# News this Week

Science  05 Oct 2001:
Vol. 294, Issue 5540, pp. 26
1. INFECTIOUS DISEASES

# Rapid Response Could Have Curbed Foot-and-Mouth Epidemic

1. Martin Enserink

To stop a catastrophic outbreak of foot-and-mouth disease (FMD), the British government has so far destroyed almost 4 million pigs, sheep, and cattle—a strategy that has been criticized as overly zealous and draconian by some farmers and animal-welfare activists. But new studies from two teams of British veterinary epidemiologists show that, if anything, the measures haven't been strict enough. If the government had implemented a more rigorous culling policy in the first phase of the epidemic, the total burden would have been much smaller, the researchers say—and millions of animals would have been saved.

Neither of the studies, however, examines whether implementing strict control policies would have been possible politically and logistically—a question that is now the subject of several investigations. Government officials, while acknowledging that, in hindsight, rapid slaughter would have been preferable, say they did the best they could under the circumstances.

The two studies paint a detailed picture of how the British countryside was ravaged this year by the so-called O Pan Asian strain of the FMD virus. Although they used different mathematical and statistical techniques, both models show that the United Kingdom was not prepared for the onslaught; the disease exploded before authorities started clamping down in earnest. One of the papers, by Roy Anderson and his colleagues at Imperial College in London, is published in this week's issue of Nature; the other, from Bryan Grenfell and colleagues at the University of Cambridge and the University of Edinburgh, is published online by Science this week at http://www.sciencexpress.org/.

FMD is one of the most contagious diseases known; infected animals shed large amounts of the virus before they become sick, and viral particles can survive on clothes, shoes, or vehicle tires. Even the wind can carry the virus to farms dozens of kilometers away. The disease can affect all cloven-hoofed animals, including pigs, cattle, and sheep. Although it usually doesn't kill adult animals, infected animals become so sickly and weak they lose their economic value.

David King, the U.K.'s chief science adviser, turned to the research teams in March, when the disease was still on the rise. Each group then started cobbling together models. Although crude, both showed that the government needed to get serious about its policy to cull infected farms within 24 hours; in addition, livestock at all adjacent properties needed to be destroyed. That advice helped break “an air of defeatism” at the Department for Environment, Food & Rural Affairs (DEFRA), says Imperial College's Neil Ferguson, and led the government to adopt the massive culling that eventually helped reduce the number of cases (Science, 20 April, p. 410).

Now, both teams have produced much more detailed models of the epidemic. They take into account things such as the location of every farm and the estimated number of pigs, cattle, and sheep each farm contained, as well as exhaustive data about the spread of the disease and the culling process, provided by DEFRA scientists on the ground. The groups also calculated a number of what-if scenarios to show how different measures could have diverted the epidemic's course. For instance, if the government had succeeded in culling every infected farm within 24 hours and every adjacent farm within 48 hours, the number of cases would have been cut by 66% and the number of farms culled by 62%, according to the Imperial College model (see graph); the other team puts those numbers at 43% and 46%, respectively.

Other veterinary epidemiologists praise the models' accuracy in describing the epidemic. At the same time, some wish the studies would have offered more clues into how exactly the disease spreads. For instance, the studies don't explain very well why the epidemic has such a long tail, says Mart de Jong of Wageningen University in the Netherlands. De Jong hopes that further analyses of the data will yield such insights.

Still unanswered is whether the government would have been able to contain the outbreak, even if it had all the data now at its disposal. When the disease was first detected in February, it had already spread across the country, and dozens of cases popped up almost simultaneously. The necessary destruction of hundreds of thousands of animals on such short notice was simply impossible, says a DEFRA spokesperson. (Holland and France, by comparison, each had a more localized outbreak around the same time; these were relatively easy to stamp out.)

Indeed, it may be more important to look ahead than back, says the University of Edinburgh's Mark Woolhouse. He says the models underscore the need to increase surveillance and to develop plans for dealing with new veterinary outbreaks. The Royal Society just created a panel to advise on the development of such a plan.

With three new cases last week, Britain is still awaiting the end of the smoldering epidemic. Both research teams caution against relaxing controls. If the current rules are strictly enforced, the team from Edinburgh and Cambridge predicts, the disease will almost certainly be stamped out by next spring.

2. BIOINFORMATICS

# Petition Seeks Public Sharing of Code

1. David Malakoff

When computer scientist Jennifer Weller took a job at the Virginia Bioinformatics Institute in Blacksburg last year, she was eager to start work on new “open source” genome-sifting software that scientists could share. But officials at the parent Virginia Polytechnic Institute and State University delayed her project for a year while they pondered how such collaborative work fit into the school's technology transfer program, which aims to patent and control the distribution of potentially valuable faculty member discoveries. “There was a lot of confusion,” she says.

Weller's project recently got the go-ahead, but the experience made her an open-source activist. She's eagerly signed a new petition demanding that the government require scientists to deposit the guts of their taxpayer-funded software into public collections. Although the 3-week-old petition (http://www.openinformatics.org/) has so far garnered just a few dozen signatures, it has sparked widespread debate.

Open-source advocates say that sharing is essential for eliminating duplicative research and perfecting programs that tame biological data. But critics and some government officials warn that mandatory sharing could hinder research by reducing financial incentives—and would probably violate federal law. “I appreciate the spirit that generated this petition, [but] there are some major problems,” says Phil Green, a prominent bioinformatics researcher at the University of Washington in Seattle.

The petition was drawn up last month by three software developers—Jason Stewart of Open Informatics in Albuquerque, New Mexico; Harry Mangalam of tacg Informatics in Irvine, California; and Jiaye Zhou of Inztro, another Albuquerque firm—who believe that publicly funded research should be made available to all. In addition, they say, public disclosure would allow closer scrutiny of existing software. “You often can't evaluate results without carefully looking at the source code used to obtain them,” says Stewart.

The solution, they argue, is for U.S. granting agencies such as the National Institutes of Health (NIH) and the National Science Foundation (NSF) to require grantees to publish their codes under open-source or “free software” licenses. That would give users broad freedom to alter and share programs. Such wide-open collaboration has already sparked the rapid evolution of several popular programs, they note, including common Web-hosting software called Apache. In science, they argue, mandated sharing could free up time and money for research. Scientists would be free to assemble new tools from existing building blocks, Stewart says, while funding agencies “could reject proposals to reinvent the wheel.”

NIH and NSF officials appear receptive, noting that both agencies already have policies that encourage grantees to make their discoveries publicly available. But they say that the 1980 Bayh-Dole Act, which allows universities and researchers to patent the results of publicly financed research, probably rules out any mandatory sharing. “I don't think Congress would allow us to overrule a university's privilege to grant exclusive licenses,” says one NIH official.

But there are other options. For instance, agencies could require researchers to be more explicit about how they will share the fruits of their research, he says, and create specific financial incentives for sharing. NIH has already launched one initiative to create a “public library” of informatics tools, while NSF review panels are encouraged to favor open-source projects.

Petition critics say that such voluntary commitments are preferable to any system that treats software differently than other scientific tools, such as cell lines or genetically modified mice. Green, who would like to scrap Bayh-Dole, says that mandated sharing “would perpetuate the myth—widespread among scientists who don't actually develop software—that it is inherently of less value than other inventions. This, in turn, tends to inhibit talented scientists from going into computationally oriented academic research.”

Such views are likely to get a full airing in January at the O'Reilly Bioinformatics Technology Conference in Tucson, Arizona, where Weller will lead a workshop on the licensing issues raised by the petition. “The [least] that can happen” as a result of the debate, says Stewart, “is that a lot of people get educated.”

3. PLANETARY SCIENCE

# Close Look at the Heart of Borrelly

1. Richard A. Kerr

Flying on a wing and a prayer, NASA's “aged and wounded” Deep Space 1 spacecraft has returned pictures of the dirty snowball buried within comet Borrelly, revealing recognizable geology on a comet nucleus for the first time. At a press conference at the Jet Propulsion Laboratory (JPL) last week in Pasadena, California, scientists described Borelly's rugged terrain and towering jets of dust and vaporized ice that hint at a potentially catastrophic demise for the 8-kilometer-long, bowling-pin-shaped object.

Launched in 1998, Deep Space 1 was designed as a test-bed for a dozen advanced technologies, including its exotic ion propulsion. A 16.5-kilometer-per-second dash through the gas and dust continually blown off a comet nucleus was an afterthought. Complicating matters, its star tracker, the spacecraft's only means of orienting itself, failed in 1999. With its camera jury-rigged as a replacement, “the encounter did not go the way we expected,” said project manager Marc Rayman of JPL: “It went perfectly.” By sheer luck, the spacecraft dodged a massive dust jet to return analyses of ions in the comet's hazy coma of dust and gas, infrared spectra of the nucleus, and black-and-white pictures sharper than any of comet Halley returned by a flotilla of spacecraft in 1986.

These detailed images revealed a terrain of diverse features. Each end of the nucleus has plateaus. A smooth, brighter plain at the center is emitting at least three columnar jets where the sun's heat is excavating a saddle-shaped depression. In addition, fractures crisscross the comet, several of them right in the thin neck of the bowling pin, according to planetary geologist Laurence Soderblom of the U.S. Geological Survey in Flagstaff, Arizona. “It's quite possible” Borrelly could break in two, either at the center or at the neck, he says. The way Borrelly seems to rotate would keep the jetting saddle continually illuminated while the comet is near the sun, adds comet specialist Donald Yeomans of JPL, hastening erosion at that spot. Eventually, the nucleus might even break into many pieces and vanish, just as comet LINEAR did in July 2000.

Deep Space 1 will meet a less spectacular end: In November, after more strenuous testing of its ion engine, its controllers will simply stop talking to it.

4. PSYCHOPHARMACOLOGY

# Drug Critic Sues After School Pulls Job Offer

1. Constance Holden

A British psychiatrist and critic of antidepressant drugs is suing the University of Toronto (UT) and an affiliated mental health center for breach of contract after the center rescinded a job offer to him.

David Healy, a reader in psychological medicine at the University of Wales College of Medicine in Cardiff, claims that his academic freedom was violated after he gave a speech last fall criticizing drug companies and arguing that the popular antidepressant Prozac “can lead to suicide.” His suit, filed in Toronto on 24 September, seeks reinstatement of the job offer at the Centre for Addiction and Mental Health (CAMH) or $9.4 million in lost salary and damages for libel. CAMH officials have told Healy—and explained in letters to their staff—that they felt his views are “extreme” and incompatible with the responsibilities he would assume. Healy is a prominent historian of psychopharmacology who in recent years has testified as an expert witness for plaintiffs claiming injury from drugs like Prozac, known as SSRIs (selective serotonin reuptake inhibitors). In August 2000, CAMH formally offered him the post as clinical director of its mood and anxiety disorders program and professor of psychiatry at the University of Toronto, at an annual income of about$250,000. Healy accepted the written offer the following month.

