# News this Week

Science  10 Aug 2007:
Vol. 317, Issue 5839, pp. 732
1. BIOSECURITY

# U.K. Labs Suspected as Source of Foot-and-Mouth Outbreak

1. Martin Enserink*
1. With reporting by John Travis and Jocelyn Kaiser.

In what could prove an eerie replay of a 1960 incident, U.K. officials and scientists this week were investigating what looks like an accidental but potentially highly embarrassing release of foot-and-mouth disease (FMD) in the county of Surrey. Tests had indicated that the virus—which by Tuesday had hit two farms—belonged to a strain that has not recently circulated in animals but is present at the Institute for Animal Health (IAH) in Pirbright, close to the affected farms, and at Merial, a vaccine company housed on the same premises.

Officials at IAH and Merial have said they are unaware of any safety breaches, but biohazard teams quickly visited both labs to look for signs of a viral escape, and scientists were further analyzing the outbreak's strain to shed more light on its origins. A government report released Tuesday night as Science went to press concluded that “there is a strong probability that the FMDV strain involved in the farm outbreak originated from the IAH or the Merial sites.” Scientists were already expressing concern that the episode could undermine public support for high-containment labs, especially a new one planned in the United States.

In the U.K., this week's images of cordoned-off farms and culling teams revived memories of the catastrophic FMD outbreak of 2001. During that episode, the government ordered the destruction of some 6 million sheep, cattle, and pigs to stamp out the disease, which also spread to the Netherlands, Ireland, and France. This time, the government response has been much swifter, and the virus may be thwarted before more than a handful of farms are affected, says Neil Ferguson of Imperial College London, one of several scientists who helped guide policy in 2001 by building models of the virus's spread. Ferguson and other modelers have been enlisted again, but with only two farms affected, “there's not a whole lot of modeling we can do,” he says.

Even if major losses to U.K. agriculture and tourism can be averted—the European Union has already imposed a ban on U.K. meat exports—the limited data so far suggest that a biosafety breach occurred. On Saturday, the U.K.'s Department for Environment, Food and Rural Affairs announced that tests at IAH had shown the virus to be very close to a strain called 01 BFS67, which was isolated in Great Britain in 1967. Merial, a joint venture between Merck and Sanofi-Aventis, grows that strain to create vaccines, primarