Pursuing science to the beat of his heart |MEDICUS 2023 Issue 3

Wang Yibin: Pursuing science to the beat of his heart
By Dr Chua Li Min, Science writer

When Wang Yibin gets caught up with his research, it is all he can think about.

“The potential impact of our findings keeps me literally awake,” said Wang. And his current project to decipher the metabolic pathways involved in heart failure is no exception.

Driven by a curiosity about the world around him, Wang has spent most of his career seeking answers to complex problems in cardiovascular health.

“Yibin is not afraid to do the most important and often difficult experiment to understand the system or the problem that he’s addressing,” said Duke University School of Medicine Professor Howard Rockman, who met Wang when they were both postdoctoral trainees 30 years ago.

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The freedom to embrace science

“I never had any fear about pursuing my own interests,” recalled Wang, who grew up with two older brothers in Nanjing, China.

“My parents gave me tremendous freedom, and I quickly recognised that if nothing else, I was a very exploratory person. I liked asking questions, even if that meant challenging an established paradigm,” he added.

And science offered him the perfect way to do just that.

For Wang, pursuing his college education at a time when China was opening up was exciting to say the least.

Captivated by the influx of ideas and information, the undergraduate science student seized every opportunity to learn about the latest developments in science—even if that meant sneaking into a lecture intended for graduate students by famed Nobel Prize laureate Andrew Huxley.

“I was fascinated by his elegant theory explaining how muscles move based on the images he captured on the electron microscope,” explained Wang, who was studying biochemistry and genetics at Fudan University in Shanghai.

That fascination led Wang to set up a science club with a few like-minded peers to work on self-initiated projects, like translating a molecular biology classic into Chinese just so that everyone in the club could enjoy the book.

He spent many hours each day absorbed in his work, checking his translations against a thick English-Chinese dictionary.

“It was all hand-written. We worked on different chapters, and I was nominated to transcribe all our translations into a single copy because everyone felt my writing was the most legible” said Wang.

“The biggest fun in science is independence.”
Prof Wang Yibin

His eyes lit up as he recalled the moment his club finished translating all the chapters from “The Eighth Day of Creation” by science writer Horace Freeland Judson: “It was amazing!”

Inspired by the role models he had read about, as well as the famed Chinese geneticist Tan Jiazhen, who was head of the School of Life Sciences at Fudan at the time, Wang decided to embark on his graduate studies in molecular genetics at the Baylor College of Medicine in the US.

Riding the wave of molecular biology

“Baylor was a mecca for human genome research,” said Wang. “We would get all this mail with dried blood samples that we analysed for specific gene mutations.”

With so much happening around him, it was an exciting time for Wang, then a PhD student: “I was very lucky to catch that wave (of genome research). That was also when we started to link particular genes to diseases.”

Over the next four years, he devoted himself to studying the gene that was implicated in phenylketonuria, a rare inherited disorder that causes brain damage if left untreated.

In those days, polymerase chain reaction (PCR) machines, which amplify genetic material by running DNA through as many as 30 or 40 hot-cold cycles, hadn’t been developed. And most of the reagents—from the enzymes to the primers required in a single PCR reaction—had to be produced from scratch.

Armed with a stopwatch, three water baths and a bucket of ice, Wang became a human PCR machine for part of his PhD time. “My timer would beep, and I would have to quickly transfer the tubes from one water bath to another,” he recalled. But he made good use of the many downtime moments, reading scientific papers.

Credit: iStock.com / Sinhyu

The next day would be spent analysing the samples on thin slabs of gel, followed by a wait of another few days to develop the results on x-ray films that would reveal whether the experiment had worked.

Just when he was about to graduate, the research centre got its first PCR machine: “It was a ginormous machine hooked to water pipes that produced a very loud hissing sound at each heating and cooling cycle. It was certainly a huge contrast compared to our modern PCR machine!”

Witnessing these developments in the field first-hand made Wang realise the transformative power of tools and technology in advancing research. “It used to take me one full week to complete a simple sequencing experiment. But now this process can be accomplished in hours, thanks to automation,” he said.

So when it was time for him to set up his lab, Wang embraced the use of new technology.

“From the traditional biochemistry approach, to genetically modified preclinical models to the cutting-edge multi-omics approach, Dr Wang is fearless in taking on any new technologies and tools,” said Dr Gao Chen, Wang’s former PhD student.

Professor Wang Yibin in his PhD lab on graduation day // Credit: Wang Yibin

Following his heart

By the time Wang graduated, one thing was clear—he enjoyed the freedom that came with being a scientist in academia, carving his own niche. “The biggest fun in science is independence,” he said.

And already Wang knew what he wanted to work on next. He wanted to understand how amino acids affect brain function, a question that was inspired by his PhD project on phenylketonuria.

Because of the gene mutation, individuals with the disease are deficient in an enzyme that breaks down the amino acid, phenylalanine. When high levels of the amino acids accumulate in the brain, it becomes toxic.

To find his answers, Wang joined Nobel Prize laureate Gerald Edelman at The Scripps Research Institute in San Diego, California.

But it was the heart that eventually gave him the flutters.

“Both the heart and brain are terminally differentiated and cannot regenerate that much. But because there are fewer cell systems to study them, research is lagging behind.”

“I came to science with a gut feeling. And in the process, I lost my mind, but I found my heart.”
Prof Wang Yibin

Wang still remembers when the full impact of that realisation set in.

