Move Provokes Bruising Fight Over U.K. Biomedical Institute
- Eliot Marshall
CAMBRIDGE, U.K.—For more than a year, researchers at a world-class biomedical institution in Britain have been battling to stop what they see as a clumsy and destructive attempt to overhaul their community. Next week, Parliament will give its view of their appeal to block a relocation from the suburbs to the center of London, possibly followed by a clear decision from their top governing board, the Medical Research Council (MRC). Both sides say this fight may leave bruises that will affect biomedical research in the United Kingdom for years.
Leading scientists at the National Institute for Medical Research (NIMR)—the largest U.K. biomedical unit, with a direct government budget of $62 million—took an angry protest to the halls of Parliament in December. In the parliamentary inquiry that began that same month, they blasted an MRC plan to move their entire facility from its perch on a green ridge northwest of London to a university site in the city. The staff's main concern, according to NIMR immunologist Anne O'Garra and others who spoke with Science, is that the advantages of the present spot in Mill Hill will be lost—including a secure animal facility and an unparalleled 19-hectare campus—with no commensurate gain.
MRC's preferred scheme for “renewing” NIMR, says neuroscientist Colin Blakemore, MRC's chief executive, is to sell the entire NIMR estate. Director John Skehel has announced that he will retire in 2006, but the scientific staff would be kept intact. The cash from the sale, as Blakemore explained in the 1 December hearing before the House of Commons Science and Technology Committee, would help pay for new facilities in central London. The final details have not been set, but an MRC task force has singled out Kings College and University College as candidate sites. It's not clear whether the government would own the new city buildings or pay a university to maintain them. Yet Blakemore concedes that moving NIMR from Mill Hill may “cost more than it will save.”
Blakemore cites several reasons for wanting to move NIMR despite the cost. He told the science committee that government recommendations dating back to 1996 and earlier have urged that the institute be brought closer to a university. And in a telephone interview, he spoke of MRC's long-held concern that NIMR is too isolated from academic and clinical life. It must change to survive, he and others argue.
A July 2004 MRC task force on the renovation plan, which included two NIMR scientific leaders, concluded that the institute's “long-term success” will depend on its ability to do “translational research”: adapting basic biology to medical uses. NIMR supports more than a dozen fields of research and is known for its excellence in infections and immunity, developmental biology, neuroscience, and structural biology, among others. But it has no clinical center and no degree-granting function. The task force found that NIMR could best make a “cultural shift” from its focus on laboratory work to clinical practice “through physical proximity to a teaching hospital.” And it found that encouraging crosstalk among different research groups “would best be achieved through colocation with a university” with “the widest possible range of disciplines.”
The two NIMR scientists who sat on the task force signed off on this report—Steven Gamblin, head of the protein structure group, and Robin Lovell-Badge, head of developmental genetics. But both now disagree with MRC's interpretation. They say they support the broad conclusions but not Blakemore's views on relocating to London. As they tell it, the consensus wanted a move to the city if this proved better than staying at Mill Hill. But in their view, MRC has not really compared the options in detail and is ignoring the conditional clause. Lovell-Badge also told the parliamentary committee that in a phone call Blakemore had pressured him to drop his resistance, but that he refused. Blakemore acknowledged that there was a conversation but denied that he intended any threat.
Gamblin, Lovell-Badge, O'Garra, and others argue that NIMR already enjoys many of the good things that the move to London might bring, such as interdisciplinary collaborations and partnerships with clinics. They offer piles of documents as proof. But they concede the obvious: that NIMR is not physically near a teaching hospital or university. On the other hand, they say, it's doubtful any London university can provide a secure, spacious animal facility like theirs. Gamblin and Lovell-Badge voiced a widely held suspicion that the university-dominated MRC wants to sell Mill Hill to have more flexibility in the budget for academic projects—and to subject NIMR staffers to the rigors of university life.
Blakemore says he has heard the rumors, but they are “completely unfounded.” There is “no hidden agenda,” he adds: “If the MRC had wanted to close down the NIMR, they would have done it” long ago and not have “spent two and a half years reviewing it.”
Parliament's science committee will offer its view of the controversy in a report to be issued on 8 February. And Blakemore says MRC hopes to issue its own decision on 10 February.
- SPACE SCIENCE
NASA Probe to Examine Edge of Solar System
- Andrew Lawler
Despite its current budget troubles, NASA last week laid out plans to launch a mission to explore the edge of the solar system. The $134 million probe, slated for a 2008 launch, will also serve President George W. Bush's exploration vision by examining galactic cosmic rays that pose hazards to humans traveling beyond Earth's orbit.
Southwest Research Institute of San Antonio, Texas, will lead the mission, called the Interstellar Boundary Explorer (IBEX). Chosen from more than three dozen proposals, IBEX is part of NASA's Small Explorer effort designed to put relatively low-cost probes into orbit more quickly than the agency's usual space science missions. “This is an exciting and breakthrough experiment for NASA to sponsor,” says Ghassem Asrar, the agency's deputy science chief. No other mission has attempted to chart the heliopause—the bubblelike transition zone where the solar wind breaks down—in such detail. IBEX won't actually make the long and expensive trip beyond Pluto. Instead, by flying in an Earth orbit beyond the magnetosphere, the spacecraft's two neutral-atom imagers can detect particles that will enable physicists to map the boundary between the solar system and deep space.
Although IBEX appears set to proceed, another Small Explorer mission—the Nuclear Spectroscopic Telescope Array, designed to detect black holes—has been delayed on technical grounds. The project, by a team at the California Institute of Technology in Pasadena, will not get a green light until at least next year, NASA officials say, because the design needs further study. And tight funding, combined with the recent reorganization of NASA's science effort, temporarily threw planetary researchers for a loop last week. On 24 January, Curt Niebur, discipline scientist for the outer planets research program, announced that $5 million for data analysis had been “redirected” and that “the future of the program is far from secure.” But 3 days later, acting director of NASA's solar system division Andrew Dantzler wrote researchers that “the funding has not been cut” but simply moved to another area “for purely administrative reasons.” Dantzler blamed the mix-up on a “miscommunication” within NASA.
- AIDS TREATMENT
A Step Toward Cheaper Anti-HIV Therapy
- Jon Cohen
The U.S. Food and Drug Administration (FDA) approved three generic anti-HIV drugs last week, a decision that finally allows U.S. government-sponsored programs to offer these cheaper pills to infected people who live in poor countries.
The Bush Administration insisted last year that the so-called President's Emergency Plan for AIDS Relief—which plans to spend $15 billion over 5 years—could only use drugs approved by FDA. Howls of protests followed, as many AIDS advocates and clinicians worried that this would rule out use of cheap treatments now popular in many poor countries. The Administration promised to process completed applications from generic manufacturers within 2 to 6 weeks.
Aspen Pharmacare of South Africa began the application process in September (Science, 8 October 2004, p. 213). On 25 January, 12 days after FDA received Aspen's completed application, it “tentatively” approved three of its drugs. (The tentative designation means that, for patent reasons, the drugs can be sold for use only in poor countries.) “I'm very pleased,” says Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases. “This is what we were hoping would happen.” The approved Aspen drugs include a pill that combines AZT and 3TC, and, separately, nevirapine. “I hope that a lot of other companies follow suit, and we can get the ball rolling with these generics,” says Fauci.
Ellen't Hoen, a lawyer based in Paris who heads the Campaign for Access to Essential Medicines run by Médecins Sans Frontières, argues, however, that FDA approval is unnecessary. The World Health Organization (WHO) has already “prequalified” many generic AIDS drugs that are in an even easier-to-use formulation—three pills mixed into one fixed dose—and U.S. insistence on additional approval by FDA “creates confusion and has wasted time and money,” says 't Hoen. “To celebrate this FDA approval as a major breakthrough is presenting a false picture.”
According to a WHO report released on26 January, anti-HIV drugs currently reach only 700,000 of the nearly 6 million poor people in the world who most urgently need treatment.
