What’s Different About Asia?

Upon learning firsthand that Asian and Caucasian patients responded differently to cancer drugs, John Wong founded the Cancer Therapeutics Research Group to study these differences.

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AsianScientist (Jul. 26, 2016) – In 1985, a young Singaporean doctor sat outside the office of the chairman of the department of medicine at Cornell University. After graduating from the National University of Singapore (NUS), John Wong badly wanted to train with the best minds in the US.

But nobody there had heard of NUS; few even knew where Singapore is.

Without confidence in his medical training, every programme he applied to had summarily rejected him. Cornell seemed like his last chance.

“I went in and gave this fifteen-minute sell,” he says. “The only difference was I offered to work for free.”

The strategy worked. Cornell took him on as an intern, making it clear that he would be on the next flight home if he did not measure up. He went on to become chief resident in medicine at the New York Hospital-Cornell Medical Center.

Now a professor in medical sciences at NUS and chief executive of the National University Health System (NUHS), Professor Wong is a highly-regarded oncologist who has led significant efforts to understand and treat cancers that predominantly affect Asian populations. As an administrator, he has also been instrumental in shaping Singapore’s biomedical sciences and academic medicine initiatives from their very beginnings.

A tremendous need at home

“I never worked so hard in my life,” says Professor Wong, of those first years at Cornell.

All his colleagues—from the medical student who visited a patient at home just to make sure she was okay, to the resident who for every case would go to the library and find three relevant references to share with the team—made a big impact on him.

“It was illuminating to see that people could work so hard and love their work so much,” says Professor Wong. “Their degree of professionalism was so intense. That was one of the biggest eye-openers for me.”

Professor Wong returned to Singapore in 1992, when only a handful of cancer specialists were practicing in the country. Singaporeans of means, he recalls, would sometimes seek treatment halfway across the world.

“I came back to Singapore because I thought there was a tremendous need. There’s no reason why Singapore can’t have the same quality of medicine,” he says, referring to treatments for cancer.

In the US, he had seen how top hospitals, by working with pharmaceutical companies to run clinical trials, obtained good drugs for their patients years before their commercial release.

One example in particular sticks with him. In the late 1980s, a drug called amonafide was found to be ineffective against breast cancer, except in the small number of Chinese-Americans enrolled in the trial (90 percent of patients in clinical trials at the time were Caucasian).

It turned out that amonafide needed to be acetylated (a chemical reaction that adds an acetyl group to the molecule) by the body in order to become active; this happens more quickly in Chinese than in Caucasians.

The drug’s selective efficacy undermined its market potential in the West; the pharmaceutical firm decided not to pursue its development.

“But just imagine if they did that trial in Singapore,” Professor Wong says, noting that the drug might have been developed as an effective treatment for Asian patients.

How could patients in Singapore enjoy the same level of access to experimental drugs? While governments and philanthropic organisations are the main funders of initial research in drug discovery, venture capitalists and pharmaceutical companies typically bear the cost of late-stage drug development.

Given the high costs and risks involved—an estimated US$2.6bn is needed to bring a drug to market, with a success rate of about 10 percent—pharmaceutical companies would need compelling reasons to shift R&D away from experienced US medical centres to Singapore, a country with little experience in clinical trials.

Understanding Asian cancers

Cancer is caused by genetic changes that affect how cells grow and divide. These changes may be inherited, or may be acquired over one’s lifetime, either as a result of errors that accumulate as cells divide, or through exposure to carcinogens such as cigarette smoke or ultraviolet radiation from the sun.

The development of cancer involves a complex combination of such genetic and environmental risk factors—consider that not every smoker will develop lung cancer, while some non- smokers may. And, as the amonafide trial demonstrated, genetic factors can also affect how patients respond to cancer treatments.

Poring over data from the Singapore Cancer Registry, Professor Wong and his colleagues noticed that Singaporean women were being afflicted with lung cancer at almost the same incidence as in the West. However most of the cases in the West were associated with cigarette smoking, whereas most of the cases in Singaporean women were in non-smokers, suggesting that doctors here may be dealing with a different disease.

In 1996, Professor Wong’s team collaborated with James Bishop, an oncologist at the Sydney Cancer Centre, to run head-to-head trials of a docetaxel and carboplatin regimen—common chemotherapy medication—for non-small-cell lung cancer in Singapore and Australia.

The results were striking—the response rate in the predominantly Chinese Singaporean population was double that in the largely Caucasian Australian. It was one of the first studies to show an effect of ethnicity on response to chemotherapy. It turned out that the drugs were metabolised more slowly in Chinese patients, giving them more time to work their effect.

