David Virshup fuelled by the thrill of discovery | MEDICUS 2024 Issue 2

David Virshup: Fuelled by the thrill of discovery
By Dr Chua Li Min, Science writer

Prof David Virshup, pictured here in his lab // Credit: Duke-NUS

Step into cancer biologist David Virshup’s corner office and you will be immediately struck by its eclectic and vibrant decor. Sitting in a corner that overlooks the heritage neighbourhood of Tiong Bahru, is a huge red Chinese drum, now repurposed as a table while vibrant works of art adorn the limited wall space, stretching out along the corridor to welcome any visitor.

Hidden within this tapestry of colours are some of Virshup’s prized possessions hinting at his deep-seated love for science—a brass antique microscope; a time-worn book on electron microscopy; and a cover from a 2018 issue of Developmental Cell.

Together, these items weave the story of a lifetime dedicated to science, one that saw him traversing the coasts of the US—twice—before moving to the little red dot, where he has lead Duke-NUS’ Cancer Stem Cell and Biology Programme since the School’s establishment.

“The level of detail he applies to troubleshooting is incredible—he will break down the experiments reagent by reagent to help you determine what went wrong.”
Asst Prof Zahra Kabiri

“He has followed a coherent path, laying very important groundwork in several fields and he has done this in a consistent way,” noted Virshup’s mentor Duke Professor Emeritus of Biochemistry Vann Bennett.

To many who know Virshup, it is this relentless curiosity that defines him, which he deftly balances with scientific rigour.

“He always encourages us to validate our results using two to three different methods,” recalled Dr Zahra Kabiri, a former PhD student of Virshup’s at Duke-NUS. “While he will get excited about new results, he never bases his conclusions solely on the first set of findings. Instead, he’ll challenge us to investigate further,” added Kabiri, who’s now an assistant professor at Duke.

Surfing the world of science

“I could have been born in Paris,” mused Virshup, adding that his father, who was a military doctor at the time, had been given two choices: specialise in cardiology in San Francisco, or general medicine in Paris, France. Keen to train as a cardiologist, he chose the former.

After his father left the military, the family settled in the San Fernando Valley, where he continued practising as a cardiologist.

It was there that Virshup was first introduced to science, beginning with invigorating discussions that unfolded at the dinner table about anything under the sun—from the inner workings of the microwave to how cells looked under his father’s brass microscope.

School science projects made for memorable father-son moments with his father doubling up as his scientific mentor. “I remember doing an experiment where we added peroxide to blood for my third-grade project. Seeing the blood foam was pretty cool.”

A photo of a brass antique microscope

This brass microscope now sits in Prof David Virshup’s office // Credit: David Virshup

On the weekends, Virshup would head to the nearby beaches of Malibu and Zuma. While the teenaged Virshup enjoyed the sun, sand and sea, equally irresistible was the pull of the lab, where he could marvel at the different equipment and reagents and learn how they work. “I just loved hanging out in the lab,” he added.

So, he spent his summer vacations working for a friend of his father’s. “He was a pathologist and I would be in his lab spinning down blood, doing urine dipsticks and things that were considered acceptable back then,” said Virshup, with a twinkle in his eye. But he was also curious about what it was like to be a doctor.

And what better way to find out than join his father on rounds at his group practice?

“He would explain the different parts of the human body and medicine—cases we had just seen, how the optic nerves were organised, so it was all very formative,” recalled Virshup.

“And he loved what he did. So much so that he founded a hospital with his colleagues because they thought they needed one in that area. He even constructed their coronary care unit,” added Virshup.

Seeing how much his father enjoyed his job inspired Virshup to follow in his footsteps. So, when it came to choosing his major at Beloit College, there was no doubt that science was the most logical choice.

The chemistry of a good equation

“The fun part of being a science major was trying to figure out how things worked,” recalled Virshup, who quickly became fascinated with the complexities of balancing chemical equations. “What I really enjoyed was biology and chemistry.”

While most nights were dedicated to studying, Virshup’s teacher also gave his class the opportunity to do basic research in the lab, on top of the routine experiments they did in class. “He introduced us to the idea that you could start doing some real experiments. It didn’t go anywhere, but it got me thinking that this was fun,” added Virshup, who majored in chemistry.

Till this day, Prof David Virshup loves to get up to draw chemical structures during lab meetings // Credit: Norfaezah Abdullah, Duke-NUS

His hard work paid off when he was offered a place to study medicine at Johns Hopkins University after aceing his Medical College Admission Test.

