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Published On January 15, 2010

POLICY

The Science Factory

At Singapore’s gleaming Biopolis complex, researchers get all the money and lab support they need. What they don’t get is time.

TWO STICK-FIGURE-LIKE SCULPTURES CAVORT NEXT TO A SIGN THAT READS: BIOPOLIS. Shuttle buses, bearing the words “Biopolis: Beyond Infinity” and images of beakers and DNA strands, buzz among nine irregularly shaped glass and aluminum towers with faces angled toward one another. Designed by the Iraqi architect Zaha Hadid, known for her dynamic, futuristic creations, each building bears a monumental name drawn from Greek mythology (Chromos, Helios, Proteos) or science (Genome, Matrix). Inside, the large lobbies resemble those of private banks or Philippe Starck hotels: gleaming marble floors, sleek reception desks and security guards with crackling walkie-talkies. Sky bridges and wide walkways connect the buildings, and the grounds are lush with palms, ferns and fountains.

Here, within view of Singapore’s central business district, a cadre of some 2,300 researchers from more than 50 countries have engineered peptide nanoparticles that can fight brain infections, discovered a way to minimize tissue damage after a heart attack, and generated a three-dimensional model of a crucial protein produced by the H1N1 swine flu virus, helping to determine the efficacy of drugs that target it—all this, and considerably more, in just the six years since Biopolis opened. To fuel this research, a Singapore government entity known as the Agency for Science, Technology and Research (A*STAR) offers everything a scientist’s heart could desire: 2 million square feet of space outfitted with flow cytometers, nuclear magnetic resonance instruments and X-ray crystallography equipment; a vast supply center; and the ability to draw from the nearly $10 billion set aside for scientific research and development between 2006 and 2010.

But there’s a catch, and some researchers say it’s major. In exchange for plum working conditions, scientists must satisfy a list of key performance indicators. Everyone agrees to write a specified number of papers and file a minimum number of patent applications by a stated deadline (requirements vary from person to person). Contracts last just three to five years, and if scientists don’t deliver, they’re asked to leave. Setting such conditions enables Singapore’s business-minded officials to get rid of what they see as dead weight and to churn out science on a strict, predetermined schedule.

Some observers, used to a system in which the results of scientific research are expected to be unexpected, contend that the highest-quality work can’t be hurried. They wonder how and whether a government can create in a few years what elsewhere has evolved over generations.

BIOPOLIS ISN’T THE FIRST NATIONAL SCIENTIFIC ENTERPRISE backed by a tremendous budget. Taiwan has poured almost $2 billion into its Hsinchu Science Park, and Saudi Arabia’s new King Abdullah University for Science and Technology has a $10 billion endowment. But according to a 2004 report by Danish business researcher Finn Hansson, most science parks are run in a fairly hands-off manner. Administrators deliver the money and take care of the physical plant, hoping to foster job creation and profitable technologies, but they don’t get involved in the scientific projects.

Biopolis, in contrast, manages almost every detail. That was the plan from the outset, as Singapore, a city-state of just 274 square miles and 5 million people, built a $360 million greenhouse in which to grow its biosciences industry. Watching the global pharmaceutical and biomedical engineering sectors add high-value jobs each year, Singapore—already one of the world’s richest countries thanks to consumer electronics and information technology exports—decided to become a knowledge-based economy. So this orderly republic, in which repeat litterers are made to dress in fluorescent yellow vests as they pick up trash, and chewing gum—the scourge of city pavements—can be bought only with a prescription, applied its customary efficiency to the task of incubating innovation.