Importantly, the data allowed doctors to make ethno-specific dose recommendations. But it also caused disgruntlement.

“I remember when I presented this data in Boston; this lady in the audience got up and called me a racist,” Professor Wong recalls.

These studies also drew the attention of pharmaceutical companies eager to tap into the growing Asian markets for therapeutic drugs. The US Food and Drug Administration (FDA) and National Cancer Institute (NCI), which had little data on non-Caucasians, were also keen to collaborate on clinical trials.

In 1997, capitalising on this interest, Professor Wong founded the Cancer Therapeutics Research Group (CTRG), a consortium of researchers from around the Asia-Pacific region. Still active today, the CTRG carries out clinical trials of treatments for cancers that predominantly affect Asian populations, including nasopharyngeal, gastric, and liver cancers.

Building programmes and recruiting whales

In the late 1990s, Professor Wong, by then vice-dean of the NUS School of Medicine, was a key member of the team that strategised Singapore’s biomedical science initiative.
The study of diseases that disproportionately affect Asians, they knew, would be an important niche for Singapore. Its three major ethnic groups—Chinese, Malay and Indian—are representative of much of Asia. Rather than competing directly with much more established Western medical centres, Singapore could instead work with them on comparative studies.

Professor Wong recalls helping to write the concept paper for what was then termed the Singapore Genomics Programme (SGP)—aimed at understanding Asian and Caucasian genomics—in one caffeine- and junk-food-fueled night, holed up in someone’s kitchen.

The SGP needed a leader. At a CTRG meeting in Hong Kong in 2000, Professor Wong mooted the idea to Edison Liu, then director of the division of clinical sciences at the US NCI.

“We were staying at such a cheap hotel that there was no place to sit—we had to sit on the floor near the elevators,” says Professor Wong. “We talked all night about Ed moving to Singapore.”

In 2001, in a recruiting coup for Singapore, Professor Liu became the founding executive director of the SGP, later renamed the Genome Institute of Singapore (GIS). He would go on to head GIS until 2011, building it from a skeleton crew of three people into a thriving institute of nearly 300. GIS researchers now study the genetic basis of diverse human diseases, including cancers, infectious diseases, eye diseases, and neurological disorders, and have identified genes associated with susceptibility in both Asian and Caucasian populations.

Bridging the gap

Medical innovations in areas such as vaccine development or organ transplantation often arise through close partnerships between medical schools and hospitals. In Singapore, however, for years administrative structures did not support this integration of clinical care, research, and education—termed academic medicine.

For decades, the NUS School of Medicine and the National University Hospital (NUH) had been administered separately.

“If you wanted to translate [apply] anything from NUS into a patient, you needed to make a case firstly to NUS and then to NUH,” says Professor Wong.

Professor Wong played a major role in linking NUH and the NUS schools of medicine, dentistry and public health under a unified governance structure. NUHS—Singapore’s first academic medical centre—was established in 2008.

The challenge, he says, is that the link between clinical care, research and education is often not intuitive. Singapore needs to integrate the three in order to develop solutions to its own particular set of health problems. Convincing the public of this is a constant uphill battle, but an important one.

“You can’t expect Western taxpayers to develop solutions for dengue or the diseases we face,” Professor Wong says.

“It’s been very rewarding to see the quality of science and the opportunities in science now completely transformed from what it was ten or fifteen years ago.”

This is also true for clinical care—it is now rare for Singaporeans to seek second opinions overseas, he adds.

His biggest concern, however, is drive: “I think the quality of our own talent, our students and our young faculty—they’re easily as good as anywhere else in the world. But what our talent needs to do is to be hungry.”

He encourages mentees to visit top medical and research centres in other countries, such as the US, to experience their level of intense professionalism.

Professor Wong now devotes the majority of his time to running NUHS. He also sees patients, some of whom have been with him for twenty years.

His packed schedule leaves him with little time for outside pursuits. But a good doctor practices what he preaches—Professor Wong at least attempts to get enough exercise and sleep, just as he asks of his patients.

This feature is part of a series of 25 profiles, first published as Singapore’s Scientific Pioneers. Click here to read the rest of the articles in this series.


Copyright: Asian Scientist Magazine; Photo: Bryan van der Beek.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Shuzhen received a PhD degree from the Johns Hopkins Bloomberg School of Public Health, USA, where she studied the immune response of mosquito vectors to dengue virus.

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