody really knew the answer. What is Parkinson’s? What is autism? And there’s a billion different ways to approach the question.”

A member of the Je lab is working on an electroencefalography or EEG electrode used to record brain activity electrode // Credit: Norfaezah Abdullah, Duke-NUS

Liberated by this realisation, Je didn’t worry about wrong answers or whether his experiment might fail but focused on how he could advance our knowledge of the brain. And where better to do that than at the National Institute of Health, which was then at the height of research funding and sprawled across 60 buildings. He entered the Graduate Research Programme as the only PhD student in Dr Bai Lu’s lab, competing with ten postdocs. His graduation requirement? One first-author paper per year in a journal of higher-impact than the Journal of Neuroscience.

“Ridiculous, right?” said Je. “So, I worked like crazy. I worked from 8am to 2am, stacking my work so that I could do multiple experiments at the same time.”

One of his productivity hacks was to attach Post-it notes to his monitor in the electrophysiology room, which he rotated so that he could see the screen through the window from his work bench. The Post-its made it easy for him to track neuron activity while he was working on another experiment like molecular cloning.

Long hours, stacked experiments and just three days off—that’s how Je spent the five years of his PhD. And the three days of leave he allowed himself? For his honeymoon in Key West.

But he graduated from the programme with an armful of papers in top journals and the luxury of applying to any lab for his postdoc.

“I decided to apply to Dr Mike Ehlers’ lab at Duke. He was awarded a young investigator award at SFN [Society for Neuroscience] as well as the Howard Hughes Medical Institute Investigator, and I thought he was a genius,” said Je.

With six confocal microscopes in the lab alone, Je was in a candy store. “Even the entire department of neuroscience put together had as many confocals as we had in Mike’s lab,” he recalled. “I had total freedom to do any crazy experiment I could think of.”

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“A person who never made a mistake never tried anything new.” – Albert Einstein

But this freedom came with a price, in the end: “My two best projects that I completed during that time were scooped.”

Because other groups had published similar work first, his projects lacked the novelty that academic journals require. This included developing a new mouse model that recapitulated what happens when the brain experiences an imbalance between excitation and inhibition, widely believed to be an underlying driver of psychosis and schizophrenia—work that had taken him three years to complete.

“This experience made my postdoc terrible,” said Je. “At the same time, my wife gave birth to our first child. And she asked me, ‘Why don’t you get a real job, not just a postdoc?’”

Without a published paper to his name from the postdoc training, that seemed an impossible ask.

“He brings a broad perspective to a project, offering knowledge, conceptual guidance and unique ways of thinking about science. To me, that was a big plus.”
Asst Prof Alfred Sun

When Je heard that Duke’s new venture in Singapore was recruiting neuroscientists, he submitted his CV.

“I got an email from Dale Purves, founding director of the neuroscience programme at Duke-NUS, inviting me to Singapore,” said Je, who returned from that trip with an offer letter in his hand.

Reflecting on the decision to offer Je the position, Casey recalls, “Dale told me that this is someone we want to take a chance on because he’s not a traditional neuroscientist. Shawn will always be out there pushing some boundary, trying to comprehend what he doesn’t understand.”

“Everyone knew it was impossible, until a fool who didn’t know came along and did it.” – Albert Einstein

When he came to Duke-NUS, Je’s first task was to make human neurons to test his hypotheses—at a time when there was no established protocol for growing neurons. He spent three years working on a protocol to make inhibitory neurons and another three growing midbrain organoids—protocols that didn’t just work for him. So far, 13 other labs have successfully grown midbrain organoids using Je’s protocol.

Dr Yu Weon Jin, a research fellow in Je’s lab, calibrates their specially made microscope for the next experiment // Credit: Norfaezah Abdullah, Duke-NUS

But he is more than a toolmaker. Together with collaborators from institutions across Singapore, Je used the midbrain organoid model to reproduce, for the first time, clumps of proteins that are a hallmark of Parkinson’s disease in humans, called Lewy bodies. They published their findings in the Annals of Neurology in 2021.

