Singapore Surprise

When a Chinese-American cancer researcher got a chance to move his lab and his family to the Far East, he was faced with one tough decision.

By Kate Ledger

Anyone who's ever ventured into a scientific laboratory knows the ambiance can seem like another planet. Researchers have this tendency to blot out everything but their lab work-including the practicalities of everyday life. That's the way it was, too, for a biomedical researcher named Wen Son Hsieh-until a couple of years ago. Then, suddenly, Hsieh found his research ambitions falling into synch with his family life in a marvelous way.

Hsieh (pronounced "Shay") had just finished a postdoctoral fellowship at Hopkins with oncologist Richard Ambinder. He'd been part of a lab team making great strides in understanding the Epstein-Barr virus, a mysterious pathogen that most people in the world encounter at some point in their lives without even knowing it. In healthy, young adults, EBV can cause mononucleosis, or in someone who's severely immunosuppressed, it can trip off certain lymphomas, but most people simply develop an immunity to the virus without ever getting sick.

For certain groups of Asians, though, particularly those from south China, the same virus acts in a much more dangerous way. In an otherwise healthy person, it spurs a tumor of the endothelial tissue in the nose and throat called nasopharyngeal carcinoma or NPC.

Ambinder's group of researchers had revealed much about the Epstein-Barr virus. They'd deciphered how the virus hides itself in tumor cells and even developed a plan for treating NPC. Hsieh had hoped to continue those studies, but he needed to study the cancer in patients, and patients with NPC just don't turn up in the United States. "In all my training," he recalls, "I'd seen four or five cases of NPC-total."

Then, out of the blue, Hsieh got a stunning job offer. Ambinder asked his newly minted postdoc if he'd like to take a giant transcontinental leap and spend three years as a researcher (and assistant professor of oncology) in Hopkins' recently established branch in Singapore. Called Johns Hopkins Singapore, the ultramodern facility is operated in collaboration with Singapore's National University Hospital, which has set its sights on becoming the leading center for cancer care in its part of the world. As part of that plan, in 1999 Hopkins recruited Alex Chang from the University of Rochester Medical School to head its Singapore oncology division. Since then, the Singapore service has grown to become a nexus of science and patient care.

Interestingly, in this tiny country of 3.5 million people, many of whom emigrated from south China, NPC ranks as the fourth leading cancer. Twenty years ago, a group of Singapore scientists even localized a gene for NPC susceptibility. Genetics, however, seems to be only part of the picture in unraveling the mysteries of why Epstein-Barr causes this cancer in Asian populations. By putting Hsieh on site in Singapore, says Ambinder, "suddenly we had an opportunity to get the answers to crucial questions. What was the virus's role? Why was it causing this cancer and not others?"

But moving to Singapore represented a monumental decision for Hsieh. Could he ask his wife, Francesca, and their then-11-year-old daughter Katherine to move half way around the world to a tiny country in the Pacific? And for Hsieh himself, giving up his life in the United States wasn't something that came easily. Although he was born in Taiwan, he grew up from age nine in Bowling Green, Kentucky, attended medical school at Hopkins and did a residency at Duke. Francesca, who'd been born in Korea, also had spent most of her life in the United States.

"We were hesitant," Hsieh acknowledges. Even though Singapore is Westernized, it's a big deal to move away from everything familiar."

But there also was much to recommend the move. Both Wen Son and Francesca would be closer to relatives who still lived in their native countries. And they could give their daughter, as Hsieh puts it, "the experience of growing up in an Asian culture-an understanding of what it is to be Chinese." And so, they took the plunge.

ADJUSTING TO SIGNAPORE took even more time than the Hsiehs had imagined. Everything from downsizing to living in an apartment, to dealing with the tropical heat felt strange. Wen Son's American mannerisms suddenly set him apart, things he'd never thought about, like his tendency to greet strangers as he walked down the street or voicing opinions at work.

"It's our practice as Americans to discuss issues without coming off as confrontational," he ponders. "Chinese are less likely to say you're wrong."

For Hsieh, differences like these prompted reflection about his own mixed-cultural characteristics. "In the United States I'm sometimes said to be too diplomatic," he says. "It's my heritage. But I'm still American enough not to be willing to let things go by without commenting on them. I just wait. Here it's more typical to manage issues completely behind closed doors."

But on the tiny island, Hsieh also found a country burgeoning with energy for the biomedical sciences. "Singapore," he says, "is building the infrastructure to be a leader in medicine. It's amazing to be part of the development from the ground up-and because decisions about funding or building tend to be made by a small number of people, things can happen quickly."

Hsieh now sees as many as four or five patients a week who have the mysterious cancer he studies. More prevalent in men than in women, the disease hits with flu-like symptoms: blocked hearing, sinus congestion and nose bleeds. "People in their late 30s or 40s might shrug off the signs as a passing cold," Hsieh says. "But it's a fast-moving cancer that grows quickly, and if it's left too long, it can be deadly." It runs in families, but nobody knows why this population of Asians is at risk.

The critical moment is fast approaching. Using the research that Ambinder began, Hsieh is about to start clinical trials of treatments for NCP. One of his tactics will be to use a vaccine that goes after EBV proteins to impel the immune system to assault first the virus and then the tumor. In a variation, Hsieh will extract immune cells from the patient and stimulate them externally (a process known as in vitro t-cell expansion) to work against the EBV. When the enhanced cells are reintroduced, the immune system attacks the virus hiding in the cancer cells. "The idea is to take advantage of the presence of the virus to kill the tumor," Hsieh explains.

In his other therapy, Hsieh will use a chemotherapy agent called 5-azacytidine to try to block the destructive cascade the virus trips once it's inside the cell. Normally, a virus has a certain set of its own genes that it turns on to begin its mischief. Other gene combinations get turned off, either because they're not needed or because they'd tip off a person's immune system to the virus's presence. But with this approach, 5-azacytidine, in effect, never lets the "bad" gene switch get turned on. Instead, alternate genes are expressed, giving an "all points bulletin" that alerts immune cells cruising in the vicinity. The technique is new and relies on the latest information on the chemical-interference process called methylation. Both tactics may be usable with several other cancers.

The stringent protocols used by Hopkins researchers in Singapore not only must pass the Internal Review Board in Baltimore but also the scrutiny of the National University Hospital and the Singapore Ministry of Health. Singapore patients tend to ask fewer questions about potential new therapies than Americans, Hsieh finds, but are just as likely to say no when it comes to testing them. Elderly patients, he notices, worry more about being used as guinea pigs. His Mandarin Chinese has proven a distinct benefit in explaining the pros and cons of participating. "The questions patients ask," he says, "are very much like at home," and most are well informed. They've gotten information off the Internet."

But as with almost everything else, what Hsieh senses most about practicing medicine in this shiny, tiny country on the other side of the world is an infectious feeling of excitement, "not like any kind of experience you could have in the U.S. or Europe. I can imagine," he says, "staying right here way beyond three years."