One of the first things you notice about Singapore’s multibillion-dollar biomedical sciences initiative is that it is dominated by high-profile foreigners. Neal Copeland, formerly of the National Cancer Institute, heads the Institute of Molecular and Cell Biology; Hong Kong-born Edison Liu, also formerly of the NCI, heads the Genome Institute of Singapore; Judith Swain, ex-dean of translational medicine at the University of California, San Diego, heads the Singapore Institute of Clinical Sciences.

And it’s the same story for the government’s four other life sciences institutes and the 40-odd private sector organizations and companies housed on Singapore’s $300-million Biopolis campus, where the cast of big pharma labs now includes the GlaxoSmithKline Centre for Research in Cognitive and Neurodegenerative Disorders, the Lilly-Singapore Centre for Drug Discovery, and the Novartis Institute for Tropical Diseases.

With a reputation for meticulous planning and execution, Singaporeans had proven skilled offshore partners for leading manufacturers in electronics, petrochemicals, and pharmaceuticals. But when the government’s powerful Economic Development Board (EDB) launched its biomedical initiative in 2000, Singapore was starting virtually from scratch. With no startup tradition and little background in research beyond fine-tuning manufacturing processes—and few students pursuing higher research degrees—the government had to look outside for scientists to kick-start everything while, inside, it launched a massive scholarship program to encourage students to pursue science careers.

Lushly verdant and neat as a pin, Singapore does not make a natural environment for discovery. The city-state of 4.5 million has been ruled by the People’s Action Party since independence in 1965 and over the years the government has banned homosexuals, publications it doesn’t like, Jehovah’s Witnesses, street performers, even jukeboxes and chewing gum. Singapore introduced downtown congestion charges decades before anyone, and thrives on planning and predictability—not to mention careful observance of boundaries. “Defamation suits in Singapore are a common tactic for controlling speech, especially that related to Singapore’s government and politics,” warned an OpenNet Initiative study two years ago.

The biomedical initiative has also drawn its critics, including a member of Singapore’s ruling family, over costs and priorities. Outsiders have wondered if the whole project could unravel because of overdependence on foreign talent. “Expansion and retention of local and imported research talent will likely be the key determinant of the initiative’s sustainability,” a U.S. Department of Commerce white paper said in 2002. In 2006, World Bank economists Shahid Yusuf and Kaoru Nabeshima put the issue in sharper focus in their book Post Industrial East Asian Cities. “Star scientists are a footloose group,” they cautioned, “and the departure of one can trigger the break-up of a team and the emigration of other key members.”

Among those answering that charge was Sir David Lane, himself a star import from the United Kingdom, and executive director of the Institute of Molecular and Cell Biology at the time. Lane said scientists naturally go where the opportunity is, and he proceeded to cite the case of an American couple who had moved their cancer research to Singapore. “Neal and Nancy Copeland sold their house, quit their jobs, and committed to Singapore in a big way,” he told Reuters in November 2006.

But then there seemed to be something to this footloose theory. Six months after Lane spoke out, it was announced that he and his wife Birgitte, a skin cell expert and executive director of Singapore’s Centre for Molecular Medicine, were accepting appointments back in Scotland. The University of Dundee promised to build dedicated labs for the Lanes, and David Lane was also to become chief scientist at four institutes within Cancer Research UK.

These jobs supposedly would still leave time for Singapore. “Sir David will be spending half his time on his work in Singapore and will be physically in Singapore for at least three months in a year,” insisted Lim Chuan Poh, chairman of A*STAR, Singapore’s Agency for Science, Technology and Research, which oversees the Institute of Molecular and Cell Biology and six other government institutes. (With 500 scientists, the institute remains the country’s largest research organization.)

Lane’s decision to go part-time was not the only blow to the biotech effort. Just before that news, it was announced that government-backed ES Cell International would gear down from researching therapies for diabetes and heart disease to commercializing earlier research, and selling stem cell lines and other research tools.

The government maintains that the move doesn’t signal any loss of faith in the city-state’s ability to lead groundbreaking research. “We’re not giving up,” asserts Swee Yeok Chu, CEO of Bio*One Capital, which is part of EDB Investments, the investment arm of the Singapore government. “We had to restructure because the therapeutic side will require further funding.” Unlike U.S. stem cell startups, which floated IPOs and raised new capital, ES Cell had neither listed nor attracted additional VC backers. So therapeutics was moved to “the public side,” Chu says, and parked in an A*STAR institute.

