Period of Adjustment

Four years ago, setting up a branch of Johns Hopkins Medicine in Singapore seemed pretty simple. It turned out to be anything but.

By Kate Ledger

The jungle is probably the last place in the world you'd expect to find a CEO. And yet it is here, to the Bukit Timah Nature Reserve, that Howard Califano comes when he needs a brisk walk-and a place to think. In this fragment of preserved primary jungle, long-tailed macaque monkeys scamper in the trees, vines dangle from the leafy canopy 40 feet in the air, and the thicket reverberates with the hum of insects. The fast-paced, modern metropolis of downtown Singapore, five miles to the east, with its whizzing traffic, beeping cell phones and sleek, fingerlike skyscrapers, couldn't feel further away.

"It's a great place to meditate," says Califano, who arrived in Singapore four years ago with a monumental charge: to guide Johns Hopkins' presence as a business and research entity on this tiny island-nation of 3.5 million people. An engineer-turned-patent attorney who had headed up the School of Medicine's Office of Licensing and Technology, Califano and his wife, Kathy, looked upon the Singapore assignment as an adventure. Their daughter Vicky, then 14 and the last of five children at home, took it otherwise. "She told me I was ruining her life," Califano recalls.

Right from the beginning, however, Califano recognized an unparalleled professional challenge. He'd be steering Hopkins-type research, teaching and patient care in a place that couldn't be more different from East Baltimore.

The task offered excitement, and it seemed straightforward. It turned out to be anything but.

Arriving in the fall of 1999, Califano took the helm of a project that was still taking shape. Hopkins' presence on the island at that point consisted of a collection of labs and a budding private medical facility known as Johns Hopkins Singapore Clinical Services. But Califano quickly discovered that it was going to take a lot more than a business plan to make the American-style operation work in a foreign country. "We've had to reinvent ourselves several times," he admits today. "It required some good, hard thinking."

The challenges of getting settled took even administrators back in Baltimore by surprise. "What we learned," says Vice Dean Steven Thompson,"is that you can't just take Hopkins to the other side of the world, open the box, and plug it in."

And yet today, Johns Hopkins Singapore is thriving. Its several successful labs have turned out a handful of patents, and it has an ambitious agenda for teaching medical students and a burgeoning medical oncology clinic that's overflowing with patients and curing disease. Still, for the pioneering administrators, scientists and physicians who first ventured out to Singapore, getting this far has meant weathering a few years of adjustments.

The idea to build a Johns Hopkins in Southeast Asia came originally from the Singapore government's vigorous entrepreneurial arm known as the Economic Development Board (EDB). In the four decades since Singapore gained its independence from Malaysia, the EDB has worked to put the city-state on the map as a multinational hub for business and investment. It's done exactly that. With the EDB's help, Singapore has developed one of the largest ports in the world and become a banking and manufacturing powerhouse.

In the mid-1990s, Singapore decided to shift its entrepreneurial focus to the life sciences. It wanted to establish the country as a nexus in the Pacific Rim for medical care and biomedical research. As the EDB looked around the world for models, it hit on Johns Hopkins-an institution known for clinical medicine and research and also with a track record for bringing important biomedical products to the market. In 1997, the agency contacted University President Bill Brody with a compelling proposal: Would Johns Hopkins Medicine be interested in setting up a branch in Singapore?

Brody was immediately intrigued. "To participate in the 21st century as an institution, you have to be global," the Hopkins president says. Singapore offered a base in Asia with a stable government, a strong economy and an English-speaking population.

For Thompson, who as CEO of Johns Hopkins International is now the East Baltimore anchor for the Singapore site and who travels there several times a year, the positives were more tied to what the relationship could offer the School of Medicine. "Here was an opportunity to enhance research already taking place in Baltimore," he says. "Investigators here were studying cancers endemic to Asia. By setting up in Singapore, they would be able see numbers of patients with those diseases. They'd get first-hand experience with pathologies that would help in developing cures."

What made the most sense, administrators decided, was to transport inherent pieces of the home model. Johns Hopkins Singapore would have a small research infrastructure and a clinic dedicated solely to oncology. Meanwhile, the Singapore government agreed to sponsor basic science studies at the Hopkins site with a five-year start-up grant of 54 million Sing dollars (about 35 million in U.S. currency). In East Baltimore, the call went out for projects that could benefit by setting up in Asia. Eight labs studying everything from genetics to atherosclerosis responded.

To fund the medical oncology clinic that Hopkins would set up, the Singapore government arranged for financial backing from four for-profit partners. Protocols for treating patients would be identical to those in the United States, but because the site would offer new medications in the form of clinical trials, highly stringent review boards, both in Baltimore and in Singapore, would oversee the adherence to research standards. Set up in one ward of the shiny, modern National University Hospital, the clinic would also provide teaching and education for Singaporean physicians. It looked from the start like a win-win situation both for the host country and its new guest.

When Johns Hopkins Singapore Clinical Services opened in the spring of 1999, the inpatient and outpatient facilities were state of the art. Even so, complications loomed. Very quickly, Hopkins realized that running a venture halfway around the world required someone on site to supervise. Califano was offered the position of CEO with the stipulation that he relocate overseas. The family packed up the house in Ellicott City, Md., and moved to Singapore.