But there was another reason for Virshup to celebrate—meeting his wife in college, who majored in Classics at the time. Their paths crossed after she went to study in the science building, where Virshup was based because the heating in her block was switched off.

While the pairing of a classics and science major seemed unlikely, the chemistry between them was undeniable. “We are kindred spirits,” reflected Virshup, sharing a mutual love for travel and adventures.

Photo showing Prof David Virshup and his wife scuba diving

On a scuba diving trip with his wife (left) // Credit: Courtesy of David Virshup

Exploring uncharted territories in the lab

That adventurous streak also drove Virshup to explore uncharted areas in the lab. Even while he pursued his medical education at Johns Hopkins, Virshup did not pass up on opportunities to do research.

His curiosity led him to embark on many projects, first as a medical student and later, as a clinical research fellow in paediatrics.

It was an exciting time for Virshup as he learnt from the best in the field. “There’s a big theme of getting the right mentor at the right time.”

“The fun part of working in the lab is that you get to chart your own path and discover new stuff. And if you make a mistake, you wash it down the sink and you start over the next day.”
Prof David Virshup

In the lab of renowned haematologist William Zinkham, Virshup witnessed first-hand how Zinkham came up with a hypothesis based on his clinical observations. This led Virshup to investigate why certain individuals with an inherited blood disorder fared better when given a drug for treating urinary tract infections. “He thought it could be caused by smoking,” said Virshup.

“It was a very simple kind of 1950s tech project,” added Virshup, who bubbled carbon monoxide through patient blood samples, under the supervision of Zinkham. “And we discovered one setting in which smoking may have been good for you. And then I got hooked to research.”

With Bennett whom he returned to on three separate occasions during his 13 years at Hopkins, Virshup delved into a range of topics, from purifying insulin receptors to screening for drugs that affected the membranes of red blood cells. “Vann was extremely hands-on in the lab and taught me how to do the very basic stuff,” recalled Virshup.

By the time he was back for his third stint, Virshup knew what he wanted to work on, and how he would get there. Even if that meant coming up with a novel method to identify the proteins involved in moving nutrients into cells.

Bennett observed: “His approach of combining biochemistry with electron microscopy was unusual back then. Most labs were either biochemistry or electron microscopy labs. But David was both as a single researcher. It was a real foreshadowing of how successful he was going to be when he became a lab director.”

That project earned Virshup a paper in the Journal of Cell Biology, as well as an NIH Physician-Scientist training award.

While balancing the demands of his clinical duties, lab work and that of a young family proved challenging, Virshup was not in it alone and had his wife’s full support.

Having witnessed her father’s dedication to electron microscopy—one which eventually led him to write a book about it—led her to understand the demands of a research career. So she remained a constant source of encouragement for Virshup as she balanced her career and the needs of the family.

A copy of the “Introduction to Electron Microscopy”, written by Cecil Hall, Prof David Virshup’s father-in-law now sits in Virshup’s office // Credit: Norfaezah Abdullah, Duke-NUS

But when his grant neared its end, Virshup had to decide on his next career move. As it so happened, the Vice Chair of Paediatrics at Hopkins, Professor Mike Simmons, had just assumed the position of Chair of Paediatrics at the University of Utah.

“So, my wife said, ‘Why don’t you just write him?’,” recalled Virshup. “He got back really fast and told me about this new programme they were building to support physician-scientists.”

After a trip to the new research building and a meeting with the programme lead, genetics researcher Ray White, Virshup was sold.

So he moved his family to Utah, where he continued his work as a physician-scientist.

Meeting Wnts

The next 17 years were filled with ski holidays and hiking trips for the Virshups, who made the most of the great outdoors the state had to offer. “Utah was a great place to grow both my career and my family,” said Virshup.

Moving to Utah also marked another significant milestone for Virshup, who established his first independent laboratory at the newly established Eccles Institute for Human Genetics.

It was there, too, where he discovered his passion for Wnts, a class of signalling proteins essential in the development of multicellular organisms.

While these proteins play a crucial role in the body, they are also implicated in certain cancers when the signalling pathway goes rogue, leading to metastasis and enabling tumours to evade the body’s immune system.

“It wouldn’t have happened if I had skipped out on the talks,” told Virshup in an earlier interview with MEDICUS, referring to the serendipitous way in which he discovered a role for the enzyme, protein phosphatase 2A (PP2A) in regulating Wnt signalling, while attending a research-in-progress seminar.