If news of ES Cell’s retreat overshadowed the larger effort, it was because stem cell therapy got much of the early hype. Alan Colman, ES Cell’s celebrated CEO, had famously participated in the cloning of Dolly the Sheep and arrived on a wave of publicity, saying he’d been seduced by Singapore’s commitment to biotech.

After the reorganization, he was named principal investigator at A*STAR’s Institute of Medical Biology, where dozens of ES Cell scientists also relocated. But Colman, too, would be heading home. In December, he revealed that he would take over as director of stem cell research at King’s College London—a job that, once again, appeared to leave enough time for a concurrent position in Singapore.

Lee Wei Ling, executive director of the Singapore Neuroscience Institute and a longtime critic of the biomedical initiative, didn’t take the news quietly. The sister of Prime Minister Lee Hsien Loong (and daughter of Lee Kwan Yew, Singapore’s founding PM and now “minister mentor”), she told Reuters: “How can you run research in Singapore on one-third or one-quarter of your time?”

Certainly, it did look like Singapore’s central planners had got in over their heads in stem cell therapies. “From my very limited perspective, I think the business model was totally flawed,” says Jan-Anders Karlsson, CEO of government-backed drug discovery startup S*Bio. Even Colman conceded that ES Cell might have been smarter devoting some energy to developing revenue earlier. “We might have made a mistake in not including it in part of the [investment] plan,” he told Nature Biotechnology (September 2007).

But to hear officials tell it, recent events don’t even qualify as a speed bump in the country’s mission to make biomedical sciences a key economic sector alongside electronics, engineering, and chemicals. The first phase (2000-2005) focused on establishing research capabilities that would support four key areas—pharmaceuticals, biotechnology, medical technology, and healthcare services.

The second phase, running from 2005 to 2010, focuses on building up strength in translational and clinical research “to bridge the gap between bench and bedside” through the government’s Centre for Molecular Medicine, and through consortia such as the Singapore Cancer Syndicate, the Singapore Bioimaging Consortium, the Singapore Stem Cell Consortium, and others. The goal is to optimize the use of resources and foster integrated development in strategic areas.

Absent occasional reverses, the government’s program to build up life sciences has proceeded apace, and sometimes in spectacular ways. Before 2000, few Singaporeans pursued research because their priority was on securing careers that would provide higher incomes more quickly. To address that, planners set a goal of creating a cadre of 1,000 Ph.D.s in life sciences and environment research.

As of February 2008, more than 400 of 700 scholarships, each worth 1 million Singapore dollars each ($725,000), had been awarded to students pursuing life sciences disciplines. “The fundamental change as a result of efforts over the last few years is a very strong interest in doing Ph.D.s in terms of doing cutting-edge research,” says Yeoh “KC” Keat Chuan, executive director of the Economic Development Board’s Biomedical Sciences Group. Besides paying for overseas study, the grants offer “a competitive salary” (he isn’t more specific) to ensure that those in long training programs do not suffer economically.

The board also has focused hard on building out infrastructure. “Singapore has a reputation for delivering what we say we’ll do,” Yeoh says. “So we say we’ll build a biomedical research hub, [and] Biopolis was built.” The campus of seven buildings, each with names of matching portentousness (Helios, Nanos, Proteos, Matrix, Genome, Centros, and Chromos), was completed in 2003.

In the meantime, the effort to reposition institutions to fit research priorities continues. Edward Holmes, UCSD’s dean of medicine before being lured with his wife Judith Swain to Singapore in 2006, is deputy chairman of A*STAR’s Biomedical Research Council and chairman of the National Medical Research Council, which together provide the bulk of funding for translational research. The appointments make him answerable to two bureaucracies—the ministry of trade and industry, which oversees the Economic Development Board, and A*STAR below that, and the ministry of health.

To Holmes, the arrangement illustrates Singapore’s determination to pull together in translational medicine. He says Singapore’s small size can sometimes be an advantage. Fusing together National University of Singapore School of Medicine, under the education ministry, and National University Hospital, under health, “into what we would recognize as a medical center” was done with remarkably little fuss, he says. “If you’re going to do translational research, you need your academic and medical enterprise joined together to make that happen.”