On 30 November, Healy delivered a lecture in Toronto on “psychopharmacology and the government of self.” In the talk, which he has given at numerous other locations and posted on his Web site (http://www.pharmapolitics.com/), he discussed negative effects of antipsychotic and antidepressant drugs, including brain injury and suicides. The lecture caused quite a stir.

Less than a week later, CAMH chief physician David Goldbloom informed Healy that “While you are held in high regard as a scholar of the history of modern psychiatry … we believe that it is not a good fit between you and the role as leader of an academic program. … This view was solidified by your recent appearance.” In a 17 May letter to his board of directors, CAMH head Paul Garfinkel wrote that Healy “has expressed extreme views that are inconsistent with published scientific evidence. These views go well beyond his peer-reviewed published work.” Garfinkel said Healy's future colleagues were “shocked” by his presentation “to the point where the Centre felt that Dr. Healy would not have the necessary respect and support of staff.”

Healy has sought support for his position, and last month 30 scientists—including Nobelists Arvid Carlsson and Julius Axelrod—signed a letter to the university saying that the case was an “affront” to academic freedom. Healy says that his views on psychotropic drugs should not have surprised university officials, who he suggests are trying to assuage Eli Lilly and Co., the maker of Prozac, which in recent years has given $1.5 million to CAMH. CAMH officials have denied that their actions have any financial motive. In an April letter to Healy (available on his Web site), Goldbloom wrote that Healy's comments about “thousands of people killing themselves … because of fluoxetine [Prozac] … were incompatible with published scientific evidence and hence incompatible with … responsibility of leadership of a clinical and academic program.” Jack Barchas, chair of the psychiatry department of Cornell University Medical School in New York City, says that Healy has done “superb” work on the history of psychopharmacology but that his claims about SSRIs are “not convincing.” Healy says that results from a small study of SSRIs on healthy volunteers support his arguments but that “confidentiality orders” prevent him from revealing additional data. But Barchas says publication is the only way for Healy to make a convincing case. “There's not a major journal in the field that wouldn't be delighted to receive a careful evaluation of this data,” Barchas says. 5. GENETICS # Closing In on the Centromere 1. Elizabeth Pennisi The centromere is one of the genome's greatest enigmas. First noticed 120 years ago under a microscope as the cinched waists of the chromosomes, these sections of DNA have until now defied the best efforts of cell biologists and geneticists to understand them. Yet the centromere is critical for the proper sorting of chromosomes during cell division; if it doesn't work correctly, the result can be cancer, defects in development, or similar misfortunes. Now, on page 109, geneticists from Case Western Reserve University and University Hospitals of Cleveland Research Institute in Ohio provide the clearest look yet at a human centromere. Huntington Willard and his colleagues have demonstrated that a 3-million-base stretch of DNA embedded in what many have called the centromere is really all it takes to make a functional centromere. To their surprise, the nature of this core DNA indicates that, rather than being highly conserved, the centromere has changed significantly during primate evolution. “It's a fundamental study using an elegant genomics and genetics approach,” comments Peter Warburton, a molecular biologist at Mount Sinai School of Medicine in New York City. For decades, researchers have known that centromeres and their associated proteins are anchor points for the spindle of fibers that separates paired chromosomes, causing the two to move to opposite sides of the cell as it divides. They have observed under the microscope that when each chromosome replicates in mitosis, the two resulting chromatids are linked at the centromere until the spindle pulls them apart. Twenty years ago, Willard suggested that repetitive DNA—short patterns of bases repeated over and over that are characteristic of the centromere in most higher organisms—could be important to the centromere's function. “I caught a fair bit of flak for suggesting that repetitive DNA had a role,” he recalls. About that same time, biologists sequencing budding yeast determined that its centromere was a small stretch of nonrepetitive DNA, just 125 bases long. This new finding suggested that the repetitive DNA, called heterochromatin, was not the actual centromere but rather flanked it. But when researchers later tried to determine the structure of the centromere in a range of organisms, from humans to flies, they hit a brick wall. Their high-powered sequencing machines stopped dead when they reached the heterochromatin. And in those rare instances when parts of that DNA could be sequenced, researchers were stymied in attempts to reassemble those parts into a whole centromere. Willard persisted, however, urging grad student Mary Schueler to take a close look at the centromeric regions in human X chromosomes. She and her colleagues also focused on centromeres from patients with Turner syndrome, who often have truncated sex chromosomes. In some of these patients, the X chromosome was chopped off right where one of the chromosome's two “arms,” the P arm, meets the heterochromatin flanking the centromere. Using these as a starting point, Schueler began working toward the center of the centromere, mapping the repetitive sequences along the way in anticipation of someday sequencing them. Called alpha satellite repeats, each “repeat” in this 450,000-base region was about 171 bases long and was almost—but not exactly—identical to the other repeats. As Schueler approached the center of the centromeric region, she found that the DNA sequence changed to what is known as a higher order array. Not only did this stretch contain recurring sets of 171-base repeats—the hallmark of alpha satellite DNA—but each set had a dozen repeats and then the entire set was repeated again. When Willard and his colleagues deleted the flanking DNA, they found that the higher order array, some 3 million bases long, could still function in cell division, suggesting that it made up the true functional centromere. The researchers put that suggestion to the test by inserting the higher order array into artificial chromosomes; it acted like a normal centromere during cell division, vindicating Willard's earlier hunch. “They showed that the sequence they were looking at was competent to be a centromere,” says Steve Henikoff, a geneticist at the Fred Hutchinson Cancer Research Center in Seattle. Because the centromeres have been so difficult to tackle, they remain as gaps in most completed sequences, including that of the human genome. But this work “is a major boost for convincing people to attack difficult [chromosome] regions,” says Daphne Preuss, another persistent geneticist at the University of Chicago who has been unraveling the centromere of the plant Arabidopsis (Science, 15 December 2000, p. 2057). To date, Schueler and her colleagues have sequenced just a bit of the centromeric region closest to the P arm of the X chromosome, but they plan to forge ahead. “It's been assumed that these regions are too difficult,” Schueler explains. “But that is not the case. You can map and sequence them.” Already the data hint at the history of the centromere on the human X chromosome. Based on the sequencing of the centromere completed to date, Willard's team concludes that the higher order array contains far fewer sequence variations—with the sets of repeats being more than 98% identical—than the flanking sequences. This suggests that the core is much younger than the flanking regions and has had less time to accumulate random variations. Another piece of evidence is that the core also harbors just one type of transposon, a rogue piece of DNA that inserts itself into the genome, and this transposon is relatively young: It exists only in humans and not other primates. Because the flanking regions share additional transposons with other primates, Willard suspects that those flanking regions are the “ancestral centromere,” with the modern centromere in the middle evolving after the ancestors of apes and humans diverged from lower primates. In this scenario, the higher order array replaced the ancestral sequence, leaving behind those “dead” centromeres as heterochromatin. And that, says Willard, suggests that although the centromere is functionally a highly conserved element, playing a key role in a range of organisms, its structure is a “highly fluid DNA sequence.” That, in turn, suggests more surprises to come when centromeres of other organisms are unraveled. 6. CAVE ART # Stone Age Artists--or Art Lovers--Unmasked? 1. Michael Balter PARIS—Archaeologists may be on the way to solving two pivotal mysteries of prehistoric art: Who were the artists, and what was the meaning of their work? Radiocarbon dating of human remains found in the recently discovered Cussac Cave in the Dordogne Valley of southern France indicates that the bones are contemporaneous with beautiful engravings of animals and human figures etched on the cave walls. Although it might be impossible to prove that the remains were of the artists themselves, the skeletons may hold clues to who frequented the cave and why it had special significance. Fragmentary human remains have been found near cave art a few times in the past, but there has been no way of knowing that these were not art lovers, accidental visitors, or squatters from some other period. But Cussac is something special. “For the first time ever, we have … human skeletons deep in an uninhabited [decorated] cave,” says French cave art expert Jean Clottes. Archaeologist Randall White of New York University agrees: No other cave “even comes close” to Cussac and its complete burials. Cussac was discovered by a caver in September 2000, but the French government kept it secret until this July (Science, 20 July, p. 423). The engravings—which include fantasy animals with deformed heads and gaping mouths, and a voluptuous female profile—were provisionally dated to the Gravettian period, based on their stylistic similarity to other cave art. This would make them between 22,000 and 28,000 years old. Ever since Cussac was found, archaeologists have been holding their breath, waiting to learn the dating results from the skeletons—four or five adults and one adolescent—found in hollows on the cave floor. Preliminary results from three bone samples analyzed by Beta Analytic, a radiocarbon lab in Miami, Florida, found that one of the samples gave a precise date of 25,120 years, plus or minus 120 years—clearly within the Gravettian period. (The other two samples did not give conclusive results.) Archaeologists led by Norbert Aujoulat of the National Center for Prehistory in Périgueux will now begin a 3-year program to excavate the burials, including the stone tools and other artifacts found with them, as well as study the engravings themselves. “The archaeological context of cave art can provide more clues about the meaning of the art than the art itself,” says Clottes. Still, unless archaeologists find artists' materials ceremonially buried alongside the skeletons, they can only speculate on what connection the humans had to the engravings. If not the artists, they could be “highly regarded individuals put there as a kind of homage,” says Clottes. They even might have been miscreants, he speculates, “people who misbehaved in such a dreadful way that they had to be put away as close to the spirits as possible, so they could not come back.” 7. GENETICS # First Gene Linked to Speech Identified 1. Michael Balter Plenty of animals can caw or roar or buzz, but only human beings can string a complex series of sounds together into speech. Now a team of researchers has identified the first gene directly involved in this uniquely human trait. The discovery may provide insights into how language is processed in the brain, and it opens the door to figuring out how and when language arose—a central question in the study of human evolution. The new gene, called FOXP2, was identified by studying members of a British family who suffer from a severe inherited speech and language disorder, as well as an unrelated child with similar symptoms. “This is the first clear identification” of a gene “with direct relevance for language ability,” says geneticist Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. Philip Lieberman, a language-origins researcher at Brown University in Providence, Rhode Island, calls the discovery “a milestone event.” But Lieberman and other researchers caution that the function of the gene is not yet clear, and that it is probably only one of a number of genes involved in speech and language. The identification of FOXP2 caps a decade of controversy over how to define the disabilities found in three generations of a family known to researchers as “KE.” Nearly half the members of the KE family suffer from the syndrome. Researchers initially identified it as an inability to learn proper grammar, and the claim led to news accounts in the early 1990s that humans have an innate “grammar gene.” But that notion was largely discounted after others reported that affected family members suffer from a wide range of speech and language problems, from garbled pronunciation to putting words in the wrong order. They also have trouble understanding speech. Now many researchers suspect that the inability to order things correctly accounts for the family members' symptoms. “The core deficit is an inability to sequence and appropriately select the small sounds that result in words and sentences,” says cognitive neuroscientist Faraneh Vargha-Khadem of the Institute of Child Health in London. This handicap extends to nonverbal sequences as well; people with the syndrome have trouble following directions to close their lips, open their mouths, and then stick out their tongues. Brain imaging studies may back up this diagnosis: Vargha-Khadem and colleagues linked the disability to defects in the basal ganglia, which connect to centers for language and movement and are thought to be involved in sequencing behaviors. To identify the genetic basis of the disorder, Vargha-Khadem's group teamed up with geneticist Anthony Monaco and his colleagues at Oxford University in the late 1990s. They localized the defect to a segment of chromosome 7, which they called SPCH1, and began to search for the critical gene. Then came a lucky break: Jane Hurst of Oxford's Radcliffe Hospital, who had originally described the KE family, found a 5-year-old boy with a similar disorder. Analysis of the boy's genome showed that a large segment of his chromosome 7 had switched places with a segment of chromosome 5, a genetic error known as a translocation. Now the Vargha-Khadem and Monaco teams report that the “breakpoint” of the boy's translocation is in the middle of a gene similar to the previously discovered FOX family of regulatory genes, which have been implicated in embryonic development. The researchers screened the KE family and found that affected members had a mutation in the gene in which one adenine nucleotide was substituted for a guanine, apparently rendering the gene inactive, the research group reports in the 4 October issue of Nature. Although mutations in the gene appear to account for this language disorder, researchers caution against calling it a “speech” or “language” gene. “It is still unclear what the gene does and what role it really plays in language development,” says Michael Corballis, a psychologist at the University of Auckland in New Zealand. For instance, Elizabeth Bates of the University of California, San Diego, contends that the core disability is a motor dysfunction rather than something specific to speech or language. The motor aspect of the syndrome has caught the attention of researchers who study chimps and other primates. Michael Tomasello of the Max Planck Institute in Leipzig points out that apes are “incapable” of controlling their mouths with sufficient precision to make consonants. “Language never would have evolved in human beings if there wasn't the ability to make a variety of sounds,” Tomasello says. The evolutionary implications of the new work have not escaped language-origins researchers. Pääbo's group is now studying FOXP2's sequence in nonhuman primates to see how it differs from the human version. This kind of comparative genetic study, says Lieberman, “may help solve the mystery of how we came to be.” 8. SCIENCE POLICY # New Regulatory Czar Takes Charge 1. Jocelyn Kaiser In his first public move as head of regulations at the White House Office of Management and Budget (OMB), John Graham came out of his corner swinging. In actions last month—a memo to agencies and two “prompt” letters—Graham, a risk-analysis expert on leave from Harvard, signaled that he intends to take firm control of regulatory policy across the government. His office won't “play a simply reactive role,” says Graham, who faults his predecessors in the past 8 years for letting agencies have free rein. Specifically, Graham clarified procedures that the Office of Information and Regulatory Affairs (OIRA) will use to evaluate economically significant regulations proposed by agencies such as the Environmental Protection Agency (EPA) and the Occupational Safety and Health Administration (OSHA). His 20 September memo reiterated that regulations not based on science will be sent back for more work. And in a shift, agencies will have to submit their cost-benefit analyses, not just their scientific assessments, to peer review. Graham's presidential appointment was controversial partly because of his emphasis on cost-benefit analysis. And some see these steps as an effort to stall regulations, harking back to the OMB of the Reagan years. Johns Hopkins University epidemiologist Lynn Goldman, who headed EPA's pesticides office during the Clinton Administration, doesn't see “the value added” by routinely reviewing economic impact analyses, which are usually done by standard methods. Graham insists, however, that the analyses behind regulations need improvement. “I think it's well recognized that the quality of [cost-benefit] documents across agencies is very uneven,” he says. And he points out that new requirements will generally apply only to regulations that will cost at least$100 million a year to implement.

In an unexpected move, Graham urged agencies to expedite two regulations that clearly pass the cost-benefit test. In a “prompt” letter to the Food and Drug Administration, Graham pushed the agency to complete a proposed rule requiring labeling of trans fatty acids—which have been linked to increased risk of heart disease—in foods. He also suggested to OSHA that defibrillators be installed in workplaces. Paul Portney, president of Resources for the Future in Washington, D.C., says that suggesting regulations, not just approving them, is “a huge change” for OIRA.

9. GENOME RESEARCH

# Possible New Heart Disease Risk Factor

1. Caroline Seydel*
1. Caroline Seydel is a freelance science writer in Los Angeles.

After embarking on a basic study of gene regulation, a research team has instead uncovered a new gene that may be an important risk factor in cardiovascular diseases. “It was a jewel that we pulled out—one that we weren't exactly looking for,” says Edward Rubin of Lawrence Berkeley National Laboratory in California, who led the multidisciplinary team.

The new gene encodes a previously unknown member of the apolipoprotein (APO) family of proteins, which influence blood lipid levels. Researchers have been fascinated by this family since it was discovered decades ago, because the proteins play key roles in transporting cholesterol, triglycerides, and other blood lipids into and out of various tissues. They also found that mutations in several of the 15 or so APO genes increase susceptibility to heart disease, because they raise blood cholesterol or triglyceride concentrations. But it's been 10 years since the last new APO gene was reported, and researchers thought they'd all been found.

Not so, reports the Rubin team on page 169. They have also shown that mutations in the gene lead to increased blood triglyceride levels in both mice and humans. “This is a wake-up call” that there are surprises in the genome even for well-studied fields, says atherosclerosis researcher Alan Tall of Columbia University. More work will be needed to confirm that APOAV variations influence the risk of human cardiovascular diseases. But if they do, the protein might be a target for new lipid-lowering drugs.

The original goal of Rubin and his colleagues from the Stanford Human Genome Center, the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas, and the University of Lille, France, was to use cross-species sequence comparisons to better understand the regulation of three APO genes that are shared by humans, mice, and rabbits, but controlled differently. But since stumbling on the new gene while doing the comparison, the researchers changed their focus.

To determine what the gene does, they knocked it out in some mice and created others that carried extra copies of the human gene. The results were dramatic: The mice without the gene had blood triglyceride levels four times those of normal mice, whereas the mice with the extra APOAV copies had levels that were only a third of normal. This showed that APOAV somehow reduces blood triglyceride concentrations. When the team realized that “not only was this gene missed, but it's important, then we really got excited about it,” recalls postdoc Len Pennacchio, lead author of the paper.

Convinced they were on to something important, Rubin, Pennacchio, and their colleagues decided to see whether variations in the APOAV gene influence blood triglyceride concentrations in humans. The team identified “markers,” changes in single bases, at four locations, three within the gene and one outside it. At each location, most Caucasians have the same base, but a minor subset has a different one. In genetic association studies, the researchers found that for each of the three markers within the gene, the less common base corresponded to increased triglyceride levels, independent of diet. The marker outside the gene showed no association with triglyceride levels. This suggests that the gene likely regulates triglyceride levels in humans as well as in mice and thus may influence their risk of developing a cardiovascular disease.

To try to pin down such a link, Rubin's lab plans to study the effects of a high-fat diet on the knockout mice and those that overexpress the gene. Finding a difference in the animals' susceptibility to atherosclerosis would provide evidence that the gene is a risk factor for cardiovascular disease. The team also hopes that others will pursue the question in humans. Even without those studies, cholesterol researcher and Nobel laureate Joseph Goldstein of UT Southwestern is impressed. This study “raises the bar for these functional genomic papers,” he says. “Hopefully every paper that identifies a new gene for the first time will be as complete as this one and as informative.”

10. POLAR RESEARCH

# Fire Guts British Antarctic Lab

1. Ben Shouse

CAMBRIDGE, U.K.—Britain's polar biology program is reeling from a fire that has destroyed its main antarctic laboratory. No injuries were reported, but the fire—which broke out on 28 September—did about $3 million worth of damage and has jeopardized about one-fifth of all ongoing British antarctic research, officials say. The cause of the fire that consumed the Bonner Laboratory at Rothera Research Station on the Antarctic Peninsula is still unknown, but the loss of the lab will set back investigations of climate change, Mars-like environments, and how organisms respond to extreme conditions. During peak research season, the Bonner Lab accommodates about 30 researchers. The blaze did not affect the station's living quarters, where 21 staff members remain safe. Three principal research projects were under way at the lab, comprising almost all of Britain's terrestrial and near-shore biological research in Antarctica. Two projects looked at how sea-floor and terrestrial communities tolerate harsh conditions and high levels of ultraviolet radiation. The third project used the Mars-like environment of some parts of the Antarctic to understand how life might have survived on Mars and how scientists can best look for signs of life on future Mars missions. The Bonner Lab also housed the continent's only year-round temperature, humidity, and ultraviolet radiation monitoring program. Restoring this program will be a top priority in rebuilding the lab. “We could potentially lose the best research of its type that's being done in the Antarctic,” says Lloyd Peck, the British Antarctic Survey's (BAS's) lead scientist for antarctic biology. But the lab will rise from the ashes soon, he predicts. Says Chris Rapley, director of BAS: “We are committed to rebuilding the Bonner Lab.” 11. DEVELOPMENT # New Hints Into the Biological Basis of Autism 1. Erik Stokstad Pushed by parent advocates, scientists are unearthing intriguing clues about what causes autism. Ongoing studies point to neuroanatomical and genetic defects Last month, with the mayor of Sacramento and a crowd of some 3000 parents and supporters looking on, construction crews broke ground on a 1.4-hectare plot on the University of California, Davis's medical campus in Sacramento. The blueprints call for two new buildings that will provide 13,000 square meters designed to do something unprecedented: provide a state-of-the-art comprehensive clinic and research center to diagnose, treat, and study children with autism. This$38.8 million facility, funded by the state of California, is a sign of the increasing research emphasis on autism, a mysterious disorder that keeps children from interacting socially and emotionally—and the power of parent advocates, who lobbied the state legislature to raise the funds.