- QUANTUM COMPUTING
Safer Coin Tosses Point to Better Way for Enemies to Swap Messages
- Charles Seife
Alice and Bob are finally splitsville. After years of sending encrypted messages to each other, they're getting a divorce. They've moved away from each other and only communicate electronically, but this creates a problem. “They want to decide who's going to keep the dog, so they toss a coin,” says Alipasha Vaziri, a physicist at the National Institute of Standards and Technology in Gaithersburg, Maryland. How to do a fair coin flip over a telephone wire?
Physicists have now shown how, using quantum computers. In an upcoming issue of Physical Review Letters, Vaziri and his colleagues describe an experiment in which Alice and Bob perform a fair coin flip quantum-mechanically; if one party tries to cheat, the deception is quickly revealed, something that scientists don't know how to guarantee with classical computers.
The fair electronic coin flip is what cryptographers term a “post-Cold War” protocol. In standard cryptography, two parties who trust each other attempt to sneak a message by an untrustworthy opponent; here, two parties who don't trust each other try to ensure that the other isn't cheating. So a good coin flip protocol should ensure that Alice, who wants to keep the dog, can't cheat Bob.
With classical computing, coin flips are tricky. There's no provably secure way for Alice to flip the coin and have Bob call the toss—and ensure that one party or the other can't cheat when determining the winner. (They could sidestep the problem by having a trusted third party do the coin toss for them. However, the only two-party classical algorithms rely on mathematical constructs that nobody is certain are tamper-proof.)
With quantum computing, though, the picture changes. Vaziri, along with physicist Anton Zeilinger of the University of Vienna and other physicists, exploited the quantum-mechanical property of “entanglement” to ensure that neither side can cheat. In their setup, Alice has a pair of photons (created by an argon-ion laser shot at a barium-borate crystal) that are entangled: Measure one and you instantly affect the other's properties.
Alice tosses the “coin” by forcing one photon's angular momentum to take one of four possible states, two of which represent “heads” and two of which represent “tails.” This changes the state of the other entangled photon, which is sent to Bob. Bob measures his photon, but because quantum ambiguity makes different pairs of the four states look the same, he's unable to determine whether Alice picked heads or tails. He calls the flip—tells Alice heads or tails—and then Alice reveals which of the four states she picked, allowing Bob to verify instantly whether he won or lost the toss.
Bob can't cheat, because he doesn't know the outcome of the flip before transmitting his guess to Alice. And it's a subtler point, but Alice can't cheat because the signature of the coin flip is inscribed in Bob's photon; if she tries to lie, then this deception will likely show up as “noise,” nonsensical data when Bob interprets his measurements of the photon. Although there's only a certain probability of catching Alice each time she cheats, it's probabilistically guaranteed that she'll be caught if the ownership of the dog is determined by 1000 coin flips.
“The big problem in the paper was to come up with cheating algorithms,” says Zeilinger, who adds that Alice would have a very hard time gaming the system. “We feel that our procedure is very safe.”
The experiment is important “because coin tossing is a task in bigger protocols, such as multiparty communications,” says Andris Ambainis, a physicist at the University of Waterloo in Canada. “When you have sufficiently strong coin tossing, you multiply what you can do securely” over communications lines, whether the parties trust each other or not, he says. And given the torrid lives of Alice and Bob, cryptographers will likely stay busy for many years to come.
Immortality Dies as Bacteria Show Their Age
- Dan Ferber
“I don't want to achieve immortality through my work,” Woody Allen once said. “I want to achieve it by not dying.” Although that's unlikely for Allen and other higher organisms, many biologists believed that immortality was possible for microbes. Now, however, a new study suggests that bacteria get old, a finding that may give scientists a new tool to understand aging. “It's one of those exciting results that makes you take a fresh look at what you think you know,” says gerontologist Thomas Kirkwood of the University of Newcastle in Newcastle upon Tyne, U.K.
Biologists already knew that when it comes to aging, all cells are not created equal. In the 1970s, Kirkwood offered the disposable-soma theory: Cells of the body, or soma, can deteriorate, but the germ line cells have to take better care of themselves because they give rise to sperm and eggs. Simple organisms such as budding yeast engage in a subtler division of labor; aging yeast parents invest their freshest components in their buds. But biologists believed that immortality was possible for microbes that divide into identical-looking daughter cells.
To test that assumption, microbiologist Eric Stewart of INSERM in Paris tracked the fate of individual Escherichia coli cells. The rod-shaped bacterium divides in half to form two identical-looking daughter cells, which contain one old end, or pole, inherited from the parent and one new pole. When those daughter cells split, only two of the four resulting cells will have poles from the original cell. Current thinking assumed that all four cells were the same.
The INSERM team tracked the growth of single cells and their descendants on a specially designed microscope slide, taking images every 2 to 4 minutes for up to 6 hours. Ultimately, they tracked 94 colonies, consisting of more than 35,000 individual cells. By comparing 7953 pairs of sister cells, the researchers discovered that cells that inherited the older pole of the parent grew 2.2% more slowly than those that inherited a younger pole. The bigger the difference in age, the bigger the difference in growth rate, they report in the February PLoS Biology—a result the team attributes to “decreased metabolic efficiency.” The results mean that even “an apparently symmetrically dividing organism is subject to aging” and “make it unlikely that natural selection produced an immortal organism,” Stewart says.
Leonard Guarente, who studies aging at the Massachusetts Institute of Technology, agrees, saying that the results “put the onus of proof on anyone who claims that cells can be immortal.”
Biogerontologist George Martin of the University of Washington, Seattle, calls the results “conceptually very important” but cautions that the cells that slow and stop reproducing may just be taking a break to repair themselves. If further study shows that the older cells are actually dying off, it would “make biogerontologists take seriously the notion that there's aging in bacteria.” And if E. coli does get old, researchers could use it to study “how aging occurs and how it's regulated,” Guarente adds, allowing them to get “right to the molecular heart of the matter.”
- U.K. UNIVERSITIES
Cash-Short Schools Aim to Raise Fees, Recruit Foreign Students
- Eliot Marshall
CAMBRIDGE, U.K.—Even Britain's top research universities say they're broke. Although they receive regular government subsidies (see p. 668), the law limits what they can charge students for tuition. (The rate is about $2170 per year at present.) In addition, compared to U.S. institutions, they get only modest gifts from alumni and philanthropies. The result is “chronic underfunding,” says a strategic plan released last week by the University of Oxford.* The problem is growing worse, according to the document put out by Oxford's vice chancellor John Ford on 24 January, and “radical” changes are needed, including higher student fees.
Currently, Oxford's income is running about $38 million per year below expenditures, according to Ford's strategic planning paper, and “nearly all of the university's core activities lose money.” The Oxford University Press helps reduce the deficit by transferring at least $23 million per year to the university. To help slow the leakage, says Oxford spokesperson Ruth Collier, the university will take advantage of a new law next year that will allow variable tuition charges for U.K. students up to about $5662 a year. The university also hopes to recruit more foreign students, who pay many times the domestic rate. Collier says the motivation is not to raise funds, because that would bring in an additional $4.7 million per year—“a tiny proportion” of the annual revenue. Rather, the goal is to make the university more competitive in the world market.
Other U.K. universities are doing likewise, including the nation's largest, the University of Manchester, which disclosed similar plans to raise tuition fees and recruit foreigners in January.
Although Oxford counts itself among the world's top five research universities, the paper notes, its “fundraising efforts … pale in comparison with those of the leading U.S. universities.” Oxford raised about $110 million overall in 2002–03, the paper points out, while in that period Harvard and Stanford raised about $495 million and $472 million, respectively. Only 5% of Oxford's alumni make annual donations, compared to 40% to 60% of rivals' alumni.