Getting settled took at least six months, Califano says. Even though street and shop signs are in English (Singapore was part of a British colony until World War II), people on the island speak three other national languages-Mandarin, Malay, and Tamil from southern India. Western foods abound, but even the hospital cafeteria offers standard dishes like cuttlefish porridge and fishball noodle soup. The Califanos moved into an apartment, found a church like the one they attended at home-"same hymns, same kind of congregation," he says, "with the only difference being that most of the people are Chinese." Vicky enrolled in a private international high school with a U.S. curriculum. And still, there were adjustments. A car, for instance, turned out to be an exorbitant expense (automobiles in Singapore can cost 100,000 Sing dollars, not including a $10,000 permit to drive), so the Califanos opted instead for public transportation.

Califano also discovered a new business environment. "There's a saying," he recounts: "An American and a Chinese businessman are negotiating a deal. The American says, 'If we can resolve these issues, we can be friends.' The Chinese says, 'If we can be friends, we can resolve these issues."

The science and clinical operations also were having to learn to fit in. To create a clinic that could deliver Hopkins-like medicine, nurses had to be trained. In Singapore, nurses typically are given little autonomy in caring for patients. Local physicians, meanwhile, were convinced that Hopkins had come to steal patients. As a group they submitted a full-page petition to the newspaper to protest the presence of the oncology facility. Clinic director Alex Chang and the other American faculty physicians finally went door to door to reassure Singapore's doctors that Hopkins had no intention of undermining their business. And still, there were slip-ups. In Singapore, health care advertising is illegal. "We used the word 'best' to describe our medical care in a letter to our own alumni in Singapore," Thompson recalls. "That word was considered a violation." Hopkins had to apologize for the gaffe to the Singapore Medical Council. Even as it began to fit in, Hopkins faced issues. A year after opening its doors, the oncology clinic still wasn't drawing patients. "We had empty beds," Califano acknowledges. The financial investors announced they were dropping out.

In 2000, Califano helped negotiate a new incarnation for the clinic. Singapore's National University Hospital would become an 80 percent shareholder. Hopkins would hold the rest. The clinic would see privately insured and self-paying patients for treatments like chemotherapy, but would work with the physicians of NUH for surgery, radiology and other cancer care. NUH physicians would rotate through and even see patients on the Hopkins wards. And the name of the clinic would change to The Johns Hopkins National University Hospital-International Medical Center.

Meanwhile, the Singapore government, which had anticipated great R&D output from the eight research labs, had determined it hadn't seen enough products. Califano began paring down to cut costs. One lab finished its agenda and packed up. Four others, Califano fit into academic departments and health organizations around the country, thereby saving the jobs of the Singapore staff. And finally, three labs with promising track records stayed on, concentrating the resources and establishing the core of Johns Hopkins Singapore.

The next year surprised just about everybody. After the events of Sept. 11, 2001, the global health care scene changed. Patients who would have traveled to the United States for treatments became wary. Others, particularly those from the Middle East, could no longer obtain visas. Suddenly, the Singapore clinic found itself with an influx of international patients seeking cancer care. "People were elated to find Johns Hopkins here," says Alex Chang, who moved to Singapore in 1999.

An international expert in breast and lung cancer treatment from the University of Rochester, Chang had been applying for a position that would take him and his wife back to his native Taiwan when he learned Hopkins was setting up in Singapore. The fact that the site would be closely connected to the oncology department in East Baltimore impressed him. "Also, I believed in the government's sincerity in wanting to build a first-class patient care facility, with education and teaching," Chang says. He applied for and got the post of clinic director.

These days, Chang begins inpatient rounds at 8:30 a.m. (along with NUH physician Elaine Lim) and switches to back-to-back outpatients in the afternoon. His patients, all of whom have cancer, represent a true geographic melange. On a recent morning, he saw a European businessman living in Singapore, a Chinese woman from the island, with whom he conversed in Mandarin, and a Middle-eastern youth who spoke only Arabic and needed help from a staff interpreter to explain his symptoms.

In January, Chang became the clinic's CEO. Last year, it turned a $3 million profit, resources that may enable it to expand the number of beds and, Chang hopes, grow its physician staff. The two current faculty physicians are Chang and Wen Son Hsieh, who moved to Singapore in 2001 following an oncology fellowship in East Baltimore.

At the top of Chang's concerns now is making the clinic a vital training ground for new physicians in Singapore and at Hopkins. "It's possible to get experience here treating cancers that are rare in the U.S.," he explains. "Even some of the same diseases present in different patterns." Breast cancer, Chang points out, affects mainly older women in the United States. In Singapore, it hits two groups-women in their early 30s and in their 50s. The clinic is bringing new treatments to the market. One in particular, now in clinical trials, is for nasopharyngeal cancer, a disease that tends to occur among people from southern China and is one of Singapore's leading killers.