Commented Casey: “The interactions Shawn had with the folks at the National Neuroscience Institute, the Genome Institute of Singapore, they helped him form the questions he was really interested in addressing.”

Sun, who worked on the brain organoid project while at the Genome Institute of Singapore, had warmed up to Je from the start: “When he picked up the phone, his accent reminded me of an ex-colleague from Stanford whom I got on with very well.”

When asked to describe his former mentor and now colleague, Sun said: “Shawn’s a genius and you can quote me on that.

Small pea-sized human midbrain organoids are grown from human stem cells to enable scientists to study how the human brain develops and communicates // Credit: Shawn Je, Duke-NUS

“He is a pure scientist, which can make him challenging to work with at times. But he brings a broad perspective to a project, offering knowledge, conceptual guidance and unique ways of thinking about science. To me, that was a big plus.”

Today, the two still talk mostly about science and life as an academic, but their friendship has deepened beyond that, as they discuss everything from the philosophical to the quotidian: children, faith, rents, health, mobile phones and movies.“

He has an opinion on almost everything,” said Sun.

Three men posing in the lab, from left: Alfred Sun, Shawn Je and Qiang Yuan

Assoc Prof Shawn Je (centre) and Asst Prof Alfred Sun (left) with Qiang Yuan, then a research fellow from Je lab // Credit: Duke-NUS

“Life is like riding a bicycle. To keep your balance, you must keep moving.” – Albert Einstein

Je not only has opinions on almost everything, he is also very competitive—not just in the lab but outside too: an avid basketball player, he joined the medical students who used to play at the back of the Khoo Teck Puat Building once a week.

“Dr Shawn was very enthusiastic about basketball and didn’t mind playing with us, students,” said Dr Matae Ahn, a Duke-NUS alumnus from the Class of 2022, who used to organise the basketball games. “The two of us were always on opposite teams as we were the two tallest players.”

While most of their talk was about the game, they did touch on science at times. “He talked about his work, his experiences and how he made it to being faculty,” said Ahn, who enjoyed these inspiring and encouraging chats.

Despite several injuries, Je would always return to the court. It was only after he earned a warning from his surgeon that performing Kobe moves would lead to a knee replacement that Je stopped playing basketball.

But even when he was laid up for weeks on end, Je didn’t sit idly. Casey recalls bumping into Je after one of his later surgeries: “When I next saw him back at work, he told me that he’d learned a new type of programming language, so he can use AI in a way that would add value to his work.”

“Strive not to be a success, but rather to be of value.” – Albert Einstein

But driven by the memory of his first encounter with that boy with autism, Je keeps returning to his search for a cure. And after talking to about 50 parents of children with autism while he was still in the US, he has an extensive list of research questions. These range from studying environmental changes, such as the introduction of Prozac, and genetic changes to changes in the immune system during pregnancy caused by infections.

Je believes that being in Singapore gives him a unique advantage in his mission to find a cure for autism: “The good thing is that Singapore is small, and I have many opportunities to interact with clinicians at KK Women’s and Children’s Hospital, whose services are used by people from all over the country.”

One such clinician is Derrick Chan. Chan had 12 patients who lived with Angelman syndrome, a rare genetic form of an autism-spectrum disorder, which occurs in about 1 in 15,000 live births in Singapore, and that triggers frequent seizures.

Using lab-grown neurons and brain organoids, Je and his collaborators at the National Neuroscience Institute investigated why these children experience seizures. Their first-of-its-kind study pointed to a single gene as the likely cause of these seizures.

Reflecting on this discovery made in 2020, Je said: “I’m very happy to be here and doing more translational work.”

He attributed this focus on translational work to Purves’ influence on him. “Dale would always ask me, ‘What’s next?’ and ‘Why is this important?’ He really helped to instill in me to focus on what’s meaningful. Don’t just chase science for the sake of it.”

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Still, some experiments conducted purely out of personal curiosity remain necessary. So, when he moved to Singapore in 2011, he began evaluating every candy bar in the supermarket here, starting with Cadbury’s which had not been available in the US at the time.

And his conclusion about the best candy? “M&Ms with peanuts, because they are not as sweet as M&Ms, and are bigger and naturally crunchy.”