Step one was to eliminate scientists’ perpetual worry: finding the money to continue their work. Principal investigators at Biopolis’s research institutes don’t have to write grant proposals for individual projects. Rather, scientists within a particular institute work out with peers and directors how to allocate the funding they share. According to Singapore’s National Survey of Research and Development, in 2007 the public laboratories at Biopolis received a total of $200 million in block funding from A*STAR, while employing just 453 Ph.D.-level research scientists and engineers. That’s more than $440,000 per researcher, nearly twice as much as the upper limit for R01 grants, the mainstay of the U.S. National Institutes of Health’s funding program. In many cases, investigators at Biopolis institutes are also affiliated with local research organizations, which provide additional funding. “Money is the oxygen you need for research,” says Lim Chuan Poh, former chief of the Singapore defense force and now chairman of A*STAR. “Our scientists don’t waste time competing for funds or stockpiling grants.”

Chia Lin Wei, a biologist at Biopolis’s Genome Institute of Singapore, credits steady funding for her signature accomplishments. Wei and her team spent three years developing a DNA-sequencing protocol that is many times more efficient than conventional techniques. By tagging base pairs from the beginning and end of a gene, then matching those against the human genome, the technique encapsulates a gene’s structure without requiring that the entire gene be sequenced. The method would have been difficult to develop with traditional funding, she says.

Yet Wei realizes that continued support is predicated upon success. By producing tangible results, she can boost the reputation of her institute and perhaps help create entire companies. Still, not every science project can turn into a patentable technology, and at Biopolis, ideas that don’t seem to be panning out may be sacrificed. “Everything we do has to be good for business,” says Wei. “When it isn’t, a project doesn’t last long.”

Biopolis leaders keep tabs on research through biannual appraisals, and a “publish now or perish” ethic seems to prevail. “You must have positive results,” says Yi-Yan Yang, a chemical engineer and group leader with the Institute of Bioengineering and Nanotechnology. “If you don’t, you don’t have anything to pre­sent.” Yang needn’t have proved every hypothesis she’s working on, but she must generate ideas worthy of a journal article or a conference submission. During the first three quarters of 2009, she published 10 peer-reviewed papers and had two more in press—an extremely respectable output by any standard. Yang has also filed several patent applications describing nanocarriers for delivering drugs, genes and other agents into cells.

Yet even Yang’s prodigious achievements don’t guarantee her place. Although traditional tenure-track jobs are on the decline in the United States, many senior researchers and team leaders at universities, the NIH and other scientific facilities still hold permanent positions. At Biopolis, by contrast, everyone is on a short contractual leash of three to five years. Wei, who left her job as a group leader at a U.S. pharmaceutical company to come to Singapore, says her family and friends thought she was crazy to move for a contract-based position—but the funding and the opportunity to work on large-scale genomic research outweighed her insecurity. Even directors such as Jackie Ying, who was raised in Singapore and taught at the Massachusetts Institute of Technology before returning to head the Institute of Bioengineering and Nanotechnology at Biopolis, are subject to the rapidly ticking contract renewal clock. Ying says the system “leaves little room for deadwood.”

WITH RESULTS, HOWEVER, MAY COME SUBSTANTIAL REWARDS. The second step in jump-starting innovation at Biopolis has been to create an overtly entrepreneurial environment, and A*STAR stands ready to help researchers take science from the laboratory to the marketplace.

A few years ago, Biopolis chemist Kim Nam Yong headed a project to develop a miniaturized bioassay platform. Bioassays test the concentration of biological reagents (such as proteins, vaccines and viruses) in a sample by incubating them with living tissue; assays are useful for diagnostics and drug discovery. The MIT-trained Kim, who held senior research positions at two U.S. bioscience startups, invented a patterned glass slide to conduct bioassays more quickly and cheaply than is possible using conventional tools.

In 2007 the commercial arm of A*STAR provided not only financial backing but also business savvy, helping Kim license his discovery, form a company (Curiox Biosystems), raise funds, negotiate with investors and hire a management team. The office has even been known to bring in public-speaking coaches to help nervous scientists make pitches to venture capitalists. (In return for startup funding and wide-ranging assistance, A*STAR gets a piece of new companies.)

