# News this Week

Science  15 Jun 2001:
Vol. 292, Issue 5524, pp. 1978
1. GLOBAL WARMING

# Bush Backs Spending for a 'Global Problem'

1. Richard A. Kerr

A group of distinguished American scientists last week confirmed that the world is warming and humans are probably to blame for most of the climate change. The quickie, 1-month analysis* by an 11-person committee of the U.S. National Research Council (NRC) also confirmed that essentially identical conclusions from an earlier 3-year international study had not been unduly distorted when summarized for public consumption. The NRC committee did play up the uncertainties in the international report, however—a point that President George W. Bush emphasized this week in calling for new research and technology initiatives to combat what is clearly a “global problem.”

In the wake of the president's rejection of the Kyoto Protocol for restraining greenhouse gas emissions, the White House had asked the National Academy of Sciences for help in formulating an alternative. Tapped for the scientific assessment job were 11 meteorologists, oceanographers, and climate scientists, all but two of whom—climatologist Thomas Karl of the National Climatic Data Center in Asheville, North Carolina, and meteorologist Richard Lindzen of the Massachusetts Institute of Technology —had avoided substantive involvement in the international assessment conducted by the U.N.-sponsored Intergovernmental Panel on Climate Change (IPCC) (Science, 26 January, p. 566). Although most committee members have kept a relatively low profile in the global warming debates, Lindzen is the country's most academically credentialed greenhouse contrarian; he has long argued that any warming will be minor. And climate modeler James Hansen of NASA's Goddard Institute for Space Studies in New York City ignited a firestorm of media attention in 1988 when he told Congress that greenhouse warming had clearly already arrived.

Despite the committee's breadth of views, its report echoed the IPCC's mainstream support for anthropogenic global warming. “Temperatures are, in fact, rising,” the report's summary concludes. “The changes observed over the last several decades are likely mostly due to human activities. …” And: “Global warming could well have serious adverse societal and ecological impacts by the end of this century.” That's just what environmentalists and activist scientists wanted to hear, particularly as Bush meets this week with his European counterparts, in part to discuss what he intends to do about global warming.

But the White House also got what it was looking for, a more clearly articulated discussion of the uncertainties in greenhouse science. Although the IPCC's bottom line “accurately reflects the current thinking of the scientific community,” even in its greatly simplified summary for policy-makers, “uncertainty remains,” says the report. It lingers in everything from the effects of soot from fires and changing cloud cover to the realism of climate models and the role of water vapor in stoking the greenhouse (Science, 13 April, p. 192). The committee reiterated the IPCC's dramatic range of possible warming; because of the uncertainties, the IPCC estimated that by the end of the century the world might warm by a modest 1.4°C or a sizzling 5.8°C.

Bush relied on this U.S. expert-certified uncertainty in an 11 June speech on global climate change from the Rose Garden. The academy's report found that the world has warmed and greenhouse gases have increased, largely due to human activity, he said. While leaving implicit the link between humans and the warming, he emphasized that the contribution of natural climate variability to the past century's warming is uncertain, as is the cooling effects of pollutant hazes. The magnitude and rate of future warming are unknown, he pointed out. And “no one can say with any certainty what constitutes a dangerous level of warming and therefore what level must be avoided.”

Bush's response, a 5-year U.S. Climate Change Research Initiative, appears to be a repackaged version of the existing U.S. Global Change Research Program begun a decade ago by his father. The new program, led by the Commerce Department, is to include an unspecified amount of money for research, climate observation systems, and computer modeling. The current program, a $1.7 billion effort involving half a dozen federal agencies, is slated for a 4% cut in the president's 2002 budget. At the same time, Bush reiterated his rejection of the as-yet-unratified Kyoto Protocol, calling it “fatally flawed.” It would damage the U.S. economy, he said, and unfairly relieve developing countries of any commitments to reducing their greenhouse gas emissions. Although “we recognize the responsibility to reduce our emissions,” Bush said, the United States won't be doing so through the mandatory emission reductions of the Kyoto Protocol. Instead, the proposals in the Administration's energy plan for energy conservation and reduced-emission energy sources such as natural gas will help in the short term. A new National Climate Change Technology Initiative is meant to address the long-term problem by developing alternative technologies such as fuel cells and carbon dioxide sequestration. 2. UNDERGROUND LABORATORY # U.S. Researchers Go for Scientific Gold Mine 1. David Malakoff U.S. scientists are asking the National Science Foundation (NSF) to pour$281 million into a hole in the ground. A new research coalition last week submitted a proposal to NSF to transform one of the world's deepest gold mines into a world-class underground laboratory for physics, geology, and extreme biology. The plan is enthusiastically backed by many researchers, and a powerful member of Congress—Senate Majority Leader Tom Daschle (D-SD) —hopes to find money to get the ball rolling. But the project faces an uncertain reception at NSF, which already has a long list of expensive projects awaiting funding.

Lab advocates are also battling the clock. The owner of the Homestake Mine in Lead, South Dakota, plans to abandon the 2500-meter-deep shaft at the end of the year, leaving it for nature to flood. “This is an unusual opportunity to create the best underground laboratory ever,” says physicist John Bahcall of the Institute for Advanced Study in Princeton, New Jersey, who earlier this year led an ad hoc review that deemed Homestake the best of several potential sites.

U.S. researchers—especially astrophysicists studying the origins and composition of the universe—have long coveted an underground facility deep enough to shelter sensitive instruments from unwanted cosmic radiation. But advocates failed to win funding for such a facility in the 1980s, prompting many scientists to export their studies to better subsurface labs in Japan, Italy, and elsewhere. Hopes rose anew last September, however, when Homestake Mining Co. announced that it would close its 125-year-old namesake, dug deep into the scenic Black Hills near Mount Rushmore.

Energized by the chance to snag for science the Homestake's 1000 kilometers of tunnels, electrical wiring, and extensive ventilation system, a group of researchers asked Bahcall to chair the hastily assembled ad hoc panel. It examined the potential uses of an underground lab and toured several possible sites—including an undeveloped area at California's Mount San Jacinto near Palm Springs and the Waste Isolation Pilot Plant, a nuclear waste dump in New Mexico. In March it gave Homestake the nod, noting that it is nearly twice as deep as the deepest existing underground facility, at Gran Sasso in Italy.

On 8 June, five Homestake advocates, led by physicist Wick Haxton of the University of Washington, Seattle, turned the committee's recommendation into a formal proposal. It seeks $281 million over 5 years, beginning in 2002, to carve detector halls, upgrade cables, build clean rooms, and begin small research projects. Major studies, however, would be funded separately, probably by NSF and the Department of Energy. Researchers are already proposing projects that would cost from hundreds of thousands to hundreds of millions of dollars. Biologists, for instance, are interested in relatively inexpensive studies that would examine the bacteria and other “extremophiles” that have adapted to the mine's harsh conditions. Astrophysicists say that they could install a$20 million detector designed to capture the burst of neutrinos created by a supernova. But it could take $500 million and a decade or more to build one of the biggest experiments envisioned for Homestake—the Ultra Underground Nucleon Decay and Neutrino Observatory, a bigger version of Japan's Super-Kamiokande proton-decay detector. NSF officials say that they will soon identify reviewers to weigh the mine's merits. Even if the idea wins good notices and the approval of NSF's governing board, however, the agency will then have to slot it into a crowded lineup of already approved projects. The Bush Administration threw NSF a curve ball this year by issuing a no-new-starts diktat for the budget year that begins on 1 October. The pending projects within NSF's physics division alone include the United States'$200 million contribution to the $660 million international ALMA millimeter telescope in Chile and the$240 million ICE CUBE polar neutrino detector.

Bahcall believes Homestake “deserves a place right at the top of the list”—even though it might delay other projects he has championed, such as ALMA. “Because of the time pressure, that is the way the game has to be played,” he says. But Joe Dehmer, head of physics at NSF, says his “concept is that, if approved, it will not preempt [projects] that are ready to go.”