The changes at Hopkins' Singapore outpost have fostered new sensibilities. "The whole undertaking started with a great spark," Califano says. "It's taken a few years to get the fires going." In that time, he and his family have built a life as ex-pats. Last year, Califano even became a permanent resident of Singapore with social security-type benefits. His daughter Vicky is now an "international kid," he says, who has friends from all over the world and is considering studying art at a university in Australia.

As for Johns Hopkins Singapore, perhaps nobody could have foreseen that the venture that began with a business-oriented slant would eventually focus on education and training. Now in the planning stage are Ph.D. programs in immunology, biochemical engineering and clinical research that will be closely tied to the East Baltimore faculty. And just this spring, the Advisory Board of the Medical Faculty at the School of Medicine voted to create a Division of Johns Hopkins Singapore as an official part of the dean's office. The Singapore government, meanwhile, enthusiastic about educating its own young people in the life-sciences, is establishing generous stipends and scholarships for students heading into the field.

Even the research arm of JHS has met with approval from its newly appointed funding board, the Agency for Science Technology and Research (A*STAR). Its start-up grant has been renewed for another five years, this time for $74 million Sing ($57 million U.S.). Under giant cranes visible on the cityscape, a vast life-sciences complex, known as Biopolis, is springing into existence. In the next year, JHS will move into two floors in the newly constructed, $10 billion science center, and there it will slowly ramp up its cluster of labs from three to 10.

The goals of Johns Hopkins Singapore have shifted from business development to world-class research, the kind published in high-impact journals. And Califano observes that his days are numbered as the CEO of the research venture. "We've changed," he says thoughtfully. "Having a business guy in charge doesn't make sense anymore. What the program needs now is an academic director, someone who can drive it from that perspective." An international search is already on for a new director. "That person," Califano says, "will make this thing what it needs to be next."

The Right Place at the Right Time Azlinda Anwar talks over research results with Robert Atkinson. Both are postdocs in Tom August's lab. When the Singapore government announced it was interested in establishing a basic science infrastructure, several Hopkins labs already were working on topics relevant to that region. Three labs that set up shop in Singapore have produced like gangbusters. The research program, now directed by pharmacologist Tom August, has generated a whopping seven patents in the last three years and has made major strides in understanding certain diseases endemic to the area. Because hepatitis is a critical health issue in Asia, biomedical engineer Kam Leong saw immediate relevance for his studies of tissue engineering. His lab in Singapore is developing an artificial liver, a device that exists outside the body and does the kind of filtration that a dialysis machine does for the kidney. The challenge is that the liver's complex clean-up must be done by an actual cellular matrix within the machine, explains co-investigator Hai-Quan Mao, who moved to Singapore to run the lab. Establishing a robust and functional cell structure that can weed toxins and enhance the blood has required understanding how liver cells adhere and how they work in the body. The lab, which is also known for its work in gene delivery, has established a handful of patents and has published its work in major journals. For oncologist Richard Ambinder, Singapore allowed his studies to reach a new level. For years, Ambinder has investigated the Epstein-Barr virus, a pathogen that's usually innocuous but in people from south China inexplicably often causes a tumor in the endothelial tissue in the nose and throat known as nasopharyngeal carcinoma. In Singapore, where NPC is the fourth most prevalent malignancy, Ambinder's group suddenly had access to patients with the disease and the opportunity to learn how the virus manages to trip off cancer and hide itself from the immune system. The lab has done just that. Co-investigator Qian Tao, who earned his Ph.D. at the University of Hong Kong and did postdoctoral work at Hopkins, is deciphering the virus's mechanism of oncogenesis. What the Singapore lab has discovered so far is that an important gene gets methylated, making the tumor cells unable to signal to the immune system that they've been infected. "Methylation has been linked to several cancers, but we showed it was happening in NPC," Tao explains. But would a drug that causes demethylation of the gene be useful in treating the disease? Tao's team was the first in the world to show on a molecular level that demethylation can force the virus to reveal its presence in tumor cells. Now, that work is being used by oncologists Alex Chang and Wen Son Hsieh, who are establishing clinical trials for Singaporean patients. For molecular biologist Tom August, setting up in Singapore represented an unexpected twist to his career. In 2001, he was asked to organize the scientific and educational programs at the Johns Hopkins site. August's research stems from the early 1990s, when his Baltimore lab discovered a fascinating method for designing DNA vaccines. It uses elements of a protein called LAMP (lysosome-associated membrane proteins), to tag DNA-encoded antigen proteins and direct them to host-immune systems. Today, August, who's a former director of the Department of Pharmacology at the School of Medicine, is using the mechanism to develop DNA vaccines that could fortify the body against certain tropical diseases and also HIV and some cancers. The vaccines contain segments of viral DNA pre-tagged for the body to haul off to an antigen-processing site known as MHC-II. "Our rationale," August says, "is to enhance the immune system's recognition of the foreign matter and thereby increase its ability to fight the viral infection. "Hundreds of people are working on DNA vaccines, but we're hoping this will bring a different technology to the field. Most exciting is how encouraging recent monkey experiments with an HIV vaccine have proven. Additionally, August's group is collaborating with a Singaporean bioinformatics group to find specific protein sequences that will make the vaccines even more precise. "The whole Singapore experience has been marvelous for us," this researcher says.