Things would have been more complicated in the United States. The 1980 Bayh-Dole Act provides incentives for universities to share scientific discoveries with industry, and most large American research institutions have offices charged with that task—but the road to commercialization can be slow and problematic. To license discoveries, scientists must request permission from their institutions, which generally own the intellectual property rights. A university might happily grant permission, but it would be unlikely to help create a business plan, participate in managing the new company, recruit investors or accept any financial responsibility.

That gap between discovery and implementation can be difficult to span. Alice Huang, president-elect of the American Association for the Advancement of Science, tells how her husband, David Baltimore, a Nobel laureate and a professor at the California Institute of Technology, has been struggling for years to attract investors to fund an approach to gene therapy that could protect against HIV infection. “He’d get $10,000 here, $100,000 there,” says Huang. “It has taken him a decade to raise the money to get going. In Singapore, if you make a useful discovery, A*STAR will step in to help—and your baby just might become a movie star.”

Though some may chafe at the notion of scientific discoveries being milked, like movie stars, for profit, making a potentially profitable discovery wait a decade for funding would be unacceptable in Singapore. “In a university environment, research can be curiosity-driven,” says A*STAR chairman Lim Chuan Poh. “Here, it must align with A*STAR’s mission: the impact on the economy.” Edison Liu, who left a National Cancer Institute directorship to start the Genome Institute of Singapore, is comfortable with that approach. “In the United States, there’s an almost perverse attention to conflict of interest, to the point where wanting to help someone is considered a conflict,” says Liu. He appreciates not only the assistance Biopolis provides in commercializing researchers’ work but also that it allows him to consult with private companies.

NIH scientists can do neither, bound by strict ethical guidelines. Several years ago, a scandal erupted when an NIH official overseeing a study turned out to have received payments from a pharmaceutical company whose glucose-lowering drug, implicated in several patient deaths, had been included in the research. While Liu acknowledges that conflict-of-interest rules are designed to protect the public, he thinks they go too far, isolating public researchers from industry colleagues. It was between 1994 and 2004, for instance, a decade when the NIH temporarily loosened its ethics regulations, that the Human Genome Project was completed, partly as a result of a collaboration between commercial and public researchers.

COLLABORATION IS ANOTHER PART OF THE INNOVATION INCUBATING equation, and at Biopolis it isn’t left to chance. Although few would question the value of interdisciplinary work, in the United States there are roadblocks. Under the traditional principal investigator system, if a biologist and an engineer envision a synergistic project, they must decide which of the two will apply for funding, and to whom. Will the National Science Foundation define their work as medical and thus outside its realm? Will the National Institutes of Health consider it physical science? The wrong guess can kill a project before it starts.

In Singapore, discipline-straddling projects are encouraged. When researchers were developing a wearable bioartificial kidney, materials scientists took charge of developing an artificial polymer to create a porous membrane, while cell biologists introduced living epithelial cells from human kidneys that could reabsorb nutrients instead of filtering them out. Such projects are possible not only because funding comes from a central, results-focused agency but also because they’re helped by a form of professional matchmaking.

For her institute, Ying says she deliberately seeks out researchers who have collaborative mind-sets and then throws them together on projects such as the bioartificial kidney. A*STAR chairman Lim personally oversees mandatory meetings of scientists from different fields at sessions organized by an agency office whose sole purpose is to foster interdisciplinary work. And Biopolis scientists aren’t simply placed in the same room; they’re given specific help in collaboration, such as lessons in the technical vocabularies of one another’s fields.

BUT GREAT FACILITIES, AMPLE FUNDING AND AN ENTREPRENEURIAL CULTURE aren’t enough to achieve Singapore’s goal of leapfrogging the country to the forefront of biomedical research and development. Everything starts with ideas, and those have to come from gifted researchers, says John Collins, COO of the Center for Integration of Medicine and Innovative Technology, a consortium of Boston-area teaching hospitals and engineering schools that aims to foster interdisciplinary work and accelerate the impact of technologies on patient care. Collins, whose organization has forged a collaboration with A*STAR, says Singapore’s top-down facilitation is important because it encourages those who want to execute a shared idea. But for the system to work, you need “magnets”—international researchers at the top of their careers.