The proposal has powerful friends, including Daschle and South Dakota Governor Bill Janklow, a Republican said to be close to President George W. Bush. They see the lab as an economic and educational engine, envisioning an underground IMAX movie theater and other tourist attractions. Senator Tim Johnson (D-SD), a member of the Senate Appropriations panel that oversees NSF's budget, has already asked for $10 million next year to keep the mine open while the science bureaucracy's wheels turn. Observers say that politicians might move to earmark more funds if the project is approved. In the meantime, Homestake's advocates are moving forward. They plan to hold a workshop next month near the historic hole to discuss what kinds of precious data the mine might yield in place of the glittering gold it once produced. 3. NAZI RESEARCH # Max Planck Offers Historic Apology 1. Robert Koenig BERLIN—For half a century, survivors of cruel experiments at Nazi death camps have been seeking a formal apology—as well as more details about the research abuses they endured—from Germany's scientific societies. On 7 June, a few of those victims finally got an explicit apology from the head of the country's premier basic research organization, the Max Planck Society, on behalf of its forerunner, the Kaiser Wilhelm Society (KWG), some of whose scientists were implicated in the nefarious research. However, the statement from Max Planck president Hubert Markl won't close the book on Nazi-era atrocities committed in the name of science: Historians are redoubling their efforts to document these activities. Markl's historic overture came here at a symposium on human experimentation sponsored by the Max Planck presidential commission that is investigating the KWG's activities from 1933 to '45. At the opening ceremony at the Fritz Haber Institute in Berlin—a former KWG center where poison-gas research was once conducted —Markl offered eight survivors of concentration-camp experiments “the deepest regret, compassion, and shame at the fact that crimes of this sort were committed, promoted, and not prevented within the ranks of German scientists.” Markl stated that “there is scientific evidence proving beyond the shadow of a doubt that directors and employees at Kaiser Wilhelm Institutes co-masterminded and sometimes even actively participated in the crimes of the Nazi regime. … The Max Planck Society, as the Kaiser Wilhelm Society's ‘heir,' must face up to these historical facts and its moral responsibility.” Markl's admission was followed by emotional speeches by two victims of Nazi physician Josef Mengele's infamous “twins” experiments at the Auschwitz-Birkenau death camp. Of an estimated 1500 sets of twins in Mengele's experiments—during which he would inject one twin with a pathogen or toxic substance and use the other as a control—fewer than 200 individuals survived the war and only about 80 are alive today. “We were used as human guinea pigs,” said Eva Mozes Kor of Terre Haute, Indiana, who barely survived Mengele's abuses along with her twin sister, Miriam. Kor, founder of C.A.N.D.L.E.S., an organization of twins survivors, said she was willing to forgive even her torturers. But warning that “forgiveness erases memory,” Jona Laks, an Israeli survivor who chairs the Organization of Mengele Twins, asserted that some scientists might use such clemency to forget the past. “The deeds of those who did this research cannot be forgiven,” Laks insisted. “We have no ‘power of attorney' to forgive in the name of the exterminated victims.” Just down the block from the conference venue is the building that once housed one of the Nazi regime's most notorious betrayers of scientific ethics: the KWG Institute for Anthropology, Human Genetics, and Eugenics. Mengele did not work for the KWG, but he had earned his Ph.D. under the institute's director, Otmar von Verschuer, who later arranged for Mengele to send blood samples from Auschwitz victims in an unsuccessful bid to find race-specific, disease-fighting proteins (Science, 2 June 2000, p. 1576). In addition to Verschuer's institute, Markl said, abuses were the most blatant at the Institute for Brain Research in Berlin-Buch and the German Research Institute for Psychiatry in Munich, both of which exploited Nazi pogroms to obtain the brains of mentally ill or brain-damaged people for analysis. Molecular geneticist Benno Müller-Hill, who first detailed the Verschuer-Mengele link in his 1984 book Murderous Science, told Science that he thought Markl's apology “had exactly the right tone. It's a shame that speech wasn't given 20 years ago.” Markl concedes that the apology and the ongoing KWG investigation have come late. “For way too long, many questions were not asked. For way too long, many connections remained uninvestigated or only dealt with by outsiders. And for way too long, many documents lay in the archives, inaccessible either because they remained classified, or because people were all too glad to disregard them,” he said. But Markl defended the apology's timing, explaining that it followed the historical commission's interim report last fall that assembled the known evidence of KWG biomedical abuses. He also pointed out that Max Planck had previously acknowledged nefarious research at the three institutes. “It's good to finally get this into the open,” says Auschwitz survivor Vera Kriegel. She and her twin sister Olga were victims of experiments in which Mengele injected an unknown fluid into their spines. “The experiments affected our bodies and our souls,” complains Kriegel, who wants to know more about what Mengele did to her. Benoit Massin—a French historian on the Max Planck team who is trying to document more links between Mengele and KWG researchers —said he was eager for any details that she could give because “we know very little so far about the Mengele experiments involving spinal injections.” Massin recently uncovered new evidence that Mengele's experiments on children's eyes at Auschwitz had been done on behalf of a scientist at Verschuer's institute. Such links are difficult to prove, because few records survived the war, and Mengele himself escaped to South America, where he died in secrecy in 1979. The commission is continuing to sift through whatever evidence it can turn up. Carola Sachse, a historian who heads the commission's six-researcher team, said the group is trying, for example, to gain access to more Soviet records related to the KWG and to concentration camps but has encountered obstacles. Although many documents of Nazi crimes are irretrievably lost, some survivors say that as full an accounting as possible of the misdeeds will ease their minds and, perhaps, help prevent similar atrocities in the future. “Human beings made Auschwitz,” says Laks. “It was here, amongst us. And there is no guarantee that it will not return— anywhere.” 4. DNA SEQUENCING # Genome Teams Adjust to Shotgun Marriage 1. Eliot Marshall CHEVY CHASE, MARYLAND—Half a dozen reporters showed up at a meeting near Washington, D.C., on 6 June expecting to see a shootout between rival experts on genome assembly. But no one fired a shot. Instead, the scientists quietly discussed flaws in both versions of the human genome sequence—one assembled by a publicly funded consortium of 16 labs and the other by the biotech company Celera Genomics of Rockville, Maryland. The participants batted around new ideas for deciphering very large genomes, possibly by combining the best methods from both teams. The goal, said Chad Nusbaum, assistant director of sequencing at the Whitehead Institute Center for Genome Research at the Massachusetts Institute of Technology, should be to find the cheapest strategy that can also “pass the platypus test”—that is, make sense of a complex genome that's never been explored. One reason the discussions, which were held at the Howard Hughes Medical Institute in Chevy Chase, Maryland, were calm is that the chief combatants were absent. Eric Lander, a leader of the publicly funded team and director of the Whitehead genome sequencing center, stayed away, as did Celera president J. Craig Venter. Gerald Rubin, Hughes's chief scientific officer, who hosted the meeting, said it would have been “a distraction to the press” to have them present. For months, Lander and Venter have been trading barbs over the quality of the other team's methods of assembling the human genome sequence from raw DNA data. Lander doesn't think Celera's whole-genome shotgun assembly—an approach that relies heavily on computer power—can work without the supporting maps and other data from the public consortium. Venter, who claims his team recently reassembled the human genome sequence without using any public data, says that Celera's method works even better on its own. The public databases are riddled with vector-contaminated DNA sequence and other problems, Venter asserts. Celera bioinformaticist Granger Sutton presented data that bolster the company's claims that its assembly method not only worked on the human genome but is improving and may be able to resolve platypus-like genomes. Sutton reported a dramatic improvement in the consolidation of human DNA sequence into “scaffolds”—Celera's term for DNA sequence that has been placed in order in large pieces but still has gaps. Celera's first draft of the genome sequence had 119,000 scaffolds; now, Sutton said, without using any public data, the company has assembled the genome sequence into just 6500 scaffolds. The “gap” area also dropped roughly in half, to 134 million base pairs. He made equally impressive claims for Celera's assembly of mouse DNA. Other speakers didn't challenge the numbers but noted that the data are not freely available and cannot be validated without a subscription. Several others, including James Mullikin of the Sanger Centre in Hinxton, U.K., argued for a hybrid approach for deciphering genomes. Mullikin outlined a plan that would begin by quickly churning out whole-genome shotgun data, partly to give information to biologists. The early data might also help determine the prevalence of problematic repeat sequences in a species, Mullikin said: The more repeats, the more tedious clone-by-clone analysis may be required to assemble the genome sequence and identify genes. In parallel, Mullikin said, researchers should collect physical markers and build maps to help locate data along the chromosomes. “You should always build a map,” because the relative cost is small, he said. Some researchers were interested in trying to assemble genome sequences on the cheap, using a hybrid method and just a threefold depth of sequencing data. But others warned that this might not produce big enough scaffolds. Even Gene Myers, Celera's informatics chief, said, “If some projects go to 3x and stop, I'm a little worried that you won't be able to get order and orientation.” Instead, he said, “you should just go to 5x and take the extra hit” in costs. The participants seemed to agree on at least two points. First, more research is needed on “repeats,” blocks of almost identical DNA sequence that appear to be 10 times more common in the human genome than in those of the fruit fly or nematode. Existing assembly programs can't handle them well and often delete them. But, argued molecular geneticist Evan Eichler of Case Western Reserve University in Cleveland, Ohio, these repeats may contain unique elements of the human genome and should not be slighted. Second, everyone wants better software for assembling genome sequences. Already, publicly funded teams at a half-dozen labs are testing new programs with names like JAZZ, Arachne, and Euler. U.S. Human Genome Project leader Francis Collins predicts that by “late summer” everyone will have access to such souped-up computer tools. If so, by September, genome assembly could be a whole new ball game. 5. NEURODEGENERATIVE DISEASE # Using the Fruit Fly to Model Tau Malfunction 1. Dan Ferber In the slow-motion train wreck that is Alzheimer's disease, different types of debris pile up inside and outside dying brain neurons. But despite decades of research, researchers still don't know exactly what kills the cells. Most attention has focused on defects in a protein called β amyloid, which clumps up into plaques outside neurons and seems to throw the switch that first steers the cells off course. But inside neurons, another protein called tau may act as an accomplice. In Alzheimer's brains, tau forms part of abnormal intracellular structures called tangles, although it's not clear whether tangle formation is the cause or result of the neuronal degeneration. It is clear, however, that other human dementias can be caused by tau defects even in the absence of plaques, indicating that here at least the tau defect is primary. Now a new fruit fly model may help reveal just how defective tau sends healthy brain cells veering off track. In work published online by Science on 14 June (http://www.sciencexpress.org/), Mel Feany of Harvard Medical School in Boston and her colleagues show that fruit flies producing human tau undergo brain neuron degeneration, although, in a surprising finding, the dying fly neurons do not contain tangles. It's “very elegant, nicely done work,” says Zaven Khachaturian, senior scientific adviser to the Alzheimer's Association. “It could change the focus of research for developing treatments [for dementias].” No mutations in the tau gene have been linked to Alzheimer's, but in 1998, researchers discovered that tau mutations do cause a group of dementias with the unwieldy name hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To find out how tau damages neurons, Feany's team introduced either the normal human tau gene or a mutant version that causes FTDP-17 into fruit flies. Flies with either gene died younger than controls, but the effect was most pronounced in those with the mutant gene, the researchers report. The results suggest that the normal and mutant tau had each taken its toll. The researchers then watched what happened to the nervous systems of both types of transgenic flies as they aged. Brain cells in day-old flies were fine, but neurons in doddering 30-day-old flies had