Holmes says that successful biotech clusters depend on a combination of inside and outside talent, and if Singapore succeeds in developing a concentration of homegrown talent, it should be able to compete eventually with a hub like San Diego. “On the basic science side, I think their track record is good,” says Holmes, who is a member of TJOLS’ editorial advisory board. “Whether we can do the same thing to bring in physician scientists and clinical investigators is where we are right now. We’re still in the very early stages.”

Holmes says he’s been encouraged by the rising tide of interest in Singapore. In a recent coup, New York City-based Ludwig Institute for Cancer Research decided to open a branch at Biopolis. And Holmes can point to a long list of specialists who have opted for Singapore; among them, Dan Tenen (Harvard University) will be joining the National University of Singapore to lead a new Research Center of Excellence in oncology and David Virshup (the University of Utah) will be leading an oncology/stem cell initiative at Duke-National University of Singapore Graduate Medical School, which opened last year. The translational and clinical research initiative has also unveiled an extensive program of investigatorships and other awards for local and foreign physician scientists.

Yeoh says coming up with a Singapore-discovered drug would be nice but given the cost in money and time, it was never the primary goal. Instead, the objective was good science and the creation of higher-value jobs by encouraging young Singaporeans to engage with top scientists who could inculcate a desire to do research.

“The proposition that we’ve created about sharing resources and scientific equipment also lowers the barrier of entry and draws talent—all this means that momentum can only increase,” he says. “We brought together over 2,000 scientists, providing a critical mass of people.” A*STAR institute researchers, for example, can be seconded to private companies to move projects along, and then stay on as employees. Startups also get access to MRI and other equipment they wouldn’t be able to bankroll on their own. “It’s like the NIH campus in Bethesda that’s open to the private sector,” Yeoh says.

Not a day goes by when Singaporeans don’t look over their shoulders, wondering whether they can compete with China and India. Yeoh agrees that both nations pose challenges down the road, but by virtue of its small size, Singapore has some advantages. “Traditionally, it’s always been very difficult to get doctors to talk to scientists, and that’s something we feel we can do better than most other locations,” he says. He also cites another home advantage Singapore brings to clinical trials: a genetic variety of Chinese, Malays, and Indians, further helping the city-state make its mark in translational research, Yeoh reckons.

When pharmaceutical production started on the island—GlaxoSmithKline started the European wave back in 1980, 14 years before Schering-Plough led the way among U.S. pharmas—the focus was pretty much all small-molecule manufacturing, including tablets. And in the context of that standardized process environment, Yeoh says it was comparatively easy to get companies to move manufacturing to Singapore. “But when we moved into biotech, we came to realize companies were a bit hesitant because dealing with live cells was more of an art than a science.” To convince itself as much as foreign investors, the government built a bioprocessing technology institute in the mid-1990s.

Between 2000 and 2003, Yeoh says, there was a sprinkling of investment “on an experimental basis.” Eli Lilly set up a small research center for 50 researchers, GlaxoSmithKline one with 30 positions.

Then in 2007, Lilly tripled the size of its local research center focused on cancer stem cell biology. “You can say the first investment is a trial, the second an endorsement of the value Singapore brings,” Yeoh says, adding that GlaxoSmithKline recently doubled its operation to 60 positions. Then there is Novartis, another “experimental” investor. Opened in 2002, its fast-expanding Novartis Institute of Tropical Diseases last year signed with two research partners to set up clinics in Indonesia for its tuberculosis and dengue research activities.

But jobs for Singaporeans remains the overriding priority. Andre Wan, deputy executive director of A*STAR’s Biomedical Research Council, says that for a start, the body is under the ministry of trade, not health or science, which is often the case in other countries.

Wan says there wasn’t a private pharmaceutical lab on the island in 2000, and today there are 20. “We now have infrastructure, we now have people, and we now have the intellectual community to collaborate with, and many are here because of Biopolis.” He cites soaring output growth in the biomedical sector and, indeed, there was a spike in 2006 of 30.2 percent, to S$23 billion ($16.91 billion).

But not everyone is comfortable with A*STAR’s self-assessment. More than 90 percent of that growth is derived from a spectacular rise in pill- and capsule-making that began years before the biomedical initiative. “What is Philip Yeo’s definition of success,” Lee Wei Ling asked in Singapore’s Today newspaper, “and can he show at least some glimpse of it?”