Oxford's student body has been expanding at 1.5% per year, while the academic staff has “remained static,” according to the report, and between 1979 and 1999, the ratio of students to teachers “deteriorated from 9:5 to 13:2.” The plan aims to reverse that trend. It also calls for boosting the fraction of foreign students from 7% to 12%. But it won't be easy.
Oxford and other top universities are already under pressure from the government to increase the fraction of students they accept from U.K. state schools. Student and political leaders, meanwhile, are lobbying against university plans that might make admissions easier for foreign students. National Union of Students President Kat Fletcher decried an approach, as she told the Guardian, that treats “international students as simply pound signs that will solve the funding shortfall.”
The Oxford plan has gone out to students, faculty, and others for comment until mid-March; after that, it will be considered for a final decision.
- SOUTH ASIA TSUNAMI
Powerful Tsunami's Impact on Coral Reefs Was Hit and Miss
- Elizabeth Pennisi
Early surveys suggest that coral reefs around the Indian Ocean survived December's tsunami in better shape than many had feared. In the sites where researchers have looked, “only a few areas were severely damaged, and the rest should recover rapidly in the next 5 to 10 years,” says Clive Wilkinson, a marine scientist with the Australian Institute of Marine Science in Cape Ferguson. In some places, divers are already helping that recovery with restoration efforts.
In the immediate aftermath of the 26 December tsunami, Wilkinson and others feared the worst. The wave's awesome power, as well as sediment, pollutants, and debris washed onto the reefs when the wave retreated, posed major threats, says Russell Brainard, a U.S. National Oceanic and Atmospheric Administration oceanographer based in Honolulu. If eroded mud and silt buried a reef, they could destroy the corals.
Off the coast of Thailand, however, many reefs were spared. In January, volunteers and academic and government marine scientists took to the water for a first look. They evaluated 175 sites in the Andaman Sea along the west coast of Thailand, rating each according to the degree of impact. Half or more of the coral was missing from 13% of the sites, says Thamasak Yeemin, a marine scientist from Thailand's Ramkhamhaeng University in Bangkok. About 40%, though, seemed untouched.
Also last month in Thailand, Sakanan Plathong, a marine biologist at Prince of Songkla University in Had Yai, and 60 assistants armed with cameras spent 3 weeks combing a smaller area, the Similan Islands, one of the country's best dive spots. “In general most Similan islands that are dive sites are still in good condition,” says Plathong. Only about 15% of the area's coral was severely damaged.
David Obura of CORDIO East Africa—a collaborative coral research program in the Indian Ocean—in Mombasa, Kenya, has similarly good news about the African coast. “We were generally surprised at the [small] and very patchy damage to the coral reef communities,” he says.
Although turbid water prevented local government and academic divers from looking at six of the 10 sites in the Seychelles selected for a preliminary assessment, the survey indicated that only 13% of the coral colonies were damaged.
The reefs that were affected suffered different levels of damage, some repairable and some not. Corals were toppled over, sometimes covered with sand and rubble. In some places, meter-high sea fans were pummeled and knocked off their perches. Several reefs were littered with debris—logs, beach beds, towels, palm trees, boat engines, and beach umbrellas. These wave-driven objects “become like bulldozers,” says Brainard. “They severely erode the coral habitat.”
After the tsunami, Plathong realized he had to act fast to save any damaged corals. He brought a brigade of 136 volunteer divers to some of the worst places in the Similan Islands. The divers worked to right corals and were able to salvage those that hadn't slid beyond reach down the sloping sea floor. They propped up sea fans—a temporary fix until they could return with marine cement. They also removed debris, although heavy objects had to be left behind. The repair efforts benefited in one way from the tsunami's power: The wave was so strong that potentially lethal silt and mud washed far out to sea in many areas.
Yet there were places “where the reefs were just planed off and stripped to bare rock,” says Wilkinson. In another part of Thailand, three of four reefs surveyed were decimated. In some places, divers measured 5 millimeters of sediment on top of the corals. The reefs off the Tamil Nadu cost in Southeast India also appear to be severely damaged, as was coral off the Andaman and Nicobar Islands. “It will take some time before we can build a proper picture of the ecological ramifications of this disaster,” says Wilkinson.
University Spending Plan Triggers Heated Debate
- Dennis Normile
TOKYO—Taiwan has adopted a $1.6 billion plan to strengthen its research universities, reigniting a debate over how much of the money should go to a handful of leading institutions. A decision rests with a new cabinet now being assembled.
On 20 January legislators voted to allocate $315 million a year for 5 years to refurbish university facilities and boost faculty salaries. Under rules set out by the previous cabinet, most of the money would go to schools with 25,000 students or more, with the goal of turning them into world-class universities. To be eligible, the schools would also need to take steps to become private, not-for-profit institutions—part of a broader campaign to streamline the government that also includes reducing the 100-plus universities on the island. Taiwan currently has only two institutions of that size—National Taiwan University in Taipei and National Cheng Kung University in Tainan. The rest of the money would be spent on research centers affiliated with a dozen or so universities with active research programs.
The Ministry of Education has published statistics showing that Taiwan is not keeping pace with its neighbors in supporting its leading universities. Per capita spending at the flagship National Taiwan University was one-12th the amount at the University of Tokyo, it noted, and one-eighth that of the National University of Singapore. The survey “confirmed the shocking disparity among the institutions,” says Chen Teh-hua, director of the ministry's Department of Higher Education.
The money, expected to begin flowing in June, will be parceled out in a competitive process. But the real fight will be over whether the criteria that will govern the competition will be revised following a December setback to the ruling Democratic Progress Party in parliamentary elections that has forced a reshuffling of President Chen Shui-bian's cabinet.
On one side are those who say Taiwan's best chance of moving up the global academic ladder is by concentrating resources. “Higher education is a competitive sport. If you don't give resources to your best, you won't be able to compete on the world stage,” says Frank Shu, an astronomer who in 2002 left the University of California, Berkeley, to become president of National Tsinghua University in Hsinchu. The new funding scheme has increased speculation that Tsinghua may merge with its neighbor, National Chiao Tung University, creating an institution large enough to occupy the first tier.
Chiang Wei-ling, vice president of National Central University, says he and his colleagues at smaller schools recognize the need to give greater funding to a few top universities. “But it shouldn't be a binary, win-or-lose situation,” says Chiang. “You have to have a pyramid, with some concentration at the top but enough incentive so other universities don't get discouraged.” A 2003 report from a committee of top academics and government leaders recommended a 60-40 split.
But the proper balance isn't the only issue. The chair of that committee, former National Central University president C. H. Liu, says that privatizing higher education “is extremely controversial and is opposed by both government and opposition legislators.” Liu and others are hoping that the cabinet shakeup will give the government a chance to rethink the entire policy.
- UNITED KINGDOM
Proposed Law Targets Animal-Rights Activists
- Gretchen Vogel
A new law could send animal-rights activists in Britain to jail for up to 5 years if they cross the line between peaceful protest and harassment or intimidation. The new rules, introduced in Parliament on 31 January as an amendment to a larger anticrime bill, would specifically outlaw campaigns that target businesses that provide supplies or services to research organizations. It would also make it illegal to protest “outside someone's home in such a way that causes harassment, alarm, or distress to residents,” according to a government statement.
Barbara Davies of RDS (formerly the Research Defense Society) in London, a lobby group that defends animal research, said the law could provide important support. “There have been amendments to laws on harassment and intimidation before, and we thought that would work. But it's getting worse,” she says. Key advantages of the new law, she says, are that it would make it easier for authorities to charge the organizers of campaigns and increase protection for companies that work with organizations that do animal research. Last summer, work stopped at a new research lab in Oxford after construction company shareholders received threatening letters from activists (Science, 23 July 2004, p. 463). And in recent months, animal-rights activists have been charged with dozens of attacks—including desecration of a family grave—against a guinea pig farm near Birmingham that supplies research labs.