Autism was long a poorly understood condition, rarely discussed. But that changed when advocacy groups began promoting research into its causes and possible treatments. In Hollywood, a movie mogul with an autistic son set up a tissue exchange bank. A New Hampshire mother of an autistic boy promoted a possible cure for autism (see sidebar on p. 37), triggering a media frenzy that prompted the National Institutes of Health (NIH) to jump-start clinical trials at record pace. In numerous congressional hearings, Representative Dan Burton (R-IN), who has an autistic grandson, has explored the largely discredited connection between childhood vaccinations and autism. Meanwhile, the rising numbers of parents requesting social services for autism has sparked fear—but few data—that the United States is experiencing a spreading epidemic of the disease (see sidebar on p. 35).

Researchers and funding agencies have responded. In 1997 NIH started a 5-year, $42 million network of collaborative programs of excellence for autism. Next month, the first large, interdisciplinary meeting of researchers interested in autism will be held in conjunction with the Society for Neuroscience meeting. The political momentum isn't flagging either: February marked the formation of a congressional caucus for autism, currently boasting 120 members. “This is a period of mobilization for autism research,” says David Amaral, director of the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, whose clinic is being expanded at UC Davis. And this increased attention is paying off, Amaral says. After years of frustration because of autism's confusing array of manifestations—and confusing patterns of inheritance—researchers are beginning to get their first solid sense of its biological basis. Behavioral studies led the way, spelling out the social and cognitive deficits that mark the disorder. Neuroanatomists have begun to identify abnormalities in brain structure, and more recently, imaging studies have provided hints of faulty circuitry. Underlying many of these problems, researchers believe, are perhaps as many as 20 genes that may interact with yet unknown environmental triggers. Together, the evidence seems to point to problems with brain development before birth and through early childhood. Although genetic factors clearly play a major role, a number of other causes and potential cofactors have been postulated, including vaccines, exposure to toxins, infection, and immunologic and metabolic problems. Whatever the causes, researchers hope to find ways to identify autistic children before or soon after birth, either with genetic tests or biomarkers such as blood-borne proteins, so that they can begin behavioral treatments sooner, when they seem more likely to succeed. A cure for autism, however, is a faraway prospect. ## A world apart First described in 1943, autism's primary manifestation is an impaired ability to relate socially with other people, although it almost always occurs with other debilitating symptoms. Autism is associated with language problems, and those who speak largely do so in a monotone. People with autism also seem to have trouble inferring what other people think and feel. “These people are very childlike,” says Nancy Minshew, a neurologist at the University of Pittsburgh School of Medicine and director of one of NIH's programs of excellence. “They can't deceive you; they are incapable of lying.” They tend to be sober-faced, suggesting that they don't feel the normal range of emotions, and yet often react with toddlerlike tantrums. Up to 60% of people with autism are also mentally retarded, with some 20% having an IQ less than 35; a small fraction are, however, gifted in some areas such as music, drawing, or calculations. Indeed, the symptoms of the disorder can vary so greatly, both in nature and severity and from person to person, that it is sometimes difficult to diagnose. The problems seen in autism seem to stem not from the senses, but from interpretation of the world. When healthy people view a laboratory film of moving triangles and a circle, for example, they infer social relationships among the objects. Autistic people usually see the shapes and movements as inanimate. They also have trouble interpreting faces. Work by Fred Volkmar and colleagues at Yale University and others has shown that when people with autism interact with someone, they generally spend most of their time looking at the mouth—not the eyes, as most people do. Likewise, Volkmar and his colleagues have shown that a part of the brain called the fusiform gyrus isn't activated when autistic people look at faces, as it is in people not affected by the condition. Another common symptom is the ability to understand facts but not concepts. “They have wonderful memory for facts, but they can't make sense of them,” Minshew explains. “They don't see a room; they see every detail.” Children with autism can learn a particular task that involves identifying shapes or colors, for instance, but they usually have trouble applying or generalizing that task to other situations. If asked what their father is like as a person, they are likely to say he's a man, he's tall, and he wears glasses, rather than saying he is kind and hard-working. Minshew believes the conceptual problems stem from difficulty processing complex information, and she says that's true not just with objects and social cues but with the motor system as well. Autistic children have trouble kicking balls, writing, or tying shoes. Functional magnetic resonance imaging studies, by Minshew's colleagues John Sweeney and Marcel Just, support this interpretation. In research not yet published, they show that higher functioning individuals with autism have reduced connections between the brain regions that support higher order cognitive abilities compared to peers of their age and IQ. Other anatomical differences have turned up during autopsies and brain scans. The amygdala, part of the brain's limbic system that helps control emotions and social behaviors, tends to be smaller. The hippocampus, a key structure in memory and learning, is usually also smaller. Both show evidence of reduced connections with other brain regions. The autopsies also revealed that the cerebellum typically has a severe deficiency of Purkinje cells, which participate in circuits involved in many brain functions. How all these findings relate to each other, however, is not clear. “There's no consensus at this point about the typical brain pathology of autism,” Amaral says. “We're decades behind the research on Alzheimer's or Parkinson's.” Brain biochemistry seems to be altered as well. A 1998 study of 30 controls and 29 autistic children showed that their blood contained on average significantly less oxytocin, a neuropeptide that regulates social behavior in animals. Larry Young of Emory University last year created knockout mice that lacked oxytocin. They behaved normally, except that they couldn't learn to recognize other mice or recognize their mother's scent, even though their sense of smell was normal. A single dose of oxytocin into the brain, however, cured the mice. “That gives you hope that if autism is related to oxytocin, it's not permanent,” Young says. To see whether this approach might work in humans, Eric Hollander of the Mount Sinai School of Medicine in New York City and colleagues injected a synthetic form of oxytocin into the blood of adults with autism. In this preliminary study, not yet published, repetitive behaviors were significantly decreased as long as the drug was administered; a placebo had no effect, the researchers report. Hollander believes that if oxytocin could be delivered in a sustained manner, it might ameliorate some symptoms. Unfortunately, there is no available compound that stimulates oxytocin receptors in a lasting manner. Indeed, it's highly unlikely that a single shot of anything will cure the disease, given the differences in brain structure and function among people with autism. ## Short circuits What creates these anatomical differences? Many researchers believe that the problems begin as neurons are finding their places in the brain, from before birth through the first 2 to 3 years of life. One hint comes from a study of neonatal blood samples archived by the California Birth Defects Monitoring Program. As child neurologist Karin Nelson of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and her colleagues reported in the May issue of Annals of Neurology, levels of several important regulators of early brain development, such as brain-derived neurotrophic factor, were elevated in children who were later diagnosed with autism. Nelson says it's difficult to know the specific effect of these elevated levels, although it may be related to another common symptom, enlarged heads during childhood. Although normal size at birth, the heads of children with autism tend to grow disproportionately faster than normal during the first 3 years of life; by adulthood, they are normal size again. One hypothesis is that fewer neurons are pruned in the brains—a process that sculpts sophisticated neural circuitry. Another perplexing feature is that 10% to 25% of children with autism seem to develop normally until symptoms of autism appear suddenly between 12 and 24 months of age. Because this is when children receive a suite of vaccinations, some parents have blamed the vaccines. Most researchers, however, don't think the evidence supports that charge. “A consistent body of epidemiological evidence shows no association at a population level” between the measles-mumps-rubella vaccine and autism, the Institute of Medicine concluded in an April report, although it could not exclude the possibility that the vaccine may contribute to autism in a few children. ## Genetic puzzle Twin studies have shown that autism clearly has a genetic component. But pinning down the chromosomal regions that contain the genes that are involved—much less the genes themselves—has been a daunting task. More than a half-dozen research groups are scanning DNA samples to find markers that are inherited by more than one autistic sibling in the same family. If a marker consistently crops up, that region may contain genes related to autism. But usually when one group homes in on an area, the others can't replicate the finding. The difficulty is probably due to extreme genetic diversity underlying the condition. Autism researchers estimate that between five and 20 genes contribute to the disorder, with some involved in certain patients but not in others. “It's the equivalent of lumping type 1 and type 2 diabetes; that's how heterogeneous this syndrome is,” says Edwin Cook of the University of Chicago. Compounding the problem, most genome scans have looked at fewer than 100 families, whereas many more than 200 may be needed to reliably find a gene in a complex disease, Cook says. But at least one chromosome region does seem firm. Last month, a group of 21 institutions, called the International Molecular Genetic Study of Autism Consortium (IMGSAC), published the strongest support yet for a susceptibility locus on chromosome 7q in a study of 153 families, one of the largest to date. Other groups have replicated the finding to varying degrees. The 7q region is interesting because a putative language gene maps there. Other regions are beginning to look strong as well. IMGSAC found additional support for loci on two other chromosomes—2q and 16p—as they reported in the September issue of the American Journal of Human Genetics. Other research suggests that chromosome 15 plays a role too. But to nail down candidate genes reliably, the groups will need DNA samples from more families. IMGSAC hopes to have 250 by the end of the year, says Tony Monaco of the University of Oxford. Researchers are also trying to identify the most useful subgroups in which to search for genes, such as overall severity of symptoms, language ability, or head size. More than 10 teams are racing to identify possible autism genes within the suspect chromosomal regions. Using sequence data from the draft human genome, they scan the region for genes that might be related to autism—say, because they are known to play a role in brain development. Then they search for mutations in DNA from affected individuals. This tactic has already led to the identification of several tentative candidates, although none of the findings has been replicated. A team led by Thomas Wassink, a psychiatric geneticist at the University of Iowa, Iowa City, has been studying WNT2, a developmental gene in the 7q region. Intriguingly, a knockout mouse that lacks part of the WNT pathway displays social abnormalities, such as not huddling with other mice during sleep. And variant DNA sequence adjacent to WNT2 is 50% more likely to occur in children with autism, Wassink's team reported in the July issue of the American Journal of Medical Genetics. Similar clues implicate the reelin gene, which is also on 7q. This gene codes for a protein that is thought to help neurons find their proper location. When the gene is knocked out in mice, they have defects in the cortical layers and cerebellum that resemble those found in the brains of autistics. A variant of this gene raises the risk of autism 3.5-fold, reported Flavio Keller, a biochemist and cell biologist at the Campus Bio-Medico University in Rome, Italy, and colleagues in the March issue of Molecular Psychiatry. A third gene, on chromosome 7p, Hoxa1, is known from knockout mice to be important in the development of the hindbrain. These mice also have features that resemble those of autism, such as misshapen ears. That led Patricia Rodier of the University of Rochester School of Medicine and Dentistry in New York state and her colleagues to search for variants of the gene in 57 autistic individuals. Last December, they reported in Teratology that about 40% carried a variant of the gene, compared to roughly 25% of relatives and controls. All three genes are reasonable candidates for shifting normal development toward autism, researchers say, but the evidence isn't compelling for any of them. “None are really strong this-is-it genes,” says Susan Folstein of Tufts University School of Medicine/New England Medical Center in Boston, who heads the Collaborative Linkage Study of Autism. Moreover, the three genes don't fit together into a neat story. Not until that happens can researchers begin to think about prenatal tests that might identify children for early intervention. ## Treatment For the moment, autism is usually diagnosed at 2 to 3 years of age. Although a few drugs can reduce some associated symptoms, none relieve the core problems. The treatment with the most scientific support is behavioral training. The most intensive therapy can take up to 40 hours a week and cost tens of thousands of dollars a year, putting it well out of reach for many families. Many studies have shown that children who receive this treatment tend to follow instructions better, learn how to imitate, and have enriched vocabularies; the largest and quickest gains, not surprisingly, occur with children who were higher functioning to begin with. But few data exist to evaluate which of the different approaches to behavioral training work best or how they compare to other interventions. Also unknown is whether some treatments are more suitable to particular subgroups of children. “It's very frustrating,” says Catherine Lord of the University of Michigan, Ann Arbor. More troubling still, says a June National Research Council report, is the limited amount of interventions available at most schools and a lack of trained teachers. Improving treatment through a better understanding of autism's causes is one of the goals of UC Davis's MIND Institute. “There's not going to be major progress until you start doing more comprehensive assessments of more kids,” Amaral says. Researchers there will evaluate different treatment therapies in a clinic designed to handle 1000 patients a month. Another new building will house lab space for biomarker research to aid in early diagnosis, supported with$4 million in annual state funding. A team of what will eventually be 20 researchers aims to tie genetic and biochemical findings with data from neuroimaging, psychological assessment, and computer-aided education. At the parents' insistence, all the comprehensive data gained at the MIND Institute will be shared with autism researchers throughout the world. That's because the parents charged the MIND researchers to rise to a new level of cooperation, Amaral says. “It's doesn't matter who solves the problem,” he says the parents told him, “just how soon it gets solved.”