Yeo had been the Economic Development Board’s longtime chairman before taking that position with A*STAR (and has since moved to a new agency promoting small companies). Lee has repeatedly complained that the biomedical initiative should focus on issues closer to home—like Hepatitis B, of which 5 percent of ethnic Chinese are carriers.

Pressed on the output figures, Wan concedes that they don’t directly reflect activity arising from the initiative, but serve as “a proxy to indicate the level of R&D activity is rising.” And it seems a fair point, but notional explanations may not be good enough at the end of Phase 2, which is focused on delivering results in translational and clinical research, where the ministry of health is playing a more significant role.

But Wan obviously believes the promise is there. Graduating up from the chemical engineering of pill-making to biologics to vaccines produced in living cells has already moved Singapore several orders of complexity higher, he argues. And Singapore’s pharma output figures definitely are changing. “Within the space of 18 months, four biologics projects were announced,” he says. “These will generate something like 1,500 jobs. Now, you can say it’s not the direct result of the research work, but the fact that we have the institutes that provide the training and the people does have a very material effect on the ability of Singapore to continue to attract [investment].”

And the endorsements can’t hurt. Massachusetts Governor Deval Patrick, for instance, has called neophyte Singapore a competitor to Boston. “For a country that entered the field only a few years ago, that’s a huge compliment,” Wan says.

But down in Baltimore, Singapore loses some of its sheen. Johns Hopkins University was invited in to set up a cancer clinic, start clinical research, and work with M.D./Ph.D. students to train a cadre of researchers. Describing it as a bad memory today, Johns Hopkins Medicine CEO Edward D. Miller remembers endless fights with bureaucrats over money. He also says the goals suddenly changed to teaching Ph.D.s.

In the end, the government terminated Hopkins’ contract “for failure to meet milestones.” Johns Hopkins Singapore focused on areas of special concern to Asia such as identifying biomarkers in esophageal cancer. Ian McNiece, an expert in bone marrow and growing stem cells, headed a team of seven investigators. But A*STAR, according to its own press release, said Hopkins failed to import enough senior researchers.

Miller argues that it is young researchers who really produce. “I hate to say it, but very few people over 40 win the Nobel Prize.” Also irksome, he says, Singapore started negotiating with Duke University to partner with the National University of Singapore to set up a medical school without inviting Hopkins in to explore what else it could do.

(It’s been hit and miss with big foreign institutions. Despite woolly talk about the momentum that the just-opened Singapore campus of Australia’s University of New South Wales would bring to the Economic Development Board’s Global Schoolhouse initiative to attract foreign students to the country, the university wound up the venture with enrollment 50 percent short of projections.) 

Miller contends that the nonprofit concept does not exist in Singapore. Everything is business, he says, so the focus is on contracts instead of partnerships. “I don’t think they will build an academic milieu which great drug discoveries will come from—it will be more driven like drug companies and, as you and I know, drug companies don’t have anything in the pipeline.”

He also sees another hurdle for the city-state. “You have in some ways this very controlled society,” Miller says. “That doesn’t allow a lot of free thought outside the boundaries, and it’s outside the boundaries where discoveries are made.”

William F. Miller, co-director of the Stanford Program on Regions of Innovation and Entrepreneurship, says Singapore will have to figure out how to commercialize discoveries if its biomedical initiative is to succeed. “You see the inputs but you don’t see the outputs,” says the former Stanford provost, who went on to lead SRI International for a decade.

Put against a comparable economy like Hong Kong’s, Singapore has few small and medium-sized enterprises as a result of policies that stress bringing in multinationals to create jobs. “Once you start that focus on the big companies, everybody focuses on them—the financial industries, government, labor, even the universities because they can get money out of multinationals and they can’t get much out of startups,” Stanford’s Miller says.

Miller argues that it is startups that ensure return on investment in research and education. “You capture more of it that way than you do if you either license it or let multinationals benefit.” Clusters should have a balanced mix of large and small companies, he adds. “If you get out of balance with multinationals, it’s very hard to shift.”

He also cites a related issue. With no startup tradition to speak of, Singapore’s venture capitalists have tended to come from the financial sector with little hands-on experience managing small companies.

Yet another government agency is trying to address the entrepreneur gap. Under its chairman, the omnipresent Philip Yeo, SPRING Singapore is charged with growing innovative companies and fostering a competitive small and medium enterprise sector.