But some animal-rights activists are worried that the measures go too far. The law could potentially target peaceful protests and boycotts, says Andrew Tyler of Animal Aid in Tonbridge, Kent, which has organized demonstrations against the Oxford lab. The prohibition against demonstrations in front of residences could allow police to shut down protests at university research facilities that happen to be near residential buildings, he worries. “Like fishermen, if you cast a wide net, you catch many nontarget species,” he says. Parliament is expected to debate the measure this spring.
- CELL BIOLOGY
Asia Jockeys for Stem Cell Lead
- Dennis Normile,
- Charles C. Mann
Less encumbered by societal restrictions on embryonic stem cells, scientists in the developing countries of Asia are giving Western researchers a run for their money
Veterinarian Woo Suk Hwang and gynecologist Shin Yong Moon leapt from obscurity to scientific stardom last February when they isolated embryonic stem (ES) cells from cloned human cells, a world first and a key step toward therapeutic, or research, cloning.
Coming from a region that rarely produces scientific headlines, the announcement by the Seoul National University (SNU) pair stunned researchers around the world. But it was no fluke. Hwang has a long track record of successful animal cloning. Moon is South Korea's leading expert in assisted reproductive technology. The duo were able to draw on the expertise of a dozen co-authors at six institutions. And when Western scientists got their first peek into the SNU lab, they were astounded to see state-of-the-art facilities—and an enviable supply of egg donors.
Largely below the radar screen, the emerging economies of South Korea, Singapore, Taiwan, and China are fast becoming major centers for human ES cell research. Like their colleagues in the advanced scientific powers—including Japan, the United States, and many European countries—researchers in the developing countries of Asia are racing to learn how to transform ES cells into human tissues and organs, which could lead to treatments for conditions that are now intractable, such as diabetes, Parkinson's disease, and spinal cord injuries.
But there is one big difference: Unlike their colleagues in the United States and much of Europe, Asian scientists have the full support of their governments. Because obtaining ES cells involves the destruction of very early stage embryos, many Western governments have placed heavy restrictions on the work. But across Asia, there is little of the conflict with prevailing religious and ethical beliefs that has Western countries hesitating (see sidebar, p. 664). Governments are ramping up funding for both basic and applied stem cell work, setting up new institutes, programs, and grant schemes, and providing incentives for private companies to join the effort. Giving these efforts a further boost, the region also has legions of lab workers willing to log long hours, and increasing numbers of expatriate scientists are returning home to work in the flourishing environment.
With all these advantages, Asia's scientists believe that they can be fully competitive in, and perhaps even lead, the race to harness stem cells. “Asia has never dominated [any field in] cutting-edge biology,” says Chunhua “Robert” Zhao, director of the National Center for Stem Cell Research in Beijing. “This could be our chance.”
Stem cell researcher George Q. Daley of Harvard Medical School in Boston agrees: “I firmly believe they have an advantage.” Although recent state funding initiatives in California and Wisconsin (see sidebar, p. 662) should ease some of the constraints hobbling ES cell research in the United States, says Daley, such efforts are no substitute for federal support, which is still restricted.
Asia does face challenges, however. These countries are still building their scientific infrastructures, and many institutions must make do with older equipment. For some groups, geographical isolation and lingering language barriers hinder participation in conferences and complicate scientific publishing. In China, a lack of coordination and a culture of secrecy among scientists hamper progress. Perhaps most pressing, says South Korea's Hwang, the entire region suffers from a dearth of experienced senior scientists to run the new programs.
A series of firsts
Asian scientists have been at the forefront of research on cloning and stem cells since its inception. At China's Shandong University, embryologist Tong Dizhou produced the world's first cloned vertebrate, an Asian carp, in 1963. He went on to create the first interspecies clone in 1973, by inserting European carp DNA into an Asian carp egg. But Tong's work remained almost unknown outside China.
Two decades later, in 1994, Ariff Bongso, an in vitro fertilization (IVF) expert at the National University of Singapore, reported the first isolation of human ES cells in the journal Human Reproduction. But Bongso was unable to keep the cells growing, so the work attracted little publicity. That changed when two U.S. groups—one led by James Thomson of the University of Wisconsin, Madison, and another by John Gearhart of the Johns Hopkins University School of Medicine in Baltimore, Maryland—almost simultaneously solved the problem of maintaining stable lines of ES cells in 1998 by growing them on “feeder” layers of mouse fibroblast cells. Bongso and colleagues from Monash University in Melbourne, Australia, and Hebrew University in Jerusalem caught up, creating their own stable human ES cell lines in 2000.
Singapore was quick to realize the scientific and commercial payoffs of stem cell research. “Given its huge potential, stem cell research has been identified as one of Singapore's niche areas,” explains Hwai Loong Kong, executive director of the Biomedical Research Council, a part of Singapore's Agency for Science, Technology, and Research (A*STAR). ES cells became a cornerstone of Singapore's $2 billion National Biomedical Science Strategy, announced in June 2000 (Science, 30 August 2002, p. 1470).
Kong says A*STAR is spending about $7.3 million per year to support stem cell research, using both embryonic and adult lines, at the country's national labs and through grants to university researchers. But that is only part of the story. Academic groups also get funding from their universities and the Ministry of Education. The amount can't be pinned down, but the National University of Singapore reports that about a dozen groups are working on stem cells. Additional money is coming through venture capital support for start-up companies working to commercialize stem cell therapies and from foreign funders attracted by Singapore's welcoming climate for ES cell research.
Among academics, Bongso continues to set the pace. In September 2002, he and his Australian and Israeli colleagues reported the first propagation of human ES cells without using mouse feeder layers—a key advance because the lines grown on mouse cells probably cannot be used for clinical applications, given concerns about nonhuman pathogens. Bongso and his colleagues have turned over their cell lines and intellectual property to ES Cell International for commercialization. ES Cell owns six of the 22 human ES cell lines currently listed on the U.S. National Institutes of Health's (NIH's) Stem Cell Registry and has supplied more than 140 ES cell lines to researchers around the world, second only to the Wisconsin Alumni Research Foundation.
In March 2002, ES Cell recruited Alan Coleman, former research director of PPL Therapeutics in Edinburgh, U.K., and a member of the team that cloned Dolly the sheep, to head its 25-person research team. The company is banking on its ability to turn stem cells into insulin-producing cells that could be transplanted into patients with diabetes. Robert Klupacs, ES Cell International's CEO, says it hopes to start human clinical trials in 2006. Ronald McKay, a stem cell researcher at NIH, says ES Cell International is definitely one of the teams to watch, as is Singapore as a whole. Although the company has yet to turn a profit, concedes Klupacs, it has been able to support its $6.1-million-a-year research program with grants from Singapore, Australia, and private investors.
The U.S.-based Juvenile Diabetes Research Foundation (JDRF) is also supporting stem cell research in Singapore. It provided a $600,000 grant to Bernat Soria of the University Miguel Hernandez de Elche in Alicante, Spain, to set up a lab in Singapore in 2002 to continue work he was prevented from doing in his native country. In February 2000, Soria reported that his group had differentiated mouse ES cells into insulin-producing cells that had alleviated diabetes symptoms in mice. He has been extending that work to humans in his Singapore lab. Although the Spanish government has since relaxed its restrictions, Soria plans to keep a lab in Singapore. “The Asia-Pacific is playing a very important role in this research,” he says.
JDRF is also putting up half the cost of a $3 million fund—the other half is coming from A*STAR—to support other Singapore-based stem cell researchers working in a number of fields, as part of a new, competitively reviewed grant scheme. The foundation is investing in Singapore, says Chief Scientific Officer Robert Goldstein, “because there is excellent science, a good environment, and really strong support for work that can't be done in [the public sector in] the U.S.,” including deriving and working with new stem cell lines.
Although numbers are hard to verify, China may be home to the largest stem cell program in Asia. The government does not release statistics, but Pei Xuetao of the National High Technology Research and Development Program's stem cell division estimates that China has “about 300 to 400” Ph.D.s working on all types of stem cells in more than 30 scientific teams across the country. Perhaps 80 of them work with embryonic cells, a proportion that is growing.