12. DEVELOPMENT

# Scant Evidence for an Epidemic of Autism

Between 1987 and 1998, the number of children being treated for autism in California jumped a whopping 273%, according to a 1999 report by the California Department of Developmental Services. Similar jumps appeared nationwide: The U.S. Department of Education reported a 556% increase from 1991 to 1997.

To many parents of autistic children and a few researchers, these startling numbers are evidence that the country is experiencing an epidemic of autism. This, in turn, bolsters suspicions that environmental factors, such as pesticides or childhood vaccines, may be to blame.

But hard data documenting an increase in actual cases are sorely lacking. “The grounds for an increase [are] completely nonexistent,” says epidemiologist Eric Fombonne of McGill University in Montreal, although others are more tempered in their assessments. Fombonne and others suspect that the rise in demand for services can probably be traced to an increased awareness of the condition, more common referrals due to the availability of better services, and an ever-broadening definition of just what constitutes autism.

Even the prevalence of autism is hard to gauge. Large studies in the last 15 years have found an average of about 10 cases per 10,000 people. Including related conditions, the figure appears to be about 27 per 10,000. But “it's by no means what I would consider irrefutable,” says Craig Newschaffer, an epidemiologist at the Johns Hopkins University Bloomberg School of Public Health. “There's a real data void here.” Indeed, some smaller studies have turned up a much higher rate. In 1998, the Centers for Disease Control and Prevention (CDC) in Atlanta investigated the town of Brick Township, New Jersey, where parents feared a high rate of autism. The prevalence was 40 per 10,000, and 67 per 10,000 for the spectrum of related conditions—the second highest rate ever seen. CDC has since begun surveillance programs in nine states to see whether that rate is typical.

Starting from such an uncertain baseline, “it makes no sense to try to interpret trends over time,” Fombonne says. However difficult, other researchers, such as those at the University of California, Davis, are trying to determine whether the rise in reported referrals in California reflects an increasing risk of autism. “I'm still not convinced that there hasn't been an increase [in prevalence],” says David Amaral, who directs the Medical Investigation of Neurodevelopmental Disorders Institute there.

Whether or not the risk of autism has changed, the number of referrals for social services is clearly going up. “That need is real,” says Newschaffer, who has an autistic child. Based on a conservative estimate of 20 cases of autism-spectrum disorders per 10,000, Fombonne points out, the number of reported cases in California so far is still an undercount.

13. DEVELOPMENT

# Desperate Parents Spark Search for New Treatment

The story of Victoria Beck is dramatic: a Lorenzo's Oil of autism. Beck's belief that the drug secretin radically improved her son's symptoms—and the media storm that resulted—raised the hopes of many parents and galvanized public and private research. But the weight of evidence so far suggests that secretin doesn't work for the core symptoms of autism, at least for most children.

In 1996, Beck's young autistic son had a routine gastrointestinal exam—many autistic children have GI problems—that involved a diagnostic injection of secretin, a drug that stimulates the pancreas. Soon afterward, his symptoms lessened dramatically, and he began speaking again, sleeping well, and eating normally for 3 months. Convinced that secretin had led to this turnaround, Beck doggedly tried to get doctors to prescribe the drug, but to no avail.

Once Beck appeared on Dateline NBC in October 1998, however, word spread like wildfire over the Web, and other parents clamored to know more. “The next day I had hundreds of e-mails,” recalls Marie Bristol Power, special assistant for autism at the National Institute of Child Health and Human Development in Bethesda, Maryland. “The rapidity with which news spreads through the community is astounding.”

Based on this report and the countless newspaper articles that followed, several thousand parents across the country found doctors who would give their children multiple doses of secretin—an “off-license” use for which the drug was not approved. Researchers became alarmed. “This was not an insignificant treatment,” says Manny DiCicco-Bloom, who studies secretinlike peptides at the University of Medicine and Dentistry of New Jersey in New Brunswick. Among the risks, he says, are inflammatory bowel disease and anaphylactic shock.

Worried, the National Institutes of Health (NIH) sprang into action, setting up clinical trials within a few months. Meanwhile, Repligen, a biotech company in Needham, Massachusetts, raised $9 million in venture funding to investigate the drug. Then, bad news. In the 9 December 1999 issue of The New England Journal of Medicine, scientists reported that the first trial showed no difference in 16 measures of behavior between 27 autistic children injected with a single dose of secretin and 29 who received a placebo. Since then, four other trials also have found no difference. But Repligen hasn't given up, modifying NIH's methodology by not testing multiple doses. In July, Repligen researchers presented unpublished data at the Autism Society of America's annual meeting in San Diego. The company's phase II clinical trial showed a statistically significant improvement in some measures of social function in children receiving multiple doses of secretin compared to a placebo. Repligen plans to forge ahead with more trials. Ed Cook, who collaborated in one of the negative trials, isn't optimistic about secretin and doesn't think physicians should prescribe it for autism until it's been shown to work. 14. METEORITICAL SOCIETY # Ancient Sky Rocks and an Unblemished Eros 1. Richard A. Kerr The events of 11 September distracted but did not disrupt the annual meeting of the international Meteoritical Society, held that week in Rome at the Vatican's Pontifical Gregorian University. Attendees heard about an ancient asteroid shower being excavated in Sweden and the mysterious smoothness of the surface of asteroid Eros. ## Asteroid Shower Hit Ordovician Earth Nondescript blobs in limestone from a quarry in southern Sweden have turned out to be fossilized meteorites from what may be Earth's earliest known asteroid shower—a bombardment that took place half a billion years ago following a massive collision in the asteroid belt. The meteorites are “a significant discovery,” says meteoriticist Harry McSween of the University of Tennessee, Knoxville. “Earth must have been pelted by a lot of meteorites.” Over the past 10 years, workers at the quarry, near Kinnekulle have saved 40 of the fossilized meteorites for geochemist Birger Schmitz of the University of Göteborg. Authenticated by their chemical composition and mineralogical texture, the specimens range from 1 to 20 centimeters in diameter, Schmitz and Mario Tassinari of the Väner Museum in Lidköping, Sweden, reported at the meeting. The meteorites come from 12 distinct levels in the quarry, spanning 2 million years, Schmitz estimates. That means the quarry, which was once a shallow sea, could not have been simply the target of a single meteor that shattered on entering the atmosphere. From their abundance, Schmitz and Tassinari calculate that meteorites of this size—and presumably much larger—must have been hitting Earth 25 to 100 times more frequently 480 million years ago than they do today. Other evidence of the asteroid shower turned up when Schmitz and Tassinari analyzed chromium-rich mineral grains from the fossil meteorites. The minerals—about the only ones not altered during fossilization—show that all the finds fall in the low-iron or L subclass of chondrite meteorites. Today, most chondrites falling to Earth are either L or H (high-iron) types, in equal proportions. Studies of L-chondrite meteorites show that many suffered a tremendous shock at about the same time the Swedish meteorites fell to Earth. A plausible explanation, Schmitz says, is that a massive collision in the asteroid belt shattered the “parent body” that is the source of all L chondrites. Such a shattering would have created a “family” of asteroid fragments traveling in similar orbits. It would also have sent a surge of smaller debris toward Earth, computer simulations suggest, most recently and accurately by David Nesvorny and William Bottke of the Southwest Research Institute in Boulder, Colorado. The Swedish limestone seems to hold a tiny sampling of that surge, Schmitz says. The lack of H chondrites in the collection so far could simply reflect a low accumulation rate like today's. If the fossil meteorite story holds up, “a lot of pieces of the puzzle come together,” says Bottke. “It would be nice to have a second site where you see a high [accumulation] rate,” says cosmochemist Alan Hildebrand of the University of Calgary in Canada, “but it certainly seems like he has a good story.” A possible weak spot, many say, is Schmitz's rough estimate that the quarry's rocks formed over 2 million years. If the actual figure were 20 million years, the calculated flux of meteorites would look much like today's. But Schmitz counters that if the rocks formed over much more than 2 million years, fossil trilobites in them would show signs of having evolved, which they don't. In fact, the early Ordovician asteroid shower, which presumably included hefty kilometer-size bodies, does not appear to have tweaked evolution at all. Like a comet shower 35 million years ago (Science, 30 January 1998, p. 652)—and decidedly unlike the impact 65 million years ago that did in the dinosaurs—it had no obvious effect on life. Let's hope we are so lucky next time. ## Asteroid Protection Something is keeping Eros—and presumably other asteroids—remarkably smooth. Closeup pictures of Eros taken by the NEAR spacecraft startled planetary geologists: Small impact craters several meters in diameter and smaller were scarcer than anyone expected, by a factor of 1000. “This is very different from the moon,” says asteroid specialist Clark Chapman of the Southwest Research Institute in Boulder, Colorado; impact craters dominate the lunar landscape down to the scale of a footprint. Either something smoothed the surface after small craters formed on Eros, he told the meeting, or—his preferred explanation—the craters never formed at all. Whatever mechanism is responsible, notes Chapman, it has to be one that doesn't operate on the moon. One possibility is a large impact that jolts the whole asteroid, shaking down the loose surface “soil” like flour in a cup. But Chapman wonders if enough of a jolt could get through the fractured interior of Eros. Electrostatic charging of fine dust grains by the sun might levitate enough material to fill in low spots like craters, Chapman says, but the obvious examples of that are too few to explain the small-crater shortage. Or the abundance of boulders discovered by NEAR might provide a physical barrier, but it would be too porous to explain the dearth of craters. Chapman looks to the Yarkovsky effect as the most promising explanation. Recently revived to explain how meter-size rocks escape the asteroid belt (Science, 13 August 1999, p. 1002), the Yarkovsky effect is the push a small rock gets when its sun-bathed, hot “afternoon” quadrant rotates into the night side and radiates its heat away. That may nudge small rocks into the zones from which the gravity of Mars or Jupiter can send them out of the belt. If the Yarkovsky effect sweeps out enough small debris, Eros might escape at least the smaller insults visited upon the moon. “That's the qualitative idea,” says Chapman. Quantitative modeling is needed now. “We need all the help we can get,” he says. 15. HUNGARY # Money and Political Muscle Help Scientist Turn the Tide 1. John Pickrell* 1. John Pickrell writes from Hertfordshire, U.K. Trained as an atomic physicist, Jozsef Pálinkás is now at the center of an explosion of support for science in Hungary HERTFORDSHIRE, U.K.—Start with a new grants program to forge closer ties between state labs and industry. Add hefty raises for faculty members. Blend in a conviction that science is the engine of economic development, and the result is a hearty meal for Hungarian science served up by a former experimental physicist-turned-politician. Jozsef Pálinkás says he's “still a scientist at heart.” But fortunately for his colleagues, the 49-year-old Pálinkás is also minister for education and chief architect of a 2-year, 61% increase, to$360 million by the end of 2002, in the Hungarian science budget. Pálinkás has benefited from a strong economy and a belated realization that the former Soviet state had let its research enterprise atrophy. But science leaders say his doggedness and political savvy have helped carry the day. “Pálinkás has brought a new way of thinking to the ministry,” says Péter Csermely, a biochemist at Semmelweis University in Budapest and chief scientist at Biorex R&D Co.