disintegrating cell nuclei and other organelles. “We saw them falling apart,” Feany says. The human tau proteins especially damaged neurons that communicate using the neurotransmitter acetylcholine—a group of cells that are also hit heavily in Alzheimer's disease. Together, the results suggest that the fruit flies with human tau mimic the tau- induced damage seen in Alzheimer's disease, FTDP-17, and other dementias in which tau goes awry, Feany says. But the absence of tangles in the transgenic flies was puzzling. Because the brains of FTDP-17 patients contain copious tangles, some researchers speculate that the cells are killed by tangles that gum up their internal works, although others suggest that soluble forms of defective tau proteins can kill without forming tangles. The flies with the mutant tau protein support the latter view, Feany says: Even though no tangles formed in their neurons, the cells died anyway. Some experts caution, however, that the lack of tangles might mean that flies aren't a good model of human dementias. “The worry is that cells are dying by a different mechanism than neurons do when they make tangles in Alzheimer's disease,” says neuroscientist John Hardy of the Mayo Clinic in Jacksonville, Florida. Others don't see a problem. “I'm not bothered one bit that [they] didn't find tangles,” says neuropathologist John Trojanowski of the University of Pennsylvania School of Medicine in Philadelphia, one of the researchers who linked tau mutations to FTDP-17. Because the protein normally stabilizes microtubules, which help ferry life-sustaining molecules to nerve endings, he suggests that defective but soluble tau might kill neurons by crippling their transport system. Others say defective tau could alter signaling cascades leading to oxidative damage or apoptosis. If the neural decay seen in the altered fruit flies does turn out to resemble that in human dementias, the fly model should help researchers work out just how tau causes neuronal death. Because flies carrying the mutant human tau gene have visibly altered eyes, it will now be easy to create and screen thousands of mutant flies to help uncover those genes whose protein products either boost or block tau's effects. That, in turn, could offer novel targets for drugs that keep neurons from derailing, which could lead to new treatments for human dementias. 6. ESPIONAGE CASE # Japan Says Cell Lines Weren't Used at RIKEN 1. Dennis Normile TOKYO—strange case of the Japanese researcher accused of taking biological materials he developed at the Cleveland Clinic Foundation in Ohio to his new job at Japan's Institute of Physical and Chemical Research (RIKEN) took another odd twist last week. RIKEN officials reported that investigators can find no evidence that the materials were ever used in experiments at its Brain Science Institute, although some of the materials may have been temporarily stored in neuroscientist Takashi Okamoto's RIKEN lab. RIKEN launched the investigation after U.S. officials claimed that Okamoto had stolen cell lines and DNA samples from the Cleveland Clinic (Science, 18 May, p. 1274). In early May, a U.S. grand jury indicted Okamoto—who worked on Alzheimer's disease at the Cleveland Clinic from 1997 to 1999—and Hiroaki Serizawa, a researcher at the University of Kansas Medical Center in Kansas City, on charges of conspiring to steal trade secrets for the benefit of a foreign government. RIKEN is technically a nonprofit corporation but is funded by Japan's government. The charges surprised many researchers, who say that scientists often take materials they have developed with them to their new jobs. A six-member team of scientists drawn from RIKEN and outside institutes traced the sources of all 194 samples of DNA, cell lines, and reagents that Okamoto's team had used in his RIKEN lab. The team also asked other RIKEN research groups if they had acquired any material from Okamoto. “We have never used any material [from the Cleveland Clinic] in experiments at RIKEN,” concluded Akira Kira, a RIKEN vice president who led the investigation. But the investigation turned up a new wrinkle. While he was still in Ohio, Okamoto allegedly shipped some biological material from the Cleveland Clinic to a researcher working at another institute in Japan. That researcher later joined Okamoto's team at RIKEN and brought the material with him. But the researcher told RIKEN investigators that the samples later disappeared from a laboratory refrigerator. The investigators believe that Okamoto e-mailed another RIKEN scientist asking about the possibility of sending materials from Ohio to RIKEN for storage. Okamoto has been on leave and incommunicado since the indictment. Serizawa has asked for a delay in his trial, scheduled to begin next month. 7. ASTRONOMY # Infrared Gleam Stamps Brown Dwarfs as Stars 1. Mark Sincell* 1. Mark Sincell is a science writer in Houston. PASADENA, CALIFORNIA—Once upon a time, a star was a star and a planet was a planet and never the twain would meet. But times have changed. Try making a statement like that today, and even polite astronomers will roll their eyes at your naivete and sigh nostalgically. Their concern is with a misfit class of gaseous balls recently discovered orbiting nearby stars or floating freely through space. It's hard to know how they formed: They seem too heavy to have developed from the slow agglomeration of material, like jumbo-sized planets such as Jupiter. Yet they are too light to ignite the nuclear fusion that powers stars. Confused astronomers named the objects failed stars, superplanets, or the noncommittal brown dwarfs. But now, the surprisingly bright infrared light from 63 brown dwarfs in the nearby Trapezium star cluster is helping make the case that the free-floating brown dwarfs are failed stars and not stray planets, astronomers told the American Astronomical Society here on 7 June.* Traditionally, stars and planets are easy to distinguish. Stars weigh more than seven times as much as Jupiter—the threshold mass for nuclear fusion—and form out of a collapsing cloud of cold molecular gas. Any leftover gas then swirls into a protoplanetary disk around the newborn star. Planets, on the other hand, weigh less than seven Jupiter masses and, according to the most popular theory, form by scavenging rock and gas from the disk. Several discoveries in the past 5 years have called this simple picture into question. Moving up from the planetary end of the mass range, several teams have identified 67 planets orbiting nearby stars. These exoplanets weigh up to 17 times the mass of Jupiter. And dropping down from stellar masses, astronomers have discovered almost 200 objects floating freely like stars in the Milky Way that weigh as little as 10 Jupiter masses (Science, 6 October 2000, p. 26). So which are the stars and which are the planets? At least part of the question has now been answered: The free-floating brown dwarfs form like stars. Although brown dwarfs have no nuclear fire in their belly, they are hot enough to emit infrared radiation, just like a human body. And if they formed from contracted clouds like a star, a warm, dusty disk should orbit the dwarf and radiate additional infrared light. It was precisely this extra light that astrophysicist Charles Lada of the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts, was looking for when his team surveyed 100 brown dwarfs in the nearby Trapezium cluster, a stellar nursery in the constellation Orion. The search, conducted in March 2000 with the 3.5-meter New Technology Telescope in Chile, was a success: 63 dwarfs showed evidence of disks. An oversized free-floating planet formed by agglomeration would not have a disk, Lada explains, so these dwarfs must have formed the way stars do. The disks could even spawn small inhospitable planets, Lada says. “This is compelling evidence,” says Geoff Marcy, an astronomer at the University of California, Berkeley. Although he is confident that the disks are real, Marcy points out that astronomers' models of brown dwarfs are still in their infancy, so it's hard to predict exactly how much infrared radiation dwarfs should produce. Better models should soon reduce that uncertainty, he says. • *198th meeting, 3 to 7 June. 8. ASTROPHYSICS # Quasars or Blazars? It's All in the Angle 1. Govert Schilling* 1. Govert Schilling is an astronomy writer in Utrecht, the Netherlands. If you had never seen a peacock and then suddenly stumbled across a pair of them—one strutting past in profile, the other facing you in full display—you might think you were looking at two different animals. Astronomers suspect they've been making a similar mistake. New observations strongly suggest that a wide variety of extragalactic objects are actually the same cosmic animal seen from different angles. The objects in question are blazars, quasars, and radio galaxies. Astronomers think that all are variations on a theme: distant galaxies, each revolving around a nucleus in which a supermassive black hole slowly consumes a hot accretion disk of swirling gas and spews some of it out in powerful jets. Blazars are extremely luminous, highly variable sources of radiation. Quasars are less energetic and steadier, and the ones that emit radio waves come in two varieties. In one case, most of the radio waves come from the quasar's bright core; in the other, most are emitted by two lobes on opposite sides of the galaxy. Finally, the objects known as radio galaxies sport two radio lobes but show no core activity at all. Over the past 15 years or so, astronomers have suggested different models to describe this bewildering variety of active galaxies. The most radical proposal came from Peter Barthel of the University of Groningen in the Netherlands, who suggested that every radio galaxy is really a quasar seen edge on, its bright core hidden by a torus of dust. Klaus Meisenheimer of the Max Planck Institute for Astronomy in Heidelberg, Germany, disliked that idea. “I couldn't believe that a quasar could be hidden from view so completely,” he says. Using the European Infrared Space Observatory (ISO) satellite, Meisenheimer set out to disprove it. If a dust torus were absorbing radiation from the central quasar, he reasoned, it would reemit the energy as infrared light. So if Barthel were right, radio galaxies and quasars should look the same to ISO. In a paper accepted for publication in Astronomy & Astrophysics, Meisenheimer and his colleagues report that that is exactly what they found. “I was really astonished,” he says. “I'm [now] convinced that the unification scheme is in principle correct.” Meanwhile, Feng Ma and Beverley Wills of the University of Texas, Austin, were working on what Ma calls “the other end of the unification scheme”: the idea that a blazar is just a radio-emitting quasar with one of its jets pointing straight at Earth. On page 2050, Ma and Wills describe how they used a sensitive spectrograph at the 2.7-meter Harlan J. Smith Telescope at McDonald Observatory in Texas to study light emitted by ionized carbon and hydrogen atoms in gas clouds close to the cores of 62 quasars. The emissions are powered by radiation from the quasars. Comparing their measurements with readings taken over the past 20 years, Ma and Wills found that in many cases the relative strength of the carbon and hydrogen emissions shows large variations, indicating that the central source varies as much as a blazar does. Their conclusion: There's really no difference between radio-emitting quasars and blazars. Blazars look more volatile and variable only because astronomers are viewing their jets head on. “There's a blazar hidden in every radio-loud quasar,” says Ma. Barthel says he is delighted with the new results, particularly those of Ma and Wills. The ISO data are less convincing, he says, because in many cases Meisenheimer's group could not detect any infrared radiation from the sources they studied. Working with his graduate student Ilse van Bemmel, Barthel has made more-sensitive observations indicating that quasars seem to be on average a little bit brighter in the infrared than radio galaxies. “But this can easily be explained by assuming certain properties for the obscuring dust torus,” he says. Meisenheimer acknowledges that his results are tentative. “But this is so different from what I had expected that I'm convinced,” he says. And with new evidence for the unification scheme arriving almost weekly, there seems little doubt that all radio-emitting active galaxies are equal— although some of the cosmic peacocks hide their dazzling tails. 9. ANIMAL MODELS # EC Boosts Funds for Mutant Mice 1. Michael Balter The European Commission (EC) has awarded a$3.8 million grant to a “virtual archive” of mutant mice used in research on cancer and a variety of other human diseases. Announced at an 11 June press conference in Rome, the award will go to the European Mouse Mutant Archive (EMMA), a consortium of European institutes that create and store mutant mice and their frozen embryos. The money comes from a special $21 million fund created last year by EC research commissioner Philippe Busquin to support bioinformatics and animal model research. Just over half of these earmarked funds were awarded last month to the European Bioinformatics Institute near Cambridge, U.K. (Science, 18 May, p. 1275). “The idea is to take programs that are working well and ensure that they are operating at the maximum possible level,” Busquin told Science. The new funds will help EMMA—which is headquartered at Monterotondo, outside Rome, and coordinates the activities of institutes from seven European countries—to keep up with the ever-increasing demands for mutant mice, whose altered genomes can serve as models for human diseases (Science, 14 April 2000, p. 248). Over the past decade, some 2500 mutant mouse lines have been created or identified worldwide, including nearly 1000 in Germany and the U.K. alone. And although only a small fraction of the mutants are stored as living animals, the cost of maintaining their frozen embryos—about 500 of which need to be kept on hand for each mutant line—runs at least$4000 annually for each strain.