As opposed to Singapore's coordinated national plan, China has a host of over- lapping initiatives from the central government, cities and provinces, private enterprise, and even semiprivate venture capital funds created by government agencies and the military. Pei pegs the total 5-year research budget at “more than” $24 million. (Dollars go further there than in the West, given China's vastly lower labor and material costs and its allocation of almost 100% of funding to research, with little overhead.)
Perhaps more important than funding levels, says Xiangzhong “Jerry” Yang of the University of Connecticut, Storrs, is that China has one of the most supportive environments for embryo research anywhere in the world. Issued in December 2003, Chinese regulations are quite “liberal,” says Yang. There is a strict ban on human cloning for reproductive purposes. But for research cloning, the guidelines include little more than a requirement that scientists comply “with the principle of informed consent and informed choice” when obtaining embryos from IVF clinics or fetal tissue from aborted fetuses. They also include a directive for institutions to monitor compliance. Wang Yu, the Ministry of Science and Technology's vice director of rural and social development, says the guidelines are “aimed at pushing forward our country's stem cell and therapeutic cloning research.”
The competition among groups and the government's reluctance to reveal information make it difficult to judge China's progress. But there is one sign of success: the growing number of foreign-trained Chinese scientists who are leaving comfortable positions in Europe and the United States to work in their native land. Sheng Hui Zhen, an ES cell researcher at Shanghai Second Medical University, says that “most major teams” in the field now have U.S.- or Europe-trained scientists in senior positions.
Sheng is a prominent example. She spent 11 years at NIH before relocating to Shanghai in 1999, where she leads a 50- person team, funded mostly by the city. The group is attempting to create functioning human ES cells by inserting the nucleus of adult human skin cells into rabbit eggs from which the nuclear DNA has been extracted. Sheng reported initial success in August 2003 in Cell Research, a peer-reviewed journal backed by the Chinese Academy of Sciences, but so far, no other lab has reported duplicating her work.
The popular press described the work as a “cross-species clone,” sparking intense ethical debate in the West. But Sheng dismisses talk of chimeric animals, noting that the only rabbit DNA in the cells is mitochondrial. Her goal, she says, is to design an alternative to human eggs for use in therapeutic cloning. She suspects that when such work becomes feasible, the procurement of eggs, which are difficult and expensive to obtain, may be the weak link. “My Chinese lab does not have everything my NIH lab had,” says Sheng. “But here I can work on this important problem, and there I couldn't.”
Some Chinese scientists have received backing for research that astonishes their former Western colleagues. Trained in Minnesota, Zhao of the National Center for Stem Cell Research in Beijing is working on stem cells from the bone marrow of aborted fetuses—work that cannot be done with federal funding in the United States and that many states have banned outright. “We have the freedom to look at these problems from many angles,” he says.
South Korea and Taiwan
To date in South Korea, the private sector has taken the lead in stem cell research. Three of the four groups that have established ES cell lines are at private IVF clinics, and for their breakthrough work, SNU's Hwang and Moon relied on a culturing technique developed at one of them. Figures for private sector spending are not officially tallied, and Hyun Soo Yoon, director of research at Seoul's MizMedi Hospital, which has a team of 18 scientists and technicians working full-time on stem cell research, also declined to disclose his group's budget.
Now the South Korean government wants to capitalize on the advances made by Hwang and Moon. At Hwang's home university in Seoul, the government is spending $50 million over 5 years to set up the Bio-MAX Institute; its goal is to foster interdisciplinary research in the life sciences, with a major focus on stem cells. Hwang will be moving his lab to Bio-MAX. Meanwhile, Moon continues to direct activities at the Korean Stem Cell Research Center. Established in 2002, the center has an annual budget of $7.5 million to support 30 researchers. And last year, the government put $5 million into a new competitive grant scheme for research related to therapeutic cloning, stem cells, and xenotransplantation. Funding could rise to $25 million per year by 2008.
In Taiwan, the government-affiliated Industrial Technology Research Institute (ITRI) is trying to nurture the island's biotechnology industry by developing stem cell expertise. ITRI researchers were the first in Taiwan to start working with human ES cells, in 2001. They have an 18-person group working to derive their own mouse-feeder-free cell lines and to learn to control differentiation. Their first target, too, is insulin- producing cells. While ITRI focuses downstream, Academia Sinica, Taiwan's premier collection of publicly funded science labs, is now ramping up a stem cell program focusing on understanding basic stem cell biology.
Although Asia's stem cell efforts are coming into their own, the region faces a number of challenges. Some worry that important stem cell research is going unpublished because of the intense interest in commercialization by Asian governments, companies, and researchers. Unlike Western biotech companies, which often seek the limelight, representatives of private companies in both Taiwan and South Korea were reluctant even to name their research topics to Science. Speaking under condition of anonymity, two Chinese researchers confessed they had not fully informed their granting agencies of what they were doing.
Deng Hongkui, a former New York University researcher known for his work on HIV, moved in 2001 to Peking University. Deng readily concedes that he has delayed submitting his research on the mechanisms of differentiation for publication for 2 years partly because his lab was preoccupied with the SARS emergency and partly, he says, because he wanted to secure worldwide intellectual property rights.
In China, researchers admit, the penchant for secrecy is heightened by rivalry and suspicion, which sometimes prevents groups from sharing data, expertise, and equipment as freely as their colleagues in the West. But they contend that this lack of communication is exacerbated by Asian researchers' continuing isolation from the scientific mainstream. Yang attributes some of this isolation to what he calls Western researchers' “inability to believe that top-rank research can come from developing nations in Asia.” The biggest challenge facing the region “is not the lack of financial resources or good bench-level researchers but the lack of leaders,” says Haifan Lin, a stem cell researcher at Duke University in Durham, North Carolina, who serves on a grant review committee at China's National Natural Science Foundation. All of these countries are trying to recruit researchers from outside their borders. Singapore has been the most aggressive, partly because it is so understaffed. Singapore also has advantages in recruiting non-natives, as English is the language of commerce and government and the city is relatively cosmopolitan. “For me, it was Singapore or nothing,” says ES Cell's Colman. Fifteen nations are represented on ES Cell's 25-person scientific team.
Some countries are already following China's lead and targeting expatriate sons and daughters. At Taiwan's Academia Sinica, most of the half-dozen Ph.D.-level researchers in the new stem cell group are Taiwanese or Chinese researchers returning from stints in the United States, the United Kingdom, or Australia. Group leader John Yu is a case in point. The former director of experimental hematology at Scripps Research Institute in La Jolla, California, Yu says he was lured back by the opportunity to get in on the ground floor of an exciting new effort and the chance to work in his native region.
Yu and other Asian scientists say they view these questions about leadership, openness, efficiency, and labor power as hurdles, not barriers, and are determined to overcome them. And they say their Western colleagues should expect to see more headline-grabbing research results come out of Asia in the next few years.
- CELL BIOLOGY
U.S. States Offer Asia Stiff Competition
- Constance Holden
Proposition 71, the $3 billion initiative designed to catapult California into position as the world leader in research involving human embryonic stem (ES) cells, is having a seismic effect across the United States. A few states—notably Wisconsin and New Jersey—are trying to become counterweights to California. Others are proposing more modest measures to make their states more attractive to stem cell researchers. Many legislators are trying to float initiatives despite substantial obstacles, such as big budget deficits. But if they don't take action, “states that have made significant investments in biomedical research”—Maryland and Massachusetts, to name two—“are genuinely concerned they are going to lose intellectual capital and resources,” says Daniel Perry of the Coalition for the Advancement of Medical Research in Washington, D.C.
Wisconsin—where the first human ES cell line was derived in 1998—is moving decisively. The state is poised for a massive new investment of $750 million in stem cell and other biomedical research over the next few years, including more than $500 million in new facilities and research support for scientists at the University of Wisconsin, Madison. Post-Proposition 71, a planned $375 million public-private research institute, the Wisconsin Institute for Discovery, has gained impetus.