After years of economic depression, things are looking up for Hungary and its 14,500 scientists. The country's rate of economic growth—currently 5% a year—puts it near the top among Eastern European nations, and it is a strong contender for future membership in the European Union. By raising its investment in science to 0.7% of gross domestic product, Hungary hopes to climb past the Czech Republic as the R&D leader in the region.

Pálinkás was trained at home, but he headed West in the early 1980s to escape a restrictive but well-supported system modeled on the Soviet Union. He did a postdoc in the nuclear physics group at Texas A&M University, using a particle accelerator to study the effects of collisions on atomic electron shells. Later he was a visiting professor at the Manne Siegbahn Laboratory in Stockholm and at CERN, the European particle physics laboratory near Geneva. But he has spent the bulk of his career at the Institute of Nuclear Research in Debrecen, which he joined in 1977 and later directed for 6 years before becoming state secretary for education in 1998.

That appointment stemmed in part from his political activism, which grew apace with his role as a respected scientist. Although he never ran for elective office, “I was outspoken and prepared to make my opinions known,” he notes. “Pálinkás possessed a special property to influence [officials] even when he had no position,” says Zsolt Bor, who heads the department of optics and quantum electronics at the University of Szeged.

Pálinkás is no longer influencing politics from the outside. He sits on the new Science and Technology Policy Council, a ministerial-level body, and chairs its Science Advisory Board, a group of leading scientists that drew up a blueprint for Hungarian science. One key plank is the idea that applied science will pay long-term dividends to the economy and the standard of living.

The centerpiece of the new effort is the National Research and Development Program, which will award $58 million over 2 years. The competitive grants will go to state scientists and industrial companies working together in five areas—quality of life, information technology, environment and materials, agrobusiness and biotechnology, and national heritage and social science. In biotechnology, for example, Pálinkás says, “we want to cover the entire innovation chain, from finding basic molecules with potential to the manufacture of new drugs.” As an additional incentive, the program allows high-tech companies to write off 200% of R&D costs against taxes. The approach has drawn raves from the multinationals. István Fodor, head of the Hungarian branch of Ericsson, the Swedish telecommunications giant, cites the “positive influence … of the extremely favorable tax allowance” in attracting foreign investment. Pálinkás wants to attract people as well. He believes that low pay has driven away many talented scientists and discouraged students from pursuing scientific careers, so he is using part of the budget increase to boost professors' salaries from$605 to $940 a month by the end of 2002. The ministry has also introduced a salary structure for academic scientists that sets standard pay rates. “Our salaries are now competitive [with other state sectors in Hungary],” he boasts. Although scientists applaud these efforts, some feel they don't go far enough. Education ministry officials estimate that more than 10% of the country's researchers may have been lost—mainly to the United States—in the past decade. “Unfortunately, a clear-cut initiative to bring back the young and talented Hungarian researchers staying in the U.S. is still missing,” says Csermely. The ministry's István Szemenyei doesn't disagree, but explains that “our first priority was to stop the [brain drain].” Increased funding, he adds, should make Hungary more attractive to young émigrés. Neighboring ex-Soviet states are looking with envy at what Pálinkás has achieved. Josef Syka, president of the Grant Agency of the Czech Republic, which provides competitive research grants, says that Pálinkás is “energetic and knowledgeable” and that he is “particularly impressed” by the large funding increases. But Pálinkás says his job is far from over. He hopes to streamline the country's current system of higher education before the current government leaves office, reducing the number of institutions and bringing their policies, curricula, and degrees in line with those in the West. He'd also like to persuade students that attractive scientific careers exist in “areas where the job market is on the rise.” Ticking off the many Nobel laureates of Hungarian birth, Pálinkás predicts that the reforms should eventually rebuild the country's shattered scientific reputation. “Science has had a rough time,” he says, “but we are on the right track now.” 16. PALEONTOLOGY # Utah's Fossil Trove Beckons, and Tests, Researchers 1. Erik Stokstad At Grand Staircase-Escalante National Monument, patience and muscle power pay off in paleontological riches GRAND STAIRCASE-ESCALANTE NATIONAL MONUMENT, UTAH—Alan Titus parks his four-wheel-drive field vehicle on a dirt road that cuts across a remote plateau here, hops out, and strides into a scrubby forest. Just minutes later, the Bureau of Land Management (BLM) paleontologist spots fragments of bone under a juniper tree and crouches to investigate. Quickly brushing away the surrounding shale, he identifies it as the broken end of a femur, probably from a duck-billed dinosaur. There are few better places in North America to scout for dinosaurs and other large Mesozoic vertebrates. All over the plateau pieces of bone litter the surface. The badlands are so rich that Titus sometimes scouts for fossils with binoculars, searching the hills for piles of orange-stained bone. “This place has enough fossils to keep an army of paleontologists happy for the rest of their careers,” he says. Yet most of the plateau has never been thoroughly prospected by paleontologists. That's about to change. Three teams of vertebrate paleontologists have started to survey the fossil diversity of parts of the monument. Despite frustrations with a lengthy permitting process and restricted access to field sites, they're finding relatively complete skeletons of new horned dinosaurs and other creatures. Graduate students are already working in the area, and Yale University is planning to set up a research program. “It's a high,” says Dave Gillette of the Museum of Northern Arizona in Flagstaff, one of the team leaders. “Everything we've touched has turned to gold.” The monument was created in 1996 with its vast trove of fossils in mind. The 760,000 hectares boast what could be the world's best record of Late Cretaceous terrestrial life—creatures that lived during most of the 20 million to 30 million years before the demise of the dinosaurs. And because the region is so remote, few large skeletons have been excavated. “I consider this to be the promised land of vertebrate paleontology in the U.S.,” says Scott Sampson of the Utah Museum of Natural History in Salt Lake City, who heads another of the survey teams. ## Revolutionary rocks Rocks in the monument date back to the middle Permian period, about 280 million years ago, but most of the excitement centers on the unique terrestrial record of the Late Cretaceous period. During this period, a doomed group of rodentlike mammals called the multituberculates was wildly diversifying, as were marsupials. At the same time, new types of dinosaurs—hadrosaurs, ceratopsians, and tyrannosaurs—were rising to prominence. “We see a whole revolution going on; the biota is changing dramatically,” says Richard Cifelli, a paleontologist at the University of Oklahoma, Norman. The revolution was absent from most parts of North America, which were covered by seas. But the monument belonged to land that stretched from Mexico to Canada. Because the climate was humid, sediment from mountains near the Utah-Nevada border was washed into lowlands, preserving the remains of plants and animals. The narrow continent was covered with thick stacks of these sediments; in the monument, they are an impressive 2000 meters thick. Elsewhere in the Western United States, the terrestrial rocks either are still buried by younger sediments or have been eroded away. In the monument, however, a large-scale gentle fold called a monocline has left more than 5000 square kilometers of fossil-rich Late Cretaceous rocks exposed. Not much work has been done on the large fossils. Partly that's because the area is so rugged and remote; the Escalante River, for example, was the last major river to be discovered in the continental United States, around 1872. Vertebrate paleontologists have focused on other fossil-rich areas, such as the badlands of South Dakota and Montana. It wasn't clear how many fossils, if any, were in this part of Utah. In fact, Herbert Gregory of the U.S. Geological Survey, who published the first geological map of the area in 1931, declared it practically devoid of fossils. “There's this myth that it's barren,” Titus says. The myth first began to fade, for a few paleontologists, in the 1980s. Screen-washing of sediment revealed sites that produced tens of thousands of tiny teeth and other so-called vertebrate microfossils, including many fish, crocodiles, frogs, and lizards. “The exposures are obscene. They drip with fossils,” says Jeff Eaton of Weber State University in Ogden, Utah. He started working in the area that is now the monument in 1982 and 9 years later bought a house nearby to be able to spend more time in the field. “I knew I would spend the rest of my life here,” Eaton says. “And I've barely scratched it.” This early work—much of it done with Cifelli—established the ages of the rocks, an important step because there are no volcanic ash beds for geologists to date. Fossils from the area also pushed back the marsupial record by 10 million years and helped reveal the geographic distribution of early mammals across North America. Big beasts are there, too. After President Bill Clinton created the national monument in 1996, the BLM commissioned a survey of the fossil resources, including the larger bones that Eaton and his colleagues hadn't focused on. The final report, published this year by the Utah Geological Survey, lists more than 800 localities with fossils—a number that Gillette estimates is just 1% of the potential. Evidence from teeth and scraps of bone suggests that skeletons of as many as 50 genera of dinosaurs may be waiting to be found. Dinosaur paleontology at the site is now getting in gear. The BLM plans to spend about$200,000 a year on paleontology there—about 20% of the monument's science budget. The money is supporting three teams on 5-year contracts to survey the fossil resources, plus a few additional excavations. Dinosaur workers say the monument fills in a geographic gap for Late Cretaceous dinosaurs, which are well known from rocks north to Alaska and south to Mexico. Because dinosaurs are believed to have migrated less than was previously thought, Sampson says, southern Utah may reveal unique facts about their ranges, ecologies, and evolutionary relationships.