Magnets were what A*STAR hoped to get from Johns Hopkins in June 2004. The scaffolding had barely come down from the Nanos building when Ian McNiece, the director of a newly formed Singapore research arm of the Johns Hopkins School of Medicine, moved with his crew into two-story quarters spanning 40,000 square feet and filled with state-of-the-art equipment. An initial handful of principal investigators, accustomed to cramped quarters and well-worn tools back home in Baltimore, were duly impressed.

Hopkins had been in Singapore since 1998, when it joined forces with the government there to establish a research, teaching and clinical program that the university hoped would become a Southeast Asian outpost for its operations. Hopkins faculty members headed satellite laboratories in oncology, urology and bioengineering at the National University of Singapore. But these scientists continued to be based in Baltimore, spending only part of the year on the island.

The 2004 agreement was far more ambitious. A*STAR wanted Hopkins to recruit scientists and settle them in Singapore to form an international division of Johns Hopkins Medicine. In exchange for delivering scientific results—the rights to which Singapore would share—Hopkins would receive funding and infrastructure support. “It was a risky move to make such a big commitment to Singapore,” says Hopkins vice dean of research Chi Van Dang, “but it was also an adventure.”

McNiece found himself a two-minute walk from the Genome building, which housed ES Cell International, a Singaporean biotechnology startup. The company’s chief scientific officer was British scientist Alan Colman, famous for cloning Dolly the sheep. McNiece and Colman, who later became executive director of the Singapore Stem Cell Consortium, could chat about research over lunch at the food court, surrounded by dozens of similar groups having similar conversations. At Biopolis, scientists from publicly funded centers drink coffee with researchers working for GlaxoSmithKline, Lilly and Schering-Plough—all of which have outposts in buildings there. That kind of casual intellectual interaction, says McNiece, made Biopolis hugely conducive to research. “It felt like a campus with corporate and academic entities mixed together,” he says. “Everyone was trying to build something new.”

But at Biopolis, things have to be built very quickly, and Hopkins was judged a step too slow. In 2006, A*STAR conducted a midcontract review and decided not to renew the Hopkins agreement, citing failure to meet eight of 13 key performance indicators—chief among them, a requirement to persuade 12 senior investigators with “international reputations” to work in Singapore. Only one Hopkins faculty member qualified. A*STAR also expected Hopkins to have initiated eight patents and eight clinical studies; neither stipulation was fulfilled.

Yet while McNiece, now at the University of Miami’s Stem Cell Institute, doesn’t dispute that Hopkins came up short on several indicators, he worries that such requirements can lead to misplaced priorities. “When there’s a benchmark for patents, people try to patent everything,” he says. “It’s a false standard for achievement.” Moreover, pressure to get results limits what scientists even attempt to do, says Daniel Kevles, a science historian and former chair of Yale University’s Program in the History of Science and Medicine. “It encourages people to pursue lines of research that have sure payoffs,” Kevles says.

In any case, McNiece contends that the plug was pulled too soon. “Our projects were just getting started,” he says. One involved developing a vaccine for the West Nile virus that would activate the body’s immune response using genetic material from the pathogen. Another was a study of somatic nuclear cell transfer, a technique for cloning any cell by inserting its DNA into the nucleus of an unfertilized egg cell. When the sword fell, McNiece was still deep in what, back home, would have been judged an early stage of recruitment.

“We were on track to be very successful,” says McNiece. “Biomedical research isn’t like the dot-com business. You can’t excel in the short term.” Hopkins research dean Dang agrees. Rather than buy big-name talent, Hopkins “wanted to grow the next generation of researchers,” Dang says. Convinced that it had hired good people, the university paid to bring them back to the United States. All, Dang says, are thriving.