In New Jersey, acting Governor Richard Codey is pursuing a regional approach. He has proposed allocating $150 million from unspent bond income to construct the New Jersey Institute for Stem Cell Research, a joint project of Rutgers University and the University of Medicine and Dentistry of New Jersey. Codey wants a ballot referendum next November to raise $230 million to bankroll research grants over the next 10 years.
In Illinois, members of the state Senate failed narrowly in November to pass a bill that would have allowed state funding for ES cell and nuclear transfer research. Now state Comptroller Daniel Hynes has designed a California copycat initiative: a statewide referendum in 2006 on a billion-dollar bond initiative. The Illinois Regenerative Medicine Institute would be created from the sale of $100 million in bonds per year for 10 years—repaid through a 6% tax on cosmetic plastic surgery.
Other states are eyeing various strategies to beef up their stem cell capacities. In Maryland, legislators are readying a proposal that would use tobacco-settlement money to open up $25 million annually for stem cell research starting in fiscal year 2007. Florida is poised to become a major player now that the California-based Scripps Research Institute plans to open its first branch in Palm Beach County. And a private group, Cures for Florida, is campaigning for a $1-billion-plus state ballot initiative for ES cell research.
Legislators in Massachusetts are chafing to get into the stem cell game, but because of the state's large Catholic population, recent pro-research measures have been quashed by the legislature. But Democrats, who are angling for the support of Republican Governor Mitt Romney, have vowed this year to push legislation to promote stem cell research through measures such as tax incentives. And in New York earlier this month, three legislators proposed a 10-year, $1 billion bond initiative that would finance the New York Stem Cell Research Institute.
On the flip side, a number of states are attempting to close the door on research with human ES cells. Nebraska, South Dakota, and Louisiana have forbidden such research. Laws prohibiting nuclear transfer (therapeutic cloning) have been passed in Michigan, Arkansas, Iowa, North Dakota, and South Dakota. Missouri is contemplating one, although scientists are warning that the state will pay a price if it adopts such a ban. The Stowers Institute for Medical Research in Kansas City, a major contributor to the biological lifeblood of the state, has said it “would be forced” to build a planned second facility outside Missouri if the measure passes.
Perry sees the state initiatives as evidence that the center of gravity in research may be shifting away from the federal government. “After generations in which a single NIH” ruled the biomedical research roost, “it's almost like the breakup of the Roman Empire.”
- CELL BIOLOGY
Asian Countries Permit Research, With Safeguards
- Dennis Normile,
- Charles C. Mann
Government officials, researchers, and ethicists in Asia readily link the region's general acceptance of research using human embryonic stem (ES) cells to its dominant Buddhist and Confucian religious-ethical traditions. But the countries of East Asia have also put a lot of thought, effort, and public debate into formulating policies that define researchers' responsibilities, as well as oversight mechanisms to ensure that guidelines are followed.
Although broadly similar, the policies adopted throughout the region differ in details. China, South Korea, Taiwan, and Singapore have all banned reproductive cloning with the intent of creating a child. All four regions also allow the derivation of ES cells from surplus in vitro fertilization (IVF) embryos obtained with informed consent; China, in addition, allows researchers to use embryos from aborted fetuses or miscarriages. South Korea's law stipulates that only embryos preserved for at least 5 years can be used. In each country except China, bioethics advisory committees have proposed national review boards to approve and oversee the derivation of new stem cell lines and each specific research project using them.
Singapore and China allow the creation of embryos through IVF for research purposes; South Korea and Taiwan forbid this. Countries are split on therapeutic cloning, or the use of adult somatic cells to create stem cells genetically matched to the donor. Singapore and China will allow it with the same oversight as for ES cells. South Korea has decided to restrict therapeutic cloning to a limited number of groups and solely for work that can't be done using typical ES cells. The country's national review board will decide which groups and projects qualify. Taiwan's advisory committee “split 50-50” on therapeutic cloning, says committee member Daniel Tsai, a physician on the faculty of National Taiwan University. It put off a decision pending further study.
Singapore, South Korea, and Taiwan incorporated societal views through high-level bioethics committees that held public hearings and made recommendations for the governments to codify into law. South Korea adopted a law governing ES cell derivation and research in December 2003. In September 2004, Singapore banned reproductive cloning but left pending the creation of a national review board. Under both laws, violators face prison sentences of up to 10 years or hefty fines or both. South Korea's review board is now being formed. Singapore's and Taiwan's need enabling legislation. For now, researchers using ES cells in Singapore must report their activities to the Ministry of Health. Until Taiwan passes legislation, says Tsai, institutions are trying to follow the recommendations of the bioethics committee; anyone violating the administrative ban on human cloning could lose a license to practice medicine or be forced out of an academic post.
Serious debate in China on stem cell research ethics began only in late 2001, after a team led by Chen Xigu of Zhongshan Medical University in Guangzhou claimed it had cloned embryos by inserting a child's DNA into an enucleated rabbit egg. Although the news was met with skepticism, and the team never published its results, the report set off a public storm. Galvanized by the furor, Chinese bioethicists held several meetings in 2002 and 2003, submitting the results to a newly formed interagency committee of the ministries of Health and Science and Technology. Issued in December 2003, the committee's “ethical guiding principles” are much less formal than other nations' regulations—they are fewer than 500 words long and specify no penalties for violation. Although the regulations are intended to “give researchers a lot of freedom,” the bottom line is clear, says Deng Hongkui of Peking University: “There will be no reproductive cloning in China.”
- DEVELOPMENTAL BIOLOGY
The Unexpected Brains Behind Blood Vessel Growth
- Gretchen Vogel
Two of the hottest fields in developmental biology—neural guidance and angiogenesis—are beginning to merge as scientists find that similar proteins control both processes
Whether in San Francisco or Singapore, almost everyone knows what the colors on a traffic light mean. But how did red, green, and yellow get chosen? It turns out railroad signals were already using these colors to guide trains. And the railroad industry may have gotten the idea from the electrical industry, which apparently used red to show that a motor was stopped and green to signal that it was running. When something works, why not use it more than once?
Evolution follows that principle too, as researchers studying the growth of blood vessels and nervous systems are beginning to appreciate. Scientists probing the development of the veins, arteries, and capillaries that guide nutrients and oxygen to cells are finding more and more evidence that the genes and proteins that were first discovered to guide growing nerve cells also direct blood vessels.
Decades of work by neuroscientists detailing the complex interactions of those cues is now giving researchers who study angiogenesis—the growth of blood vessels—a boost in their understanding of the vascular system. “Neurobiology has made an immeasurable contribution to angiogenesis,” says David Anderson of the California Institute of Technology in Pasadena, who noticed some of the first overlaps. “All the insights we've gained from studying these signaling systems in the nervous system have put us in a much better position to understand how they work in the vascular system.”
At the same time, one of the most powerful triggers of blood vessel growth, a protein called vascular endothelial growth factor (VEGF), is turning up in nerve cells and may play a key role in keeping them healthy and alive. “There is remarkable overlap in the use of these [signaling] systems,” says David Ginty of Johns Hopkins University in Baltimore, Maryland.
These insights not only are inspiring a new respect for the complexity and precision of growing blood vessels, but they also have potential medical implications. Animal trials suggest that VEGF is a potential weapon against amyotrophic lateral sclerosis (ALS), an incurable disease that attacks nerves and gradually paralyzes its victims. And for those trying to control the growth of blood vessels—either to stop them from supporting cancerous tumors or to help them regrow after illness or injury—the nerve proteins offer a wealth of new targets to manipulate.