Already there are finds, although none of the discoveries has been published yet. So far, the cast of characters includes the back half of a hadrosaur with skin impressions and an articulated tail, found by Titus in 1998. Working last summer in rocks the same age just outside the monument, Gillette and his colleague Barry Albright excavated a 75% complete therizinosaur, a strange plant-eating dinosaur—one of only two such specimens discovered outside Asia. The team also dug up two marine reptiles called pliosaurs, including the most complete specimen known from Utah. A team led by Sampson has found a hadrosaur of its own, plus armor from a new giant crocodilian and what appears to be a new genus of horned dinosaur. To top it off, just last month they discovered remains of what could be a new species of tyrannosaur. The skull of another new ceratopsid genus was found in 1998 by a crew working for the Utah Geological Survey.

## Obstacle course

The work poses special challenges—the first of which is getting permission. Each application for an excavation permit has to be reviewed by a BLM archaeologist and botanist and by other specialists to make sure no other resources are threatened by the dig. That takes 3 to 6 months on average. “Some people may be discouraged by the hoops and hurdles you have to go through to get a permit,” says Sid Ash, a paleobotanist affiliated with the University of New Mexico in Albuquerque. The wait can complicate grant writing, Gillette notes, as some funders require a permit with an application. “It's a big balancing act,” he says.

An even bigger problem is access to fossil sites. About half of the monument is wilderness study area—land that Congress may declare wilderness. Combined with other BLM restrictions, the designation puts more than 65% of the monument off limits to motor vehicles, including half of the existing roads. “We do not make exceptions lightly,” says monument manager Kate Cannon. One of the few was the excavation of the hadrosaur tail, for which Gillette and other researchers were allowed two trips to drive along a closed road to carry tools in and remove the bones.

Eaton says that almost all of the hundreds of sites he's worked are now inaccessible by vehicles—which are needed to remove heavy samples of sediment. “I'd like other people to test my findings,” he says. “That's difficult when they can't get to the site.” For his own research, Eaton has had to pack out a 1500-kilogram sample of rock in 20-kg bags loaded into a frame backpack.

Members of the Utah team also had to resort to muscle power last year while digging up their ceratopsian skull. To haul it away, they put each of three 360-kg blocks of sandstone on an old car hood and spent 5 days dragging them half a kilometer to a dirt road. “It was comic,” says Utah's state paleontologist, Jim Kirkland. “If we'd driven in, we could have swept out the tracks.”

Despite the hurdles, Kirkland and others are glad to be working in the monument. “It really is going to explode in the next few years,” Sampson says. “I plan on working there the rest of my career.” Others clearly feel the same way about the possibilities. This summer, a crew from Yale University examined some of the monument's Triassic rocks—strata from the early days of the dinosaurs—to beef up their collections and begin a field program for up to a dozen graduate students. Titus has high hopes for all the researchers: “It boggles my mind to think of what they'll find when they really get going.”

17. # So Many Choices, So Little Money

1. Elizabeth Pennisi*
1. With reporting by Evelyn Strauss, Michael Balter, Robert Koenig, and Dennis Normile.

With the human genome almost finished, leaders of the project are trying to decide where next to focus their energies. They're debating a plethora of options, from more sequencing to proteomics—some of which could break the bank

Just months after they pulled off one of the greatest feats in biology—deciphering the human genome—the leaders of that international effort find themselves in a quandary: What to do next?

When biologists mounted a megaproject to sequence the human genome a dozen or so years ago, the goal was clear, even if how to reach it was not. As James Watson of Cold Spring Harbor Laboratory in New York state, who led the U.S. Human Genome Project (HGP) in its early days, put it, that goal was to find out what makes us human. The effort promised to transform 21st century biology, opening up avenues of research previously impenetrable. The allure was undeniable, and the public—and Congress with its deep pockets—embraced the idea.

But now that most of the 3 billion bases in our 24 chromosomes are in order, the goal is considerably more amorphous—and harder to sell. Should the huge centers created for the task now go on to sequence the genomes of other organisms? Devote themselves to discerning the functions of the estimated 45,000 genes? Plunge into a “Proteome Project” that would identify and characterize all proteins? Develop new technologies to speed analysis? Or, when the researchers finish the genome, should they pack up their bags and go home, bequeathing their fantastic new tool—the sequence—to the biological community?

Packing up their bags is not an option. A massive infrastructure is already in place. The National Institutes of Health (NIH), for instance, created a new institute specifically for the job, funded to the tune of $1.4 billion over the past 10 years. The Wellcome Trust, a British biomedical charity, put up more than$300 million just for the HGP, and numerous other countries contributed in kind, helping make it the biggest biology project ever. Equally compelling, with the genome sequence almost in hand, a wealth of scientific questions are waiting to be answered. But no one is quite sure about the best way to tackle them.

“I can tell you what we plan for the next couple of years. But further out, it is more difficult to predict,” says Michael Morgan of the Wellcome Trust. “A lot of the ideas are out there, and a lot of people are discussing them in a lot of different venues,” says Gerald Rubin, science director of the Howard Hughes Medical Institute in Bethesda, Maryland.

And, for the most part, leaders of the public project are continuing to think big. Indeed, a number of the proposed projects—such as analyzing hundreds, even thousands, of genes, proteins, or protein interactions at once—potentially rival and perhaps even surpass the HGP in scope. And although big-ticket pilot projects have been started, none has the immediacy or finiteness of sequencing the human genome. “There's a big issue of how we continue to capture the public's imagination,” concedes William Gelbart, a developmental geneticist at Harvard University. If the public loses interest, Gelbart and other academic biologists fear, too much of the work will take place behind the closed doors of industry.

## Job one: Sequence

Everyone agrees that the first job for the international HGP is to finish at least one vertebrate genome—preferably the human genome. The goal is to complete this task by 2003.

Also high on the list is the sequencing of other genomes. Comparing those new genomes to the human genome will help researchers pinpoint hard-to-find genes and DNA regulatory regions and reveal secrets of evolutionary history. For that reason, “large-scale sequencing will continue to be a major activity for the next five, if not 10, years,” says Francis Collins, director of the National Human Genome Research Institute (NHGRI), which funds a large portion of the U.S. share of the HGP.

The mouse, rat, zebrafish, and puffer fish genomes are already under way, although none is near completion. The mouse should be sequenced in great detail by 2005 at the latest. For the others, the research community and the funding agencies are debating how thoroughly to sequence them. Will two or three passes over the genome do? Or is more in-depth coverage needed to make sense of the sequence and render it reliable?

The Sanger Centre in Hinxton, U.K., plans to expand its sequencing efforts beyond the human, mouse, zebrafish, and microbes that it's working on now. At the 10th International Strategy Meeting on Human Genome Sequencing in Hangzhou, China, in September, Chinese and European researchers agreed that they should set up a joint project to sequence the chicken genome (Science, 7 September, p. 1745), with the Sanger Centre possibly taking a lead role. China and other European collaborators have begun work on the pig genome, while Japanese and German collaborators are pushing forward on the chimp. “Having a zoo of genomes is going to make a tremendous difference,” says David Haussler, a computer scientist at the University of California, Santa Cruz.

Moving beyond the half-dozen organisms already in the pipeline, other researchers are clamoring to have their favorite sequenced. Setting priorities will be key, says Collins, because sequencing funds and capacity cannot accommodate too many more species unless sequencing costs decrease substantially. At a July workshop, NHGRI-invited experts set ground rules for selection in the United States, at least. Advocates of deciphering, say, the cow genome will need to submit a description of the size of its genome, the organism's place on the evolutionary tree, the ease of performing genetic analyses on it, the size of the community that studies it, and the ways the sequence will aid the interpretation of the human genome.

## Gold-standard genes

In terms of mining the human genome, the top priority is to get “the gold-standard set of human genes,” says Haussler, a sentiment shared by both academic and corporate scientists. A number of companies, such as Invitrogen in Carlsbad, California, and several publicly funded groups have projects well under way. But a straightforward task—particularly if there are less than 45,000 genes as predicted—it is not. Already researchers have realized that the one gene-one protein dogma is wrong—and that one gene, by having different combinations of its coding regions converted into what is called an expressed transcript, might specify several proteins. This process of generating multiple transcripts is called alternative splicing.

“There's a huge amount of work that needs to be done to understand the full complement of expressed transcripts,” Haussler notes. “It will be tremendously difficult.” The first iteration of the gold-standard set of genes will likely contain just the straightforward sequences, or transcripts, from those 40,000-plus genes, with the alternatively spliced transcripts coming much later. Researchers in Japan, Germany, and the United States have independently begun defining the genes, by generating what are called full-length complementary DNAs (cDNAs) that represent the transcript sequence.

Since 1999, NIH has put $25 million into the Mammalian Gene Collection. In this effort, researchers first define the sequence of the cDNA and then warehouse each in bacterial clones for use by researchers. As of September, the collection contained 19,000 putative and 6700 confirmed human cDNAs. Japanese scientists are well along in generating both mouse and human cDNAs. They started in the mid-1990s developing efficient ways to produce these cDNAs, and by last year they had produced a comprehensive collection of 20,000 mouse cDNAs that are now available to the public. More recently, they have applied that expertise to human genes (see sidebar). Germany is investing$5 million a year in a European cDNA effort, headquartered at the German Cancer Research Center in Heidelberg. With that money, says group leader Stefan Wiemann, the team will not only generate cDNAs but also pinpoint where the proteins specified by those cDNAs work in the cell. The German project has placed data for several thousand putative cDNAs on the Web.