He was, once again, listening to a lecture, this time by his postdoctoral supervisor Professor Kenneth Chien at the University of San Diego, California: “That was when I realised how the heart and the brain were so much the same.”

Immediately, Wang saw an opportunity to address questions in cardiovascular disease using his expertise in genetics to study diseased tissues from preclinical models and humans.

“I like to say: ‘I came to science with a gut feeling. And in the process, I lost my mind, but I found my heart’,” he chuckled.

“We were just beginning to discover how cells respond to changes in the environment internally through signalling pathways, and that’s exactly what I believe the heart is doing.”

So Wang focused his initial efforts on studying signalling pathways in the heart.

While these pathways provided some answers as to why the heart fails, Wang realised they did not hold true for all patients.

“We missed a very important equation in our original understanding of heart failure. It turned out that one major, major change in patients was their metabolism—they are unable to utilise energy optimally. Particularly in heart failure patients with preserved ejection fraction who are often old, and suffering from other complications, such as obesity and diabetes, as well as hypertension. Because of the stiffened muscles in their left heart chamber, they are unable to pump sufficient blood around the body,” he said. “And every standard therapy we tried with them didn’t work.”

Determined to get to the bottom of this, Wang pressed on, turning to the area he knew best, the genome. And what he discovered led him back to where he began: amino acids.

“We found that a specific form of amino acid metabolism was altered in heart disease,” explained Wang.

“Yibin is not afraid to do the most important and often difficult experiment to understand the system or the problem that he’s addressing.”
Prof Howard Rockman

At the time, the role of amino acid metabolism in metabolic diseases such as heart failure was unheard of.

This breakthrough offered hope for a potential therapeutic target that could restore heart function for these patients with preserved ejection fraction. “We discovered that targeting amino acid metabolism had a huge impact on the disease outcome,” added Wang.

These findings have since been developed into drugs that have progressed to clinical trials. “I was consulted throughout the process, so it was really exciting,” said Wang.

To Rockman, Wang’s achievements came as no surprise. “It’s a combination of creativity and experimental courage that have enabled him to make very important discoveries over the course of his career,” he observed.

The courage to challenge the existing paradigm

It took Wang and his team at the University of California, Los Angeles many years to convince the scientific community of their findings.

Recounting his journey, he said: “I went through a lot of self-doubt because I looked at our data, and couldn’t believe what we had found. So we generated a lot of data to convince ourselves, and others, that this was really important.”

But it wasn’t just data that the team collected.

They had also benefitted from this experience in less tangible ways. “Dr Wang challenged us to think as independent scientists, and also taught us the importance of interpreting data with rigour,” recalled Gao, now an assistant professor at the University of Cincinnati, who was part of the research team working on the project then.

Added Wang: “I realised that if you are rigourous in your approach and your conclusion is solid, the findings will speak for themselves. That’s the beauty of science. When everybody else starts to confirm your results and pharmaceutical companies start to develop new therapies—that’s the best validation.”

It is a story that he continues to write with his team at Duke-NUS where he now leads the School’s Cardiovascular and Metabolic Disorders Programme, as well as with his collaborators at Duke.

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Having served on the scientific advisory board of the National Heart Centre Singapore for years prior to joining Duke-NUS, Wang had long had his finger on the pulse of research developments at the Programme. The rapid pace at which progress was made excited him, and when the opportunity to assume the directorship arose, it didn’t take long for Wang to decide.

“Yibin was exactly the type of individual we were looking for to lead the Programme”, said Professor Patrick Casey, who at the time of Wang’s recruitment was the Senior Vice-Dean for Research. “He had stellar research credentials in both cardiovascular sciences as well as in metabolic disease, exhibited excellent EQ and leadership traits, and was clearly still in the ascending portion of his career. As soon as we finished the first interview, we knew we had found our person; the task then was to convince him to move halfway around the world and join us!”

Sharing his vision for the programme, Wang added: “The Programme has an important role to play in the face of Singapore's ageing population, with rising healthcare costs brought about by the burden of cardiovascular and metabolic illnesses. We strive to advance our current knowledge of these diseases by harnessing cutting-edge technologies, and to provide impactful solutions to tackle these challenges by translating innovative discoveries into real-world applications through further research and collaboration.”

Wang (back row, centre-left, in blue) and members from the Programme at Duke Durham for a joint symposium held in collaboration with the Duke Cardiovascular Research Centre and the Duke Molecular Physiology Institute // Credit: Wang Yibin

Since helming the programme, he has championed initiatives to encourage interactions between the faculty here and at Duke, starting with a series of monthly seminars that have culminated in a joint symposium held earlier this year in Durham, in collaboration with the Duke Cardiovascular Research Centre and the Duke Molecular Physiology Institute.

Drawing parallels between networks of genes and molecules to research collaborations that are forged in real-life, he stressed: “A strong network offers robustness, fresh ideas as well as an opportunity to survive and thrive in response to changes in our environment. We have an academic home that is outside of Singapore, and that has always been one of Duke-NUS’ unique strengths that we should continue to draw upon to make a greater impact in science and research together.”

The lighter side

Outside of the lab, Wang enjoys cooking, hiking, watching movies, and playing the 二胡 (erhu) or Chinese fiddle.

"I love to cook ChaShu made from pork belly, but it's not necessarily the most successful according to my wife and daughters!"

And when family and friends visit, his favourite tune to entertain them with is “Amazing Grace”.

Wang Yibin with erhu

Wang playing the er-hu // Credit: Wang Yibin