The tipping cell
One of the first signs of flirtation between the two fields came in 1998: Michael Klagsbrun of Children's Hospital in Boston and his colleagues reported in Cell that neuropilin, a cell surface protein originally identified as a receptor for a signal that guides growing nerves, also responds to VEGF (Science, 27 March 1998, p. 2042). Klagsbrun's observation “was an amazing discovery,” Ginty says, although in hindsight it makes perfect sense, because both the blood vessel and nervous systems are “vast networks of complicated connections.” Later that year, Anderson and his colleagues reported that another set of neuronal guidance molecules, cell surface proteins called Ephrin B2 and EphB4, were also present in the developing vascular system.
Before these new observations, blood vessels were largely thought to form along a path of least resistance, without much active guidance. But the recent work paints a subtler picture, in which guidance molecules provide precise attractive and repulsive cues to specific growing vessels, notes Christer Betsholtz of the Karolinska Institute in Stockholm, Sweden. Work by Betsholtz and his colleagues revealed some of the first evidence for that precision. They showed in 2003 that specialized cells at the tip of developing blood vessels are attracted by slight changes in the concentration of VEGF. That reminded many biologists of what they see at the front of extending axons: the long extensions of a nerve cell that reach out and connect with other cells. “There are certainly some differences,” says Ruediger Klein of the Max Planck Institute of Neurobiology in Martinsried, Germany, “but if you look at the pictures [from Betsholtz], the tip cells look very much like an axon's growth cone, extending and sensing the environment and responding to cues.”
And the tip cells seem to respond to at least some of the same cues as growth cones. Last November in Nature, a group led by Anne Eichmann of the College of France in Paris described how those tips respond to netrins, a family of secreted proteins that help attract some axons and repel others during the formation of the spinal cord. How nerve cells react to netrins depends on which receptors they express, and, the new work shows, blood vessels can also react in different ways to the chemicals. Eichmann, with Peter Carmeliet of the University of Leuven in Belgium and Mark Tessier-Lavigne of Stanford University in California and their colleagues, reported that the gene for one of the previously identified netrin receptors, called Unc5b, is expressed in the tip cells of developing blood vessels. When the team created mice and zebrafish that made a faulty version of UNC5B, the vascular system of the mutant animals had far more sprouts and branches than normal—suggesting that the tip cells were impervious to a “stay away” signal from netrins. Indeed, the team subsequently showed that Netrin 1 causes the sprouts of rat blood vessels growing in culture to retract.
But that is not the whole story. In a paper published nearly simultaneously in the Proceedings of the National Academy of Sciences, Dean Li and his colleagues at the University of Utah, Salt Lake City, showed that Netrin 1 can also encourage the growth of new blood vessels, suggesting that the molecule may reprise its sometimes attractive, sometimes repellent role in the vascular system.
Eichmann and her colleagues have come across hints of other roles for netrins and their receptors in blood vessel development. They found that the UNC5B receptor is widely expressed in arteries, which deliver oxygen-rich blood to tissues, but it is apparently absent in veins, which return oxygen-depleted blood to the heart.
The early work on ephrin and Eph molecules from Anderson and his colleagues had showed a similar pattern. In their 1998 paper that established some of the first links between neuronal guidance and angiogenesis, the team showed that Ephrin B2 is expressed in arteries but not veins. Conversely, the ephrin receptor called EphB4 is expressed in veins but not arteries. These data were the first sign that arteries and veins are molecularly distinct at the earliest stages of development. Klein and his group confirmed that finding several months later and showed that the proteins could prompt the growth of new capillaries.
Anderson and his colleagues found another bond between developing nerves and blood vessels. They showed that in the skin of developing chicks, arteries are guided in part by the development of nerves, whereas veins are not. They also studied mice lacking Semaphorin3A, one of the proteins that neuropilins recognize. These animals develop badly misdirected nerves, and their developing arteries followed the deviant paths of the nerves, providing more evidence that the systems are closely intertwined.
That observation is consistent with work on semaphorins by two other groups, one led by Ginty and the other by Brant Weinstein of the National Institute of Child Health and Human Development in Bethesda, Maryland. Each showed last year that semaphorins keep developing blood vessels on the straight and narrow. According to their research, zebrafish and mice lacking semaphorins or their receptors develop strikingly disorganized vessels.
A role in blood vessel growth for a fourth category of neuronal guidance molecules—the Slit proteins and their Robo receptors—may be emerging as well. In 2003, Jian-Guo Geng of the Shanghai Institutes for Biological Sciences at the Chinese Academy of Sciences in Shanghai and his colleagues reported that a wide variety of tumor cells produce a protein called Slit2, and that endothelial cells, the precursors of blood vessels, express the receptor Robo1. They suspect that the tumor cells might be using Slit proteins to attract new blood vessels to the growing tumor tissue. And in October, Roy Bicknell of Oxford University and his colleagues reported evidence in the FASEB Journal that a newly identified Robo receptor, which they call Robo4, is present in areas where new blood vessels are forming.
Neuroscientists are also learning from angiogenesis researchers. VEGF, the classic trigger of blood vessel growth, is showing up more and more in studies of nerve growth and development. The first clues to VEGF's neuronal role came from experiments in Carmeliet's lab at the University of Leuven in Belgium. To sort out some of the multiple roles VEGF plays in vascular development, Carmeliet and his colleagues created several strains of mutant mice that carried slightly altered versions of the protein. The mice seemed to develop normally but became ill as adults. “To our surprise, we found that they had motor neuron degeneration similar to that seen in ALS,” says Carmeliet.
Normally, VEGF is expressed in response to low oxygen levels—it attracts new blood vessels to tissues that are short of oxygen. Carmeliet's mice carry a mutation that prevents that oxygen-dependent increase in expression, suggesting that perhaps a lack of VEGF leaves nerves vulnerable to hypoxia. Indeed, in studies of nerves in culture, introducing VEGF seemed to help the cells survive stressful conditions such as low oxygen or serum deprivations.
There are early hints that VEGF might play a role in some human ALS cases as well. In a study of 2000 people in England and Sweden, Carmeliet and his colleagues found that those carrying a certain version of the VEGF gene, one which seems to lower its overall production, were 1.8 times more likely to develop ALS than the general population.
Carmeliet and his colleagues have tested in animal models of ALS whether increasing production of VEGF combats the condition. In one rodent trial, they injected into muscles a rabies virus, which homes in on and infects nerve cells, modified to churn out VEGF. The mice that received the virus took longer to develop ALS-like symptoms and survived longer than their untreated counterparts. Working with a rat model of ALS, the team has also injected the VEGF protein directly into the cerebral fluid and documented similar benefits. The team is now preparing human trials, Carmeliet says, which could be under way within 2 years.
Angiogenesis researchers are hoping that the molecules that originally held the promise of regrowing severed or damaged nerves may pay off in another clinical area as well: the fight against cancer. These researchers have been attempting to fight tumors by cutting off their blood supply—essentially starving them to death. The finding that neural guidance molecules influence normal blood vessel growth has suggested a wealth of potential new targets, says Tessier-Lavigne: “There is every reason to believe [these molecules] will regulate pathological angiogenesis as well.”
The discoveries in both fields may have even wider impact. Eichmann and her colleagues have shown that mice lacking neuropilin-2 have defects in their lymph systems. Similarly, in the 1 February issue of Genes and Development, Klein and his colleagues describe how mice lacking Ephrin B2 develop major defects in their lymphatic systems as well. Nature, it seems, has made the most of a good idea.
- U.K. UNIVERSITIES
'Darwinian' Funding and the Demise of Physics and Chemistry
- Daniel Clery
Britain's scheme to favor the highest-scoring research teams—abetted by other changes in society—is decimating chemistry and physics departments
CAMBRIDGE, U.K.—The word “university”—from the Latin universitas—suggests the whole, the world, or the universe. But is an institution still worthy of that moniker if it doesn't teach chemistry or physics? Universities in the United Kingdom seem to think so. Over the past decade, they have announced a steady stream of department closures, and now less than half of all U.K. universities offer undergraduate chemistry degrees. Physics has suffered a similar decline. “It's a disaster,” says chemistry Nobelist Harry Kroto of the University of Sussex.