These groups are now discussing whether they can merge their efforts to get the job done faster, because many cDNAs remain to be discovered. The sticking point, at the moment, is how quickly their work will become available to the broader scientific community—and in what form. “We've had several meetings on coordination issues,” notes Wiemann.

Wiemann hopes that his group will get some of the $175 million that Germany committed in March in an effort to boost Germany's profile in genomics. But that is not guaranteed. And whereas Collins says the Mammalian Gene Collection is a “meat-and-potatoes endeavor” that will continue, others worry that it could lose out to costly, glitzier projects. “We need to make the commitment to [finishing] this or we won't have this [essential] gene set,” Haussler insists. Without it, adds Robert Strausberg, director of the Cancer Genomics Office at the National Cancer Institute, studies to determine the function of these genes will be undermined: “For the world of genes and proteins, [the collection] is a platform for going forward in proteomics and functional genomics.” NHGRI and the Wellcome Trust are talking about collaborating on another project—this one to take the next step in studying genetic variation. Even before a draft human genome sequence was finished, a public-private partnership called the SNP Consortium began cataloging single-base differences, called single-nucleotide polymorphisms (SNPs), that pepper the genome. These simple variations, in which one person has a different base at a particular location than someone else has, can help researchers pinpoint particular genes and variations involved in disease. Yet even with 3 million SNPs in the public databases, geneticists have had difficulty using them effectively (Science, 27 July, p. 593). Earlier this year, several groups found that particular sets of SNPs tend to occur in blocks along the genome. By mapping these blocks, or haplotypes, researchers now think they can simplify their searches for genetic defects (Science, 27 July, p. 583). “We not only want to know the SNPs individually, but we want to know their neighborhoods [in the genome],” explains NHGRI's Collins. Although building a haplotype map could cost$100 million over the next several years, enthusiasm is mounting.

## Technology development

But other projects with high price tags may be slower to gain momentum, in part because public purses aren't large enough to fund them all, at least at their current costs. Researchers are eager to pursue three broad areas: functional genomics, proteomics, and bioinformatics. Functional genomics aims to understand how genes are regulated and what they do, largely through massive parallel studies of gene expression over time and in a variety of tissues. Proteomics promises to make the identity, function, and structure of each protein known and to elucidate protein-protein interactions. New developments in bioinformatics would enhance the ability of researchers to manipulate, collect, and analyze data more quickly and in new ways. Experts predict that more biologists will do their work in silico, using the computer to synthesize, analyze, and interpret the many terabytes of data now being generated.

None of this comes cheap, however, and in some instances the experiments are not yet possible. “The whole area of proteomics is in a muddle,” Collins points out, noting that the goals and even definition of proteomics are unclear. Collins worries that proteomics and the databases and bioinformatics it requires could become “the part of the budget that eats the rest.” And although many researchers are incorporating microarrays and DNA chips into efforts to learn when and where genes are turned on, for instance, they lack the more sophisticated, automated approaches needed to study all the proteins those genes encode. “We don't know how to make the measurements [of function and interactions] that are really critical in a high-throughput manner,” notes Leroy Hood, director of the Institute for Systems Biology in Seattle.

Until researchers do, embarking on massive endeavors, say, to describe all protein-protein interactions or to characterize the many ways in which a gene can be expressed—so-called alternative splicing—might be foolish. “I think technology development is going to be a key part of the future,” Hood says, echoing the arguments he made at the outset of the HGP, when he pushed for faster and cheaper sequencing technology.

The sequencing technology that emerged from the HGP, says Harvard genome researcher George Church, is as important as the sequence itself. He thinks technology development should be a big part of new grants, because that could lead to reduced costs, not only for sequencing but also for efforts in proteomics and functional genomics: “The cost determines what questions you ask.” Both Hood and Church are particularly interested, for example, in technology that can monitor and pinpoint multiple protein-protein and protein-gene interactions in living cells. They are looking to NHGRI, as well as other NIH institutes and the Department of Energy (DOE), to help stimulate these pursuits. Nascent strategic plans at NHGRI will likely reflect the importance of technology, says Collins.

Another technology that needs an infusion of funds is scientific computing, says Gene Myers, a bioinformatics expert at Celera Genomics in Rockville, Maryland. “This area is now pushing the envelope of what we are able to do,” says Myers. The problem, he says, is not so much computer power but the lack of efficient methods to move large amounts of information around. Genome data can fill thousands of CD-ROMs, and no one knows how to send that much data from one computer to another quickly, or even how to move it around within a single machine, he says. New algorithms for interpreting and analyzing these data are also needed, he and others say, as are ways to visualize and present genomic information to researchers. “The sequence is not in a state where someone like me, a geneticist, can manipulate it,” says Mary-Claire King of the University of Washington, Seattle.

DOE is primed to take the lead in scientific computing for biologists. As part of its Genomes to Life program, slated to start in fiscal year (FY) 2002, DOE biologists will team up with their colleagues in advanced scientific computing to build a computational infrastructure combining hardware and software development. With this infrastructure in hand, DOE plans to explore regulatory networks, determine how protein complexes—life's molecular machines—operate, and assess the function of microbial communities.

“Computation is central to what we do, and this is a strength we have at DOE,” says Ari Patrinos, who directs biological and environmental research at the agency. Overall, he expects to have $20 million in FY 2002, which will help support “fairly large teams of people working on complex problems.” Even though DOE wants to put large teams to work on these problems, not all genome research and technology development needs to be done that way. “We may not need big science,” says Church, who argues that postsequencing goals might be better met with “many labs in which there would be more diversity of machines and more clever engineering—some of which could drive costs down.” So, while NHGRI, the Sanger Centre, and funding agencies across the globe are debating what the next focus should be, they are also trying to assess the right mix of “mega” and little science. In the United States, NHGRI will devote the next year to polling biologists from many fields about these questions. The answers it comes up with could shape genomics for decades to come, not just in the United States but around the world. 18. # Japan and China Gear Up for 'Postgenome' Research 1. Dennis Normile, 2. Yang Jianxiang* 1. Yang Jianxiang writes for China Features. TOKYO AND BEIJING—When the human genome project was first conceived in the late 1980s, Japan hoped to play a major role. Funding, however, proved elusive. So although Japanese teams did decipher a good chunk of chromosomes 21 and 22, the country contributed just 6% to the draft sequence published last February. China managed even less. But now, as the focus moves beyond human sequencing, neither country will be content with a bit part. “There is a feeling [among policy-makers] that Japan was left behind in sequencing, and the country wants to be better prepared for the next stage of genomic research,” says Akiyoshi Wada, director of the Genomic Sciences Center of the Institute of Physical and Chemical Research (RIKEN) in Yokohama. It will be, if Japan's Ministry of Education, Culture, Sports, Science, and Technology wins approval for an ambitious bundle of “postgenome” projects (see table). With a total proposed budget of$570 million for the fiscal year that begins next April, it would be considerably more than the U.S. National Human Genome Research Institute expects to spend.

As elsewhere, debates have been intense over which aspects of genomic work should get priority (see main text). As a compromise, there is something in the proposal for just about everyone, although proteomics, with its expected payoffs in drug development, is getting the lion's share through the Protein 3000 Project. The goal of this project is to determine the structure and function of 3000 proteins over the next 5 years. That will be a challenge, acknowledges Kunio Miki, a protein crystallographer at Kyoto University—but he says it is probably doable “if anticipated advances in technology are actually realized, particularly in automating the time-consuming processes of sample preparation.”

The work will be done at up to seven new protein structure centers to be created at universities and at RIKEN's new center for nuclear magnetic resonance (NMR) imaging, a key technique for determining protein structures. Japan also has the world's most powerful synchrotron radiation facility for x-ray crystallography: SPring-8, located near Kobe. This facility will be used to handle the larger, more complex proteins that can't be resolved with NMR.

Shigeyuki Yokoyama, who heads RIKEN's protein research group, says that the 3000 proteins will be Japan's share of an emerging international effort, involving at least 11 countries, that aims to determine 10,000 protein structures over the next 5 to 10 years. Yokoyama, who is on the organizing committee, explains that the 10,000 proteins are a first step toward resolving the structure of at least one representative protein from the estimated 15,000 to 20,000 protein structure families. “We believe that once you have the structure of one protein in a family, you will be able to model the others,” he says.

The International Structural Genome Organization, as it will probably be called, will likely be officially launched late this year or early next. The group's first scientific meeting is scheduled for October 2002 in Berlin. Yokoyama says the group hesitates to put a price tag on the project because current costs—about $80,000 per structure—make it unreasonably expensive. “We need to improve the success rate and make the whole process more efficient,” he says. Japan's new centers should have plenty of proteins to analyze, thanks to several Japanese efforts to accumulate libraries of complementary DNAs (cDNAs). These are synthesized strands of DNA containing only the transcript sequence that codes for proteins. Next spring, when a RIKEN group led by Yoshihide Hayashizaki finishes a 3-year,$45 million project, data and clones of more than 80,000 mouse cDNAs will be available, one of the largest such collections for any organism. Other groups are working on human cDNA libraries and the plant model organism Arabidopsis thaliana. The cDNAs themselves will also be used in microarrays for profiling gene expression patterns.

After a late start on genomics, China rallied and recently announced its 1% contribution to human sequencing and is forging collaborations to sequence the genomes of the pig and chicken. China is also contributing to an international rice sequencing effort while tackling two other rice varieties on its own.

Although work is currently focused on mapping and sequencing, Chinese scientists anticipate moving beyond, perhaps “to focus on identifying genes, compare the pig genome with the human genome, and find pig models for human diseases,” says Merete Fredholm of the Royal Veterinary and Agricultural University in Copenhagen, Denmark, which is collaborating with the Beijing Genomics Institute (BGI) in the Sino-Danish Pig Genome Sequencing Project.

In addition to the purely scientific benefits, the collaborations are strengthening ties among research institutes in China, the United States, and Europe. The latest tie is a new sister center relationship between BGI of the Chinese Academy of Sciences and the Whitehead Institute Center for Genome Research at the Massachusetts Institute of Technology. The two institutes expect to exchange researchers and collaborate on developing technologies. Eight BGI computer specialists were to have traveled to Whitehead in September to explore joint software development; the trip was postponed when flights were halted because of the recent terrorist attacks in the United States.