Yet the money is well spent, comments biochemist Adelbert Roscher of the University of Munich, who works with a group of German labs that recently created several dozen new mutants. “Mouse models are necessary initial steps for transferring the new knowledge coming out of genome programs into clinical use,” he says. “The work of EMMA will speed up this process.”

10. CONDENSED-MATTER PHYSICS

# Switch-Hitter Materials Tantalize Theorists

1. David Voss

At one point in the movie Blade Runner, the evil techno-mogul Eldon Tyrell presses a button that suddenly darkens his office windows. A science-fiction moment? In fact, physicists have known for years that by lacing certain simple compounds with hydrogen they can perform the opposite trick, turning shiny metal conductors into clear insulators.

Now a team of physicists and materials scientists has closed the loop. In the 4 June issue of Physical Review Letters, they report that they take the compounds—hydrides of the rare earth elements yttrium and lanthanum—and change them back into shiny conductors by flashing them with ultraviolet (UV) light. The UV-triggered switchable mirrors are intriguing both in their basic physics and for possible applications to optoelectronics, says co-author Tom Rosenbaum of the University of Chicago. “These are amazing materials.”

The strange properties of hydrides first came to light 5 years ago, when researchers led by Ronald Griessen of Free University in Amsterdam were searching for new superconductors. His team looked at metal hydrides, materials that act like sponges capable of absorbing huge amounts of hydrogen. They didn't find superconductivity in samples of yttrium hydride, but they did discover that high-pressure hydrogen turned it from a shiny metallic YH2 film to a transparent insulator made of YH3.

In the latest work, the Amsterdam group has joined forces with physicists at Chicago and learned to trigger the reverse effect with light. They took a thin yttrium film sealed with palladium and placed it in a hydrogen pressure cell cooled to a temperature of 0.35 kelvin. By dosing it with hydrogen, they made the insulating compound YH3 and monitored its electrical conductivity with tiny wires attached to the sample. When they flashed the film with a UV strobe light, the conductivity shot up—a sure sign that the insulating material had changed into a metallic form. “We can basically ‘dope' this material with UV light,” says Rosenbaum.

The results may help illuminate one of the toughest questions in condensed-matter physics: how materials go from metal to insulator and back again. Such transformations, called Mott transitions after the British physicist Neville Mott, who first tried to nail down the theory, have vexed researchers for years. Many of them are tied to basic changes in a material's crystal structure—changes that take place abruptly enough to pull the rug out from under researchers probing the mechanisms of how the electrons interact and influence the change from metal to insulator. As a result, says theorist Steve Girvin of Indiana University, Bloomington, “our theoretical understanding of the metal-insulator transition remains very poor and confused despite a lot of work on this.”

But remarkably, the metal hydrides undergo a smooth, continuous transition rather than an abrupt one. That makes them a valuable test-bed for studying these peculiar quantum phase transitions. In one series of experiments, the researchers were able to extract so-called critical exponents—numbers that characterize how the conductivity changes with temperature and electron density in the hydrides. They discovered that the hydrides have unusually large exponents unlike those of any other metal-insulator transition. That may indicate that hydride transitions belong in a theoretical category, or universality class, all their own, Rosenbaum says. “Either we have a new universality class, or we really don't know how to do the theory yet. Either way, it's an interesting package.”

Other physicists say it's premature to speculate about what the data from the hydrides mean; quantum phase transitions are still too difficult to understand, they caution. “It's a wonderful new system,” says Subir Sachdev of Yale University, “but the interpretation of the critical exponents is less persuasive.” Much more work needs to be done to make this part conclusive, he says. “For these transitions with disorder and strong electron interactions, nobody has a clue what is going on.”

In addition to opening up some deep puzzles for condensed-matter physicists, the metal hydrides might provide an interesting material for practical applications. High-tech window shades aside, companies such as Phillips have already started looking at the hydrides for computer displays. The latest work, in which UV light triggers the switching of metal properties, hints at the possibility of light controlling light—a trick that researchers in fields such as optical computing and fiber-optical network switching are eager to master. Taming the rare earth hydrides and understanding their fundamental physics should keep researchers busy for some time to come.