DANG AND MCNIECE ARE PART OF A U.S. ACADEMIC TRADITION IN WHICH scientific knowledge advances incrementally and young scientists who follow their own curiosity may one day blossom into Nobel laureates. Published papers accrue until they demonstrate a university’s eminence in a field and help it attract funding and high-profile faculty members. Nine of the 10 universities topping U.S. News and World Report’s 2009 rankings in the biological sciences have been around for more than a century. In those literally old-school settings, radical work may emerge slowly from long periods of trial and error. A case in point is the 25-year project that ultimately led to Stanley Prusiner’s discovery of prions: proteins with aberrant folds that turn them into pathogens.

“In the United States, we believe intellectual pursuits will lead to ideas we didn’t know existed,” says Huang of the AAAS. She points to the discovery of telomeres—special sequences of repeating DNA at the ends of chromosomes that protect cells from aging and death. “When they were first noticed, nobody thought these sequences were terribly important,” she says. “Because Carol Greider and her mentor Elizabeth Blackburn were curious, we now know telomeres tell us a great deal about cell growth control, cell death, inflammation and cancer.” If Blackburn, Greider and their colleague Jack Szostak of Massachusetts General Hospital—the three shared the 2009 Nobel Prize in Physiology or Medicine—had been Biopolis scientists, they might have been hard pressed to justify their curiosity and forced to move on to something else.

“Traditionally, the NIH and most academic centers take a long view, creating fertile ground for important collisions of novelty, serendipity and relentless pursuit of a single hypothesis,” says physician John Parrish, executive director of CIMIT. “Singapore wishes to invest in research that can rapidly translate into commerce.” If the goal at Biopolis is to hurry innovation—without worrying whether some kinds of research might be left behind—there is ample evidence of success. Its institutes are churning out papers, patents and promising startups, and in a study by three policy research institutes, Singapore ranked as 2009’s most innovative country; the United States was eighth. That progress shouldn’t be surprising, says Kevles. “Of course innovation can be hurried,” he says. “It just has to be in areas where the path is already relatively clear.”

Huang points out that Singapore’s desire for reliable scientific dividends actually puts it in a position to fill an important gap between curiosity-driven and translational research. Now that the function of telomeres has been shown, for example, there is still much to be done before anyone can conduct a clinical study on, say, an anticancer drug based on telomere research. Telomeres and the enzyme that controls them must be observed in specific cancer cells, and scientists have to test specific methods of inhibiting their production. That kind of project, Huang says, one that has a good chance of producing a valuable application but is too expensive for most universities and too long-range for most corporations, is where Singapore might play an important role.

“Science is a continuum,” says Huang. “The kind of research that involves showing that a great idea actually works and taking it to the point where it’s useful for something—that’s not well supported in this country. It is in Singapore.”

 

DOSSIER

1. “Innovation Nation: How America Is Losing Its Innovation Edge, Why It Matters, and What We Can Do to Get It Back,” by John Kao [Simon and Schuster, October 2007]. Kao, a former professor at Harvard Business School, examines the Biopolis experiment, argues that the United States is falling behind other nations in fostering radical ideas, and lays out a plan for reclaiming our culture of innovation.

2. “Post-doc Journal,” by Amanda Goh, Nature Jobs, January–December 2008. In this series of 10 articles, a young postgraduate scientist reflects on the challenges, successes and unique laboratory culture she encounters in her first year at Biopolis.

3. “Why University Inventions Rarely Produce Income: Bottlenecks in University Technology Transfer,” by Paul M. Swamidass and Venubabu Vulasa, The Journal of Technology Transfer, August 2009. This empirical study of 99 U.S. research universities highlights the obstacles to commercialization of scientific discoveries, including a failure to actively market inventions and a lack of legal expertise in the complex patent application process.

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