Prof David Virshup in his office // Credit: Norfaezah Abdullah, Duke-NUS

For Virshup, Wnts were an expansion of his work in the search of proteins that PP2A binds to, the knowledge of which would provide insights on the molecular mechanisms of the enzyme in cells.

“So, we went from phosphatases to looking at phosphatases that are involved in Wnt signalling,” said Virshup, who hopes that his quest in unravelling the complexities of Wnt signalling could lead to the discovery of potential targets for therapy in certain cancers.

And I will walk 14,000 km across the globe

While moving to Singapore never occurred to Virshup, that changed after he came across an advertisement in Science.

“I saw Pat’s name at the bottom of the ad. And I knew Duke is a class operation and Pat was a guy I would be happy to work for,” said Virshup, referring to Professor Patrick Casey, the School’s former Senior Vice-Dean for Research and now Virshup’s fellow colleague at the Programme.

“The very first thing I did was: ‘Ask the wife’,” he grinned. After the all clear from his wife, one email and several phone calls, Virshup flew to Singapore, where he met Casey.

On what made him recruit Virshup, Casey explained: “It became clear very quickly that he had the leadership qualities. Within a month, we were on the same page and within six months, he was in Singapore. He was our first international recruit.”

(L-R) A moment captured during the School’s early days with Professor Patrick Casey, Emeritus Professor Shirish Shenolikar from the Duke-NUS Cardiovascular & Metabolic Disorders Programme, Prof David Virshup, Professor Scott Summers from the University of Utah, and Virshup’s colleague from the Programme Professor Ong Sin Tiong // Credit: Courtesy of Dolliss Ang

But that’s not the only thing Casey remembers Virshup for.

“He helped us finish off the renovations for the temporary facilities so we could start doing research. Because he got here early enough, he also gave his opinion on the configuration of the Khoo Teck Puat building. So he was involved in all aspects, certainly of Level 7,” recalled Casey. And that’s where Virshup continues to grow the Programme, as well as his research on Wnts.

With his team, he challenged paradigms, cracking the mystery of where Wnts originate in the gut, as well as the role of other key proteins such as porcupine (PORCN) and Wntless in promoting Wnt signalling in cancers. “When people think about those two proteins and their role in Wnt signalling, they automatically think about David Virshup,” remarked Casey.

Prof David Virshup shares a group photo with his lab // Credit: Duke-NUS

Inspiring the next generation

Virshup has also taken his research one step further by developing a drug, ETC-159, that prevents PORCN from triggering Wnt signalling, offering hope to patients with Wnt-addicted cancers.

With this drug, his team has made further discoveries, such as why stromal cells in the intestines are resistant to Wnt inhibitors—a finding that made the cover of a 2018 issue of Developmental Cell, as well as their recent breakthrough on why some pancreatic and colorectal tumours resist targeted anti-Wnt drugs.

While he is proud of what he has accomplished, what gives Virshup the most satisfaction is seeing students and junior researchers mature under his guidance.

For fellow clinician-scientist Kabiri, her time in Virshup’s lab has inspired her to be meticulous in her research, just like Virshup. “The level of detail he applies to troubleshooting is incredible—he will break down the experiments reagent by reagent to help you determine what went wrong.

“And because he’s trained as a doctor, he’s always thinking about the body as a whole and how we have to do everything at the physiological level, so it was fun and inspiring to learn from him.”

Echoing the same sentiments, Dr Xu Peng, a former graduate student from Virshup’s lab previously, added: “The joy of doing science in his lab has motivated me to continue my scientific career in academia, with the hopes that someday I will become a great scientist like him.”

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Xu, now an associate research scientist at the Yale School of Medicine, still looks back at the eureka moment he shared with Virshup with fondness: “We were trying to make sense of interacting proteins of PP2A-B56, a phosphatase family protein in David’s office when he suddenly exclaimed in excitement: he’d spotted a phosphorylation site. It’s incredible how he was able to spot the phosphorylation motif just by reading the raw protein sequence.”

But it is exactly this blend of passion and curiosity that continues to propel Virshup forward in uncovering the intricacies of Wnts.

“You have to want to do it, and you have to love it. The fun part of working in the lab is that you get to chart your own path and discover new stuff. And if you make a mistake, you wash it down the sink and you start over the next day,” he concluded.

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Among his eclectic décor and many prized possessions that document 17 fulfilling years at Duke-NUS, there remains just space for one last addition: a painting by his wife, who started taking art lessons after moving to Singapore.

A painting by Heidi Virshup

Virshup, Heidi. Peaceful village. 2024