11. THE FUTURE OF NIH

# Who Will Be Custodian of the Crown Jewels?

1. Eliot Marshall

As it nears the final year of an unprecedented spending spree, the world's largest biomedical research organization has no permanent leader in sight

Before he resigned in December 1999 as director of the National Institutes of Health (NIH), Harold Varmus tried to pave the way for a successor. He asked his superiors to send the White House a list of names headed by Gerald Fischbach—a former Harvard University neurologist he had helped recruit in 1998 to lead the National Institute of Neurological Disorders and Stroke. Varmus reasoned that an internationally known scientist and an outsider with a vision of where NIH should be headed—a replica of himself—would be the best person to build upon his successful 6-year stint, which included a planned doubling of the NIH budget in 5 years.

But Varmus's cloning experiment ran afoul of politics. One powerful legislator said he wanted to continue working with Ruth Kirschstein, Varmus's deputy and a consummate insider (see profile). The Clinton White House—worried that any nominee might trigger a battle in Congress over the sensitive issue of embryonic stem cell research—did not act. As a result, this month marks Kirschstein's 18th as acting director of the $20 billion biomedical colossus, while Fischbach ended his short career as a civil servant last year and returned to academe as medical dean and health affairs chief at Columbia University. With the rumor mill churning out the same stale names, researchers are beginning to ask how much longer the world's biggest and most prestigious biomedical research agency can thrive without a permanent chief. Their concerns coincide with NIH's need to chart a soft landing after the budget doubling ends in 2003 (see p. 1992). The transition from wildly inflationary to just moderate growth could reawaken some of the old tensions that wracked the community in the early 1990s, when competition for funds was intense. How well NIH is prepared for that new era has become a burning question for the biomedical community. “NIH needs a leader who has a clear mandate from the White House to do the job,” says oncogene researcher Michael Bishop, chancellor of the University of California, San Francisco, who shared a Nobel Prize with Varmus in 1989. The NIH chief is not just a spokesperson for biomedicine but a champion for all of science, says Maxine Singer, president of the Carnegie Institution of Washington in Washington, D.C., who finds it “discouraging” that no appointment has been made. Apart from money, one of the touchiest subjects for the next NIH director will be the government's policy on human stem cell research. The Clinton Administration had planned to permit funding of some research on human embryonic tissue. But the Bush Administration, facing conservative opposition, is backing away. Future policy has been debated intensely at the White House in the past few weeks—all the way up to the president's office, according to disease advocacy groups involved in the talks. There was no decision at press time, but community leaders say that the uncertainty about stem cell policy could make it more difficult to recruit “the very best” scientist as NIH director. ## Running on momentum The NIH powered through the 1990s with a tremendous burst of energy. It was fueled by new money and a novel kind of leadership. Varmus brought an outsider's perspective to NIH, with the goal of making it seem less like a government agency and more like a hot-shot academic center. A Nobelist in molecular biology, Varmus imported his lab from California and continued to oversee postdocs' research during his entire directorship. In public meetings, he affected the informal dress of an academic. And with the support of his boss, Health and Human Services (HHS) Secretary Donna Shalala, he took steps to make NIH more welcoming to other members of the academic elite. A series of administrative changes gave the NIH director more authority to recruit top staff and offer higher salaries. Varmus also followed through on recommendations from a review panel that proposed changes to improve science on campus. Young scientists got a clear set of guidelines on how they could advance through the system to achieve “tenure” at NIH. For the first time, Varmus organized formal 5-year performance reviews of the institute directors. And he lobbied the institutes to kick in money from their own budgets for joint research projects on targeted initiatives, like sequencing the mouse genome, that no single institute could afford on its own. The value of such trans-NIH initiatives is open to question, however. National Cancer Institute (NCI) director Richard Klausner, for example, thinks joint projects work only when they arise from the “scientific grassroots”—in particular from the institute directors. The first challenge for the next NIH director, some say, will be to win the cooperation of those directors and to fill vacancies with outstanding scientists. During Varmus's 6-year tenure, 16 new institute directors were appointed. Three have since left, and one major position—the directorship vacated by Fischbach—remains unfilled at the time of this writing. Recent years have been “good times for recruiting,” Kirschstein notes: “Once you recruit one or two good people, others want to join.” Although she believes that NIH has sustained the momentum built up under Varmus, one of his recruits says, “we're all waiting to see who's the next boss.” Varmus also wanted to boost the authority of the NIH director's office and cap the number of independent fiefdoms. During his tenure at NIH and after, Varmus decried the “proliferation” of NIH administrative centers, arguing that “having more institutes also means less flexibility, less managerial capacity, less coordination, and more administrative burden” (Science, 9 March, p. 1903). He proposed merging the current 27 centers and institutes at NIH into half a dozen and argued unsuccessfully against the creation that year of the National Institute of Biomedical Imaging and Bioengineering. More proposed institutes are “waiting in the wings,” he warned, and should be resisted. But the idea of streamlining NIH's structure is “not popular,” says David Nathan, a former member of the NIH director's advisory committee and former president of the Dana-Farber Cancer Institute in Boston. Kirschstein isn't sure that proliferation is a problem, either, although she didn't respond directly to a question about it. “There was a time when people thought that if there were new institutes, every institute would gain,” she says. “For a while that was true, but it remains to be seen if it is true now.” The NIH director's most important job, says one insider, is to express a vision “that can blow you away.” Nathan believes that the NIH director “ought to be a good teacher, the kind of person who can really explain things.” Shalala, now president of the University of Miami, emphasizes the need to instill a sense of trust: “You can't miss a beat. … NIH has to continue to demonstrate that these extraordinary increases are going to be well spent.” But all agree that it's difficult for anyone without the president's backing to design a grand strategy for NIH. ## Holding the fort For now, the responsibility of leadership falls to Kirschstein, a dedicated civil servant who has been in NIH headquarters, “Building 1,” for the past 8 years. She and her husband, Alan Rabson, deputy director of the NCI, have worked—and lived—on the NIH campus since the mid-1950s. Their extraordinary tenure, combined with those of other long-serving institute directors and top administrators, provides an institutional memory that keeps the NIH on course. In a recent interview, Kirschstein said she's very comfortable in the top job because “I have been here a long time … and I know NIH.” It would be “tempting,” she added, “to be passive when you're in an acting capacity, but I have no intention of doing that; there's too much exciting science going on.” Still, Kirschstein seems likely to take her cues about scientific initiatives from other directors. And her own goals and methods of advancing them are more consensus-oriented than her predecessor's: “I would never dream of saying to an institute director that this is an initiative I want to do.” Instead, she says, “we would sit down and talk about plans together.” Asked to cite an example of a new project that interests her, Kirschstein mentioned a “biomedical infrastructure network” called the Institutional Development Award (IDeA) program. A darling of Congress, which last year more than doubled its funding to$100 million, IDeA now funds special offices in 23 states and Puerto Rico to enable their researchers to compete more effectively in peer review. Its aim is to distribute NIH's largesse over a broader geographical area. The program, modeled after one at the National Science Foundation that began 20 years ago, languished during the Varmus era—and got a chilly reception last week when Kirschstein described it to the NIH director's advisory committee. But she likes it.

Kirschstein also stresses the importance of investigator-initiated grants, NIH's bread and butter. “The first commitment we all have is to the individual research grant,” she says. An old assumption that one-third of applications deserve funding may understate the quality of the ideas being submitted, she adds, noting with approval the testimony of some NIH institute directors that the rate could rise to 40% or 45% without sacrificing quality. But more funding must also go into “shared resources,” she notes, to improve access to data collections and expensive instruments like synchrotrons and imaging machines.

One area where Kirschstein seems to have been far ahead of the curve is in her concern about underrepresented groups in biomedicine: “I have been an advocate [for women and minorities] since the first day I came to NIH” in the 1950s. In 1974 she became the first woman appointed to run an institute—the National Institute of General Medical Sciences, the focus for basic science. The NIH's current lineup of three women and two African-American directors (out of 27) “is not enough,” she says. Most recently, she supported the creation last year of the National Center on Minority Health and Health Disparities, bucking Varmus's no-more-institutes principle. Kirschstein is widely praised for her efforts on behalf of the disadvantaged and for preserving NIH programs in that area despite legal attacks on affirmative action.

But stability and collegiality are not necessarily enough to get NIH through uncharted waters. Although it would be an exaggeration to say NIH is on autopilot, it's in “a caretaker mode,” says Gerald Rubin, the chief scientific officer of the Howard Hughes Medical Institute in Chevy Chase, Maryland. “We're pointed in the right direction, … but the landscape is going to change, and you have to be concerned about whether we're going to run ashore.”

The Bush White House has avoided any comment on potential candidates for permanent NIH director, and Bishop says the rumor mill “has never been quieter than it has been in the last month.” Earlier in the year, it was filled with the names of several inside candidates—including Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), Klausner, and Steven Hyman, director of the National Institute of Mental Health. There were also reports that prominent Texans might be in line for the job, among them cancer researcher John Mendelsohn, president of the University of Texas M. D. Anderson Cancer Center in Houston, and Nobelist Michael Brown, a molecular geneticist at the University of Texas Southwestern Medical Center in Dallas.