Steven Fang also wonders about the city-state’s bioscience ambitions. The founder and CEO of Singapore-based, Australian-listed Cordlife, he oversees “the largest network of private cord blood banks” in the Asia-Pacific region. In 2003, Cordlife decided to recast itself as a therapeutics company and acquired Chelmsford, Massachusetts-based Cytomatrix. One of its IP assets enabled adult stem cells to multiply, opening up the possibility of multiple-use transplant, Fang says. “The other technology allowed us to try to differentiate adult stem cells into T-cells for rebuilding immune systems.” But with commercialization too far off to contemplate, Cordlife spun off a reconstituted Cytomatrix, kept 41 percent, and signed up two Australian investors, Deakin University and Barwon Healthcare.

Fang agrees that Singapore knows how to build infrastructure. “And we have initiated the step of having the headcount and the hard skill sets,” he says. “But research is partly an art, and what is important is an environment for creativity and innovation. And that is hard to buy.”

To help fertilize overall sector development, the Economic Development Board’s biomedical VC, Bio*One Capital, has built a portfolio of more than 50 companies. With field offices in Boston and San Francisco, it scours the globe for prospects that might profitably set up on the island. CEO Chu says it focuses on medical devices, therapeutics, and services, mainly contract manufacturing and research.

Biologics was the last big gap Bio*One worked on, and it has scored some successes, starting with Basel-based custom manufacturer giant Lonza Group. That deal called for Lonza to build a large-scale mammalian biopharmaceutical facility in Singapore. As luck would have it, South San Francisco-based Genentech was looking for extra capacity and signed for the new Bio*One-Lonza joint-venture plant, taking an option to buy it. So Bio*One quickly tapped Lonza to build a second one.

“Because of that one project, others looked at Singapore and said, ‘Hey, it has more than technical synthesis capability, they also have biologics right now,’” says Chu, who notes that the city-state has attracted (US) $1.5 billion of biologics manufacturing investment to date. Many of the companies in Bio*One’s portfolio today have operations in Singapore. It has a significant investment in South San Francisco-based Fluidigm, which makes integrated fluidic chips designed to analyze DNA and tissues for drugs, sorting out the vast data that used to take a room full of machines and robots to process. “We figured out how to take all these huge, highly automated machines and miniaturize all the fluidic elements and put them onto high-density chips,” says CEO Gajus Worthington.

The executive says Singapore emerged as an ideal spot for its operations because of its semiconductor acumen, expertise in materials science, and its growing work in biochemistry and life sciences, all at the industrial level. Singapore was affordable, had the skills, provided IP safeguards, and offered not only funding but set-up help. “That saved us months and months.”

Another Bio*One portfolio company, S*Bio, was Singapore’s first biotech company to undertake a Phase I clinical trial—with an anticancer compound called SB939, and a histone deacetylase (HDAC) inhibitor targeting solid tumors and hematological cancers. With deep exposure in big pharma and biopharma, scientists in the city-state “made it possible to do a discovery program in less than 12 months, which is very unusual,” says Jan-Anders Karlsson, S*Bio’s CEO. S*Bio also cut the time it took to prepare the new compound for trials to only nine months, Karlsson adds.

Bio*One-backed Merlion Pharma focuses on antibiotics and has taken two compounds into clinical trials in the last 12 months, according to COO Chris Molloy. He describes the company’s finafloxacin compound, now completing Phase I trials, as “a highly potent eradicator” of Helicobacter pylori (H.pylori), a bacterium present in the stomach lining in half of the human population. A factor in gastric ulceration, H. pylori is also the only bacterium designated as a class I carcinogen by the World Health Organization. “Finafloxacin is specifically activated under acidic conditions,” Molloy says, adding that most marketed antibiotics become less active under acid conditions—just when infection usually occurs. “We are seeing up to a thousand-fold difference in activity between our compound in acid conditions and the marketed gold standard.”

There is no question that Singapore has captured the world’s attention with its commitment to biomedical research, and that it has become a magnet for international talent. Karlsson says half of S*Bio’s scientists are Singaporeans, and the rest foreigners who were either recruited in Singapore or came from abroad. “It’s a lot easier to get people to move here than it is to get someone to move to Germany,” he says. “For one thing, it’s English and cosmopolitan—people know they will be understood.” Whether those scientists will stay, and whether they can succeed in creating a world-class center, is what remains to be seen.