Department closures became headline news late last year when Exeter University announced plans to close its chemistry department, and Kroto threatened to hand back an honorary degree from the university. It was a surprising case particularly because Exeter's chemistry department was not failing: Almost all its work met a national standard of excellence, as judged by the 2001 Research Assessment Exercise (RAE), a government scheme that grades university departments. And during the 2004–05 academic year, Exeter had seen a 21% rise in applications to study chemistry. Nevertheless, the university's senate voted in December to close the chemistry department and concentrate on a new school of biosciences and on strengths in physics and sports science.
Ask researchers why this is happening, and they generally respond that the government, which is the main source of money for U.K. universities, is not providing enough for expensive lab-based courses such as physics and chemistry. This public contribution “has never been able to finance science departments to operate at even a minimum level,” says Philip Kocienski, head of Leeds University's School of Chemistry. But other forces are at work, too. Demand for physics and chemistry classes has been steadily falling as students are lured into more career-specific courses such as sports science, forensic science, and media studies. And the once cozy world of British academia is now a competitive marketplace in which universities must vie with each other for government research money and attract as many students as possible to maintain their income. Some researchers suspect that current funding policies are designed to weed out the weak and concentrate resources in a smaller number of superdepartments. “It's a Darwinian exercise,” says Kocienski.
The government has taken a hands-off approach so far, respecting the universities' autonomy. But the row over Exeter's withdrawal from chemistry has forced the government to rethink its neutrality. In December, then-Education Secretary Charles Clarke asked the Higher Education Funding Council for England (HEFCE) to look into ways to protect five strategic areas of study, one of which includes all of science, engineering, technology, and mathematics. Whether this will halt the closure of physical science departments nobody knows. One thing is certain: No new money will be available.
Get 'em while they're young
No amount of new money would get around one critical fact: Physical sciences are not as popular among prospective university students as they once were. Although absolute numbers of applications have stayed fairly stable, Prime Minister Tony Blair's Labour government has successfully worked to increase the number of students going into higher education. As the total expanded, the fraction going into physical sciences grew smaller and smaller. (In the United Kingdom, students apply to universities to study a particular subject, and they specialize in their chosen major from the beginning.) “There is a serious supply-side problem,” says metallurgist Graeme Davies, vice chancellor of the University of London.
What motivates teenagers to choose one course over another is not a simple question, but many blame science's declining appeal on the lack of good role models in the classroom. Britain's school system has long had a problem attracting science graduates into teaching; other careers offer much better salaries and opportunities for advancement. As a result, few high school pupils are taught physics or chemistry by teachers with degrees in those subjects. John Enderby, president of the Institute of Physics (IOP) in London, says the crisis in science departments is “a symptom of the underlying cause: We don't value teachers.”
Other social incentives are at work, too. Few high school students see the benefit of studying a basic science. Meanwhile, television has made jobs in forensics, for example, seem glamorous, and universities now offer courses that appear to provide a fast track to that career. Member of Parliament Ian Gibson, former head of biological sciences at the University of East Anglia in Norwich, says university administrators “will teach anything to get students.” Gibson, now Labour's chair of the House of Commons Science and Technology Committee, says police chiefs have told his committee that they don't want such graduates. What they need are “good chemists and physicists.” Simon Campbell, president of the Royal Society of Chemistry, says “it is up to us” to make careers in science attractive.
Follow the money
Attracting students is not enough to keep a department afloat, however, as Exeter's experience has shown. Many believe that government funding policies are quietly changing the shape of higher education by channeling research funding into science powerhouses while leaving other departments to founder.
Government funding to universities is distributed by HEFCE and partner councils in Scotland, Wales, and Northern Ireland. For the current academic year, HEFCE, by far the largest of the four councils, will distribute $11 billion to English higher education institutions, of which $7.2 billion goes in support of teaching and $2 billion for indirect costs associated with research. The teaching portion is divvied up according to how many students the university enrolls and how expensive their courses are to teach. So each humanities student earns a university $6600, while each undergraduate in lab-intensive subjects such as physics and chemistry, for example, wins the university 1.7 times as much ($11,000). Medics, dentists, and vets earn a fourfold boost ($26,000).
Many researchers argue that this extra funding is not enough to cover the costs of lab buildings, materials, and support staff. “Chemistry is expensive to teach,” says Campbell, and HEFCE provides “woefully inadequate funding.” Enderby agrees: “In all subjects the full cost of teaching is not met, but the shortfall is greatest for the laboratory sciences.” HEFCE spokesperson Philip Walker counters that the allowances are based on a study of what universities actually spend. “We have to have a fair and transparent means to allocate the money,” he says. In any event, Walker points out, once HEFCE has done its calculations, the money is given to the university as a lump sum. “Universities can allocate the money internally as they want.” The implication is that Exeter itself bears the chief responsibility for the choices it made. “Exeter's chemistry department was not a dying animal,” says Stephen Chapman, head of the School of Chemistry at Edinburgh University. “It was shot rather than left to die.”
Academic cattle market
Departments that find they cannot manage with the teaching grant from HEFCE often end up subsidizing teaching from their research income. But not all departments have this luxury, as HEFCE research grants vary greatly in size depending on the quality of a department's research output. In 1992 HEFCE launched the RAE, its quality-control survey, which it repeats roughly every 6 years. Specialists in each subject rate the research in all university research departments and grade them on a scale from 1 (the lowest) to 5*, the score reserved for departments with “international excellence” in more than half of the work submitted for review. These grades have a major impact on funding, so before each new RAE, departments scramble to hire the hottest new researchers in the hope of bumping up their rating.
Most U.K. research departments cluster around the top end of the scale, with the peak of the curve around the boundary between grades 4 and 5. But following the 2001 RAE, many departments were shocked when the government decided to focus on the top achievers, pushing more of HEFCE's research funding into the highest-rated departments. Since that assessment, departments rated lower than 4 have received no research funding from HEFCE; those rated 5 and 5* get approximately three times as much per researcher as those rated 4. And since 2001, many 4-rated departments, such as chemistry at Exeter, have found themselves fighting for survival.
Although the RAE is a painful process, it's widely credited with having improved the quality of research in the United Kingdom. But many think it may have gone too far, and HEFCE is reviewing the system before the next RAE in 2008. “The RAE aims to starve out the weak, and it's been quite effective. But now it's cutting into flesh rather than fat,” says Kocienski. “Vice chancellors are all too ready to use the RAE to cull expensive departments,” adds Kroto.
Cooperation not competition?
Gibson thinks the current crisis is the result of politicians forcing university administrators to think like business people and make decisions on purely financial grounds. “There is a lack of understanding among academic bigwigs about the needs of chemistry and physics,” he says. Kocienski, voicing a pessimistic view, says the current total of about 40 chemistry departments may dwindle further to just 20: “I suspect that the government has this number in mind, too.” The physics community is concerned that as closures continue, ever-larger swaths of the country will be left without any physics department. Students may have to travel farther from home to study physics, the IOP warns, and businesses will not be able to work with local researchers on R&D projects.
In Scotland, universities are already trying to counter the trend by taking a pragmatic approach: They are teaming science departments together for greater strength rather than letting the weakest go to the wall. Six Scottish physics departments have formed SUPA, the Scottish Universities Physics Alliance, and chemists from four universities will meld into two superdepartments: EastCHEM and WestCHEM. Each of these bodies will be entered into the RAE as a single department. Last November, these initiatives won $70 million for the next 4 years from Scottish funding bodies. “We have a vision of where we are going in chemistry and physics,” says Edinburgh's Chapman. “We're not going to close things because one department is not doing well.”
Other changes may be coming. Education Secretary Clarke's decision to consider protecting strategic subjects is a sign that the government may have concluded that it cannot govern higher education by a form of natural selection. “Do we need every department to be world beating?” asks Enderby: “No. Do we need a widespread education in physics? Yes.”