But Mendelsohn and Brown have said they have not been formally interviewed by the Administration—and both say they're inclined to stay in their current jobs. Klausner was one of several interviewed by the White House but is rumored to be off the list. At this writing, Fauci remains the most visible candidate. But he also wants to remain in charge of his current portfolio at NIAID, an unlikely pairing. Current HHS Secretary Tommy Thompson hasn't said anything on the subject other than to grumble that the nomination process is so slow it's “ridiculous.”

It took the Clinton Administration almost 9 months to get Varmus vetted and confirmed, and it may take at least that long to get the next permanent NIH chief in place even after a nominee is in sight. In the meantime, biomedical researchers are praying that NIH—steaming forward toward a budget that will have doubled within 5 years—doesn't run into any really foul weather.

12. THE PEOPLE

# Ruth Kirschstein and Alan Rabson

1. Eliot Marshall

Every institution has a hidden wiring plan. At NIH, the circuits all seem to connect to Ruth Kirschstein. For more than 4 decades, she and her husband Alan Rabson, both M.D.s and civil servants, have worked and lived on NIH's tree-shaded campus in Bethesda, Maryland. That's a lifetime of service as colleague, friend, and supervisor of the government's top biomedical scientists.

Kirschstein, 74, is NIH's acting director. She took on the job in January 2000, succeeding Harold Varmus, under whom she served for 6 years as deputy director. Rabson is deputy director of the oldest and largest part of NIH, the National Cancer Institute (NCI). Unofficially, Rabson also has been a troubleshooter for institute director Richard Klausner and counselor to scores of worried patients, including senators and celebrities. The secret of their long-lived success. Instead of making waves, Kirschstein and Rabson make friends and allies.

“I had always wanted to come to this place,” says Rabson about the campus he first visited in 1952 during a sightseeing trip to the nation's capital. Three years later the couple moved to Bethesda from New Orleans, where Kirschstein had been teaching at Tulane University School of Medicine and Rabson had been a Public Health Service pathologist. Rabson went to a pathology lab at NCI, and Kirschstein became the first clinical pathologist at NIH's clinical center. A few years later they rented a house on the NIH campus—one of a handful then available to officers in the Public Health Service—in which they still live. Their son, molecular geneticist Arnold Rabson, grew up on the NIH campus, played in its labs, and is now an associate professor of molecular genetics and microbiology at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School.

“I love it,” says Kirschstein about NIH. “This has been my whole life; I have never worked anywhere else.” After completing her residency at the clinical center, Kirschstein moved into NIH's division of biologics, which later became part of the Food and Drug Administration. She helped identify a disease-causing batch of oral polio vaccine in trials and developed new tests which identified the Sabin vaccine as the best for public use.

In 1974, Kirschstein began climbing the NIH administrative ladder, becoming director of the National Institute of General Medical Sciences (NIGMS). The first woman to head any institute, she supported rapidly moving developments in cellular and molecular biology, says Maxine Singer, president of the Carnegie Institution of Washington in Washington, D.C. In 1990, while director of NIGMS, she also served as the first director of the women's health program.

As NIH's top official, Kirschstein stresses the importance of balance and stability. That contrasts with her predecessor, who encouraged turnover because “change is healthy.” Kirschstein concedes that there's a risk of complacency “if people go a very long time.” But she adds quickly, “I haven't seen that.”

13. THE BIG THREE

# NCI's Richard Klausner

1. Eliot Marshall

Lenfant is a champion of clinical research and somewhat uneasy about the 1990s gold rush in molecular medicine. Sometimes, he says, people at NIH act as though “if you don't talk about molecules, you don't do anything.” But he believes that his philosophy fits squarely into NIH's mission: “My goal is to see that basic research is applied … to the practice of medicine.” He worries that “much of the research we do becomes an academic trophy. I don't like that. I am very interested in public health.” He boasts that “one of my best investments” is a $15 million program to train ambulance crews and speed up treatment of heart attack victims. Although he holds strong beliefs, Lenfant may owe his long run at the helm to his receptivity to new ideas. “I think he actually has gone with the flow,” says Thomas Caskey, a molecular geneticist at Baylor College of Medicine in Houston and former Merck Co. executive, who says that there was a period in the early 1990s when NHLBI lagged in its support of molecular research on heart disease. When people pointed this out, the institute responded. “You might say he didn't move soon enough,” Caskey notes, but the fact that Lenfant did move shows that he “has been a good administrator.” The cardiovascular research community “thinks highly of him” and his skills as a manager, adds an NIH insider. Lenfant seems to enjoy his seniority, and he's good at defending his status. “He's as territorial as hell,” the staffer says. According to several sources, the two previous NIH directors—Bernadine Healy and Harold Varmus—took a run at Lenfant but backed off after realizing that he isn't easy to budge. 16. THE NUMBERS # NIH Prays for a Soft Landing After Its Doubling Ride Ends 1. David Malakoff Why won't a$2.8 billion increase buy any more individual grants next year? The answer is keeping researchers and NIH officials up at night

For years the U.S. biomedical community has charted the well-being of its most important benefactor, the National Institutes of Health (NIH), with a single number—how many new and competing research grants the agency awards each year. The number is a proxy for the system's support of individual investigators, and a steady rise was long seen as the best way to ensure the future of academic biomedicine.

No longer. Next year, despite an expected $2.8 billion increase designed to keep NIH on track to double its budget to$27 billion in 2003, the number of competing awards is projected to remain exactly the same as this year (see graph). Ironically, the stagnation in new grants is occurring largely because NIH has already committed much of its new money to paying for more than 25,000 existing grants. The growing size of these grants is also adding to the strain (see graph), as is a rise in spending on “big biology,” ranging from expensive equipment and new buildings to clinical trials and research collaborations that involve dozens of institutions and hundreds of scientists. Indeed, virtually every NIH interest group has shared in the doubling bonanza—from patient groups advocating more research on “their” disease to scientists urging greater spending on the agency's intramural program.

But the good times won't last forever. That reality has fueled speculation that the postdoubling years may include cuts in everything from the size and number of grants to clinical research to state-of-the-art lab equipment and databases. One ominous sign is preliminary Bush Administration budget plans that call for NIH to get annual budget increases of only 2% after 2003—a far cry from its recent 13% to 15% annual boosts. Another is the slumping economy, which is expected to trim surpluses by reducing government revenues. Then there's the massive tax cut recently approved by Congress, which will start to take its biggest bites just as NIH's budget growth slows.

“It's a very strange time,” says Dave Moore of the Association of American Medical Colleges in Washington, D.C. “We're in the midst of unparalleled success, but we're already worrying about what happens when it ends.” Even if Congress provides larger than minimal increases, “the time is coming when we must decide which [projects] will not move forward,” says cancer researcher Phil Sharp of the Massachusetts Institute of Technology in Cambridge, Massachusetts, who leads a National Cancer Institute (NCI) advisory panel. Adds Moore: “The math is inescapable.”

Officially, acting NIH director Ruth Kirschstein says the agency is ready for slower growth. Last month she appointed a special committee that she promises will work “very hard over the summer” on a plan to ease the pain of withdrawal from NIH's doubling habit. Privately, however, NIH insiders say that the planners face limited options, in large part because of spending commitments and policy decisions made years ago. Nearly 50% of the agency's $2.4 billion budget increase this year, for instance, is already committed to previously awarded grants—which run nearly 4 years on average (see sidebar on p. 1993). Still, the directors of NIH's 27 institutes and centers don't appear flustered. “We saw this coming and prepared for it from the beginning,” says Anthony Fauci, head of the$2 billion National Institute of Allergy and Infectious Diseases (NIAID), the third-largest member of the NIH fleet. Some of the cost-containment strategies used by Fauci and other institute directors—from restraining the number of new grants to emphasizing one-shot spending on infrastructure—are certain to be featured moves in NIH's postdoubling dance.

But that doesn't mean they will be popular with rank-and-file scientists. Some NIH officials are bracing for the laborious task of explaining why, in the midst of apparent plenty, the agency is showing restraint in grantmaking. Exhibit No. 1 is holding the number of new grants steady at about 9150 in 2002 despite a proposed 14% budget increase. “We need to think about how we align the expectations of the grantees with what we think we can do,” says Richard Klausner, head of the NCI.

Former NIH director Harold Varmus contributed to those expectations by predicting a few years ago—optimistically, in retrospect—that the number of new grants would reach 12,800 in 2003. Indeed, lowering the expectations of researchers “may be the challenge facing a new director,” another senior NIH official predicts. One soothing thought: Under virtually any likely scenario, the postdoubling NIH will still be making more and larger grants than at any other time in its history.

## Spending spree

Boom-and-bust cycles aren't new for NIH. In the 1980s and early 1990s, the agency had to reduce grants and trim spending in response to slow-growing budgets, putting researchers on a financial roller coaster. But the current doubling sprint—the agency's budget historically has taken 7 to 9 years to double—has poured so much money into the system so quickly that it may have permanently altered the perceptions of researchers. It's certainly been a balm for such recurring sensitive issues as improving intramural research or tinkering with peer review. In 2002, for instance, NIH officials expect to fund a record 36,143 grants—up 34% from 1997, the year before doubling began, and up 51% since 1993. The average grantee also will be getting more money than ever, about $367,000 a year—a$25,000 jump over this year and 36% higher than in 1998.

At the same time, the agency has launched a vast array of initiatives and extended its reach into fields where it once had a limited presence. Several institutes have stepped up their support for clinical research in response to concerns that NIH wasn't doing enough to move basic research findings into medical practice. The agency now pours nearly $6 billion a year into clinical studies, including those at 80 major centers, which sponsor 9000 investigators and involve tens of thousands of patients. There are also new loan repayment programs to pay off the education debts of scientists who agree to get involved in clinical research. The arrival of big biology has meant spending hundreds of millions of dollars to buy specialized machines, build massive shared databases, and assemble research consortia—such as the one that is unraveling the human genome—that involve dozens of players. “The classic image of the lone scientist making great discoveries in a small laboratory is a faded image of the past,” Judith Vaitukaitis, director of NIH's National Center for Research Resources, recently explained to a House spending panel looking at NIH's growing support for infrastructure. By 2003, for instance, NIH will have spent tens of millions of dollars to double the number of synchrotron beamlines available to biologists studying the structure of everything from proteins to tissues. Another$20 million will have gone to developing a nationwide network of mouse-breeding facilities that provide specialized mutant mice to scientists.

Sustaining this cornucopia of grants, clinical trials, and infrastructure won't be easy. Informally, NIH officials say that preliminary studies project that some institutes would need annual budget increases of 7% to 12% after 2003 to sustain existing programs and keep pace with expected inflation. But with key lawmakers already signaling that they are “going to take care of NIH, then move on to other priorities, I don't know how [we] could pull off those kinds of increases,” says Moore. “The scientific rationale may be there … but the politics are very difficult.”

## Eyes on the future

Given such predictions, many institute directors—including those of the big three—have already trimmed their sails. At NIAID, for instance, Fauci notes that he and his advisers long ago made the “somewhat unpopular decision” to hold down the number of new grants to individual investigators, choosing instead to focus on increasing the size of grants and building infrastructure that often has low carrying costs. As a result, he says, NIAID's new grant numbers will decline slightly next year, to 985, from 1004 this year.

At the second-ranked National Heart, Lung, and Blood Institute, director Claude Lenfant outlined similar choices in an April letter to grantees, explaining why the number of new grants awarded by his institute in 2002 will decline by nearly 10%, to 911, compared to last year. “The generous increase in our budget does not translate into an ever-increasing number of successful competing grant applications,” Lenfant wrote. At the same time, he noted that the average grant has gotten bigger.

At the $3.74 billion NCI—the largest member of the NIH family—Klausner notes that the cost of grants has risen faster than the institute's budget in recent years, steadily eating into the pool of money available for new projects. The amount of money for new initiatives is shrinking fast, from$262 million in 2000 to $176 million this year, with a continued drop forecast for 2002. “Next year will be the most difficult by far,” predicts Klausner. In response, NCI is capping the increases that can be requested by investigators seeking renewal of their 3- and 4-year awards and ordering a special review for grants larger than$500,000 a year, a category that's growing rapidly. By 2003, however, Klausner predicts that enough existing grants will have expired to ease the transition to slower growth rates.

Although the report of the special postdoubling committee isn't due until fall, the agency's 2002 budget request offers some clues about the strategies it might recommend for spending future budget increases wisely. One is to continue investing heavily in infrastructure. For instance, NIH officials are touting plans to spend tens of millions of dollars over the next few years on high-end equipment—specialized electron microscopes, supercomputers, and other machines costing $500,000 or more. There is also talk of making a dent in an estimated$6 billion backlog in needed construction and renovation projects at universities and research hospitals. Both types of spending are attractive because, unlike grants, they can be paid for in a single budget year.

Last year, similar ideas led Representative David Obey (R-WI), the senior Democrat on the House panel that oversees NIH's budget, to ask whether such spending “really was the way the science is going, or a way to move larger sums of money now that you are getting these increases?” This year, however, there were virtually no such challenges at a House hearing on NIH's infrastructure proposals. And in the Senate, Tom Harkin (D-IA), the new head of the spending panel that oversees NIH's budget, encouraged officials to think about giving more cash to grantees who need bigger labs and better equipment.

Researchers are seconding that idea. Last week, for instance, an advisory group led by William Brody, president of Johns Hopkins University in Baltimore, Maryland, recommended that NIH boost construction and renovation grants to $1 billion a year—from$75 million this year. But Kirschstein deferred the idea until December.

Another issue likely to be aired in committee discussions is the impact of “modular” grants. Under the streamlining policy, a legacy of former director Harold Varmus and implemented in earnest last year, all grants of $250,000 or less have been awarded in increments of$25,000. The idea was to reduce the amount of paperwork for smaller grants. But it has had the unintended side effect of boosting overall spending: Lured by the lack of paperwork, more investigators appear to be requesting funding levels closer to the ceiling, and renewal grant amounts are routinely rounded up.

In his letter, for instance, Lenfant noted that his institute limits renewal grants to a 10% increase, so a $100,000 grantee can ask for up to$110,000 the second time around. Under the modular grant approach, however, the grant is rounded up to $125,000. The development is “one noteworthy cause” of rising grant costs, Lenfant wrote. Klausner would also like to see peer reviewers take a closer look at the costs of proposed research. The thousands of scientists who review proposals to NIH are currently instructed to focus on scientific merit, and Klausner says that most study sections routinely recommend funding levels very near the investigator's request. But those budgets are “often far in excess of what we can realistically provide,” says Klausner. The process of negotiating lower amounts has “become an enormous stress on program staff,” he says. Resolving these issues to everyone's satisfaction, however, still won't solve NIH's budget crunch. Observers say that only a miracle will prevent stagnation and slumps after 2003 in the number of grants, infrastructure spending, and clinical research. Doubling has “given everyone a little something to celebrate,” notes one NIH official. But the bill is rapidly coming due. 17. THE NUMBERS # NIH Stays the Course in Choosing How to Spend Its Growing Budget 1. David Malakoff The National Institutes of Health (NIH) is in a groove—or a rut. Two recently released reports* examine how it has spent its huge annual budget increases, and what it would do with the rest of a projected$14 billion infusion over 5 years. The short answer: Its decisions largely mirror existing budget priorities. But a bigger budget has caused some management problems.

In particular, more than half of recent increases have gone to increasing the number and size of extramural grants (see pie chart). That is just fine with many researchers, who believe that allowing deserving academic scientists to follow their instincts is an idea that never goes out of style. “I would be disappointed to see [NIH] retreat from individual investigators … or not sustain their purchasing power,” says cancer researcher Phil Sharp of the Massachusetts Institute of Technology in Cambridge, who leads a National Cancer Institute advisory panel.

The big budget boosts have also allowed growth in NIH's other funding mechanisms, from R&D contracts to its intramural program. Although the reports don't detail exactly where the dollars flow, they do provide a laundry list of nearly 150 new and planned initiatives. Not surprisingly, many of the featured projects target diseases or issues that are both medically important and politically popular. In a bow toward drug control, for instance, one current initiative promises to fund efforts to warn physicians about the dangers associated with an increasingly popular “club drug” called gamma hydroxybutyrate (GHB) and to help toxicologists and pharmacologists study GHB's biological and behavioral effects. Others push to accelerate the development of vaccines against Alzheimer's disease and AIDS, or employ gene chips—which can tell researchers which genes are active in certain cells—to study the role of genes in everything from alcoholism to arthritis. Other projects focus on translating basic research into practical treatments. One set of clinical trials, for example, will test—often for the first time—the efficacy of different approaches to treating drug addiction, from counseling to medications. Another is developing a database that will help cancer investigators more quickly identify when candidate drugs are ready for clinical trials. One other promises to develop an artificial salivary gland—a tube filled with saliva-producing cells—that could be implanted in patients with swallowing problems.

Although biomedical research advocates say these and other projects are good investments, some worry that the growth may be taking a toll on NIH program managers. Institute directors report that frontline project managers are juggling more grants—sometimes hundreds at a time—and burning out more quickly. At the National Cancer Institute, for instance, the average grant manager now has less than 3 years of experience and turnover is approaching 20% per year.

But help may be coming. NIH wants money for more staff to manage the grants, and Congress, which in recent years has held down growth in this area, seems supportive of increases that would keep pace with NIH's expanding research portfolio.

18. THE WINNERS

# Even in a Time of Plenty, Some Do Better Than Others

1. Jocelyn Kaiser

“Fat cat” basic researchers, directors of large trials and surveys, and genomics Pooh-Bahs top the list of scientists with the most NIH funding

With a 25-person lab and eight grants from the National Institutes of Health (NIH), virologist Joseph Sodroski of the Dana-Farber Cancer Institute in Boston has a lot going on. “There are people from all over the world here,” he says, “and keeping everybody fulfilled and happy is a challenge.” And his research keeps sprouting in new directions, from how HIV envelope glycoproteins help the virus enter cells, to their cytopathology, to their possible role in vaccines. Federal funding is the food that nourishes those ideas, so even though his plate is full already, Sodroski says, “if an idea comes along that looks fundable, I'll probably write a grant [proposal].”

That drive netted Sodroski $4 million in NIH funding last year, putting him in the upper echelons of the agency's basic research grantees and at the very top in terms of number of grants. A leading AIDS researcher and skilled proposal writer, Sodroski has benefited from an exploding NIH budget that has allowed the agency to award more and larger grants (see p. 1992). In this time of plenty, NIH grant administrators early this year examined what they call the “fat cats”—principal investigators (PIs) with six or more grants—to make sure that NIH's 27 institutes and centers are not funding duplicative work and PIs aren't overextended. Extramural research chief Wendy Baldwin concluded that “there was nothing to be concerned about” for the 30 or so people on her list. Science decided to take its own look at the people at the top of the funding heap, examining the total amount of money received and number of grants. Recipients were divided into three groups—those who do mostly basic research, clinical and social science researchers, and genomics centers. The leaders receive$3 million or more a year, eight times what the average investigator receives. At the same time, the portfolios of most of the top investigators include grants shared with other labs. Identifying the top- funded researchers from an NIH list of grants awarded in 2000 wasn't an easy task. (Baldwin calls NIH's grant data “a morass.”) The totals for individual PIs are the sum of many variables—from their institution's indirect costs and salaries to whether the research involves cells or transgenic mice or primates, or relies on expensive equipment or subcontractors. The tables are also a snapshot for 1 year.

Those on these lists say the money brings plenty of headaches, including 18-hour days writing grant proposals and setting aside time to prepare and host site visits from outside reviewers. Although most pine for more time in the lab, they say they're driven to seek more research funding by a surfeit of ideas, as well as the trend toward big biology. Many also believe that outside collaborations and big labs provide the best training for the next generation of investigators.

At the top of basic research money winners (above) is prion researcher Stanley Prusiner of the University of California, San Francisco (whose work involves costly biosafety facilities for mice). He's a Nobel Prize winner, as are two others in the top 10 (cell biologist Alfred Gilman of the University of Texas Southwestern Medical Center in Dallas and neurobiologist Paul Greengard of Rockefeller University in New York City). Other ranking investigators include pioneers in their field, such as gene therapy researcher Ron Crystal, who ran the biggest lab at NIH before moving to Weill Medical College of Cornell University in New York City in 1993.

Greengard says he's ambivalent about the honor: “I've thought for a long time that there is an ideal limit on lab size.” But he says it's hard to turn down the constant influx of talented young scientists interested in working with him and the “exciting ideas” that come along. As a result, his group now numbers some 40 people, up from about 30 a decade ago. “I'd much rather have a smaller lab, but I don't have the willpower” to say no, he confesses.

Other top-funded scientists don't necessarily maintain big labs. Instead, they owe their lofty rank to being a PI on a center grant, or more often program grants—called P01s—that are equivalent to several R01s split among various labs. They are attracted to these grants because they allow for interdisciplinary and collaborative science that can't be done on an R01.

Michael Gimbrone of Harvard Medical School in Boston, who for 23 years has done pioneering work on atherosclerosis with a team ranging from engineers to molecular biologists, says that the combined brainpower on a grant that involves about five other labs creates “a SWAT team” for solving problems. Rainer Storb, head of transplantation biology at the Fred Hutchinson Cancer Research Center in Seattle, says he's been driven to grow lately by promising discoveries such as a new technique that allows bone marrow transplants to be used on more patients. “Working as a group [of 125 basic and clinical people] has given us an enormous amount of strength,” Storb says. “Without that you can't push this very complex field ahead at the breathtaking pace we have.”

These researchers share a belief that big programs are a good way of doing science and training scientists. Gene therapy researcher George Stamatoyannopoulos of the University of Washington, Seattle, for example, has only 19 people in his lab. But his two P01s allow him to jump-start the careers of young researchers who don't have enough publications to compete on their own by essentially giving them their own R01. A few years after becoming part of the program grant, he says, these young scientists “are all extremely well funded.”

Others on the list head brand-new collaborations involving multiple institutions. They include Ian Wilson of the Scripps Research Institute in La Jolla, California, who last year got a large grant for a structural genomics initiative, and Seigo Izumo of Harvard's Beth Israel Deaconess Medical Center, whose collaborative grant for cardiovascular functional genomics “is not something a traditional lab can do.” NIH officials see these consortia as the wave of the future: Gilman received $8.8 million last year for a cell-signaling alliance shared among 20 institutions in what's called a “glue grant,” the first of many from NIH. What does it take to get these large, shared grants? A critical mass of talented investigators and strong institutional support are essential, researchers say. “You've also got to set up some management structure,” Wilson says. In his lab, that means putting Ph.D.s who would otherwise gravitate to biotech companies in charge of areas such as computing, x-rays, and cloning. Not every researcher wants to join collaborations, however. Science found that basic PIs with many grants (below) tend to run large, self-contained labs. The predilection for multiple grants, they say, stems in part from hard times at NIH in the early 1990s. Tight budgets often led institutes to cut the size of a grant sent in for renewal, forcing investigators to apply for a second R01 to cover their costs. Scripps virologist Michael Oldstone admits that the system was inefficient. “I'd rather have half as many grants and the same amount of money for research,” he says. But PIs who pile up the R01s have their reasons. “I think it's a good thing that it's not one big hunk but that I competed for these grants six times,” says human geneticist Aravinda Chakravarti of Johns Hopkins University in Baltimore. And some don't see a need to limit the number of grants going to a single lab. Bigger labs “are the main source of training for the future,” says Sodroski. “I'm not sure [funding] more investigators is better.” The rapid growth in NIH's budget has improved everyone's chances of getting money, he adds. “So what's the big deal?” Of course, those at the top say that not everybody wants or should try to be a rainmaker. “I think it's a choice. It would be a terrible thing if we say simply that having more money [means you are] more successful,” says Chakravarti. Baldwin agrees that there are “lots of different ways to measure success,” including the ability to sustain funding. In that arena, the apparent winner is Harold Scheraga, a protein chemist at Cornell. He's just sent off a renewal for an R01 he's had for 45 years—one that has provided data for more than 1000 papers. At the age of 79, Scheraga, who has a 20-person lab, brought in$717,000 last year from NIH for his university.

Scheraga has embraced many new ideas and technologies over his career. But he hasn't changed his mind about the value of being an independent investigator, in no small part because he can stay in closer contact with the work. “I have a wide range of expertise in my lab,” he says. And as for grant size, he says, “I just ask for what I need.”

“I'm just euphoric that my scientific peers have given me the opportunity,” says Donald Morton (top), a cancer researcher at the John Wayne Cancer Institute in Santa Monica, California, who tops Science's list of the best funded clinical researchers. Morton manages $12 million worth of trials, including$7.8 million for a cancer vaccine that he's worked on since the 1960s.

This ranking includes only investigator-initiated clinical projects and centers. It leaves out some larger trials, including AIDS drug trials, that are instigated by NIH, as well as cooperative cancer centers. Other top-funded principal investigators (PIs) include bench-to-bedside research on leukemia treatments by Frederick Appelbaum of the Fred Hutchinson Cancer Research Center in Seattle and work by psychologist Thomas Coates of the University of California, San Francisco, on promoting behaviors that prevent AIDS. Also on the list is a teenage health study, which PI Richard Udry of the University of North Carolina, Chapel Hill, calls “one of the most expensive and complicated surveys ever done.” The results will provide social and biological data for countless researchers.

The NIH grants for the major publicly funded genome sequencing labs are way off the charts, reflecting the biggest of big biology—and the race to sequence the human genome that ended last year. Topping this list of five is Eric Lander's Whitehead Institute in Cambridge, Massachusetts, which got a whopping $65 million in 2000. (The sprint to the finish swelled his total, which stood at$13 million in 1995.) “That is truly production”—reagents and automated equipment, not so much people—says Jane Peterson, a grants administrator at the National Human Genome Research Institute. Lander (above) says his high-volume operation is nevertheless an exhilarating scientific endeavor involving 20 senior researchers: “It has the spirit of a fun 20-person lab.”

Peterson says the “hallmarks” of these investigators are hiring “good lieutenants” and “an ability to manage a big production facility. It's not something you learn in graduate school.” Although the human genome grants will wind down when finishing steps are completed in 2003, demand for sequencing other organisms and comparative genomics will keep these labs busy (Science, 16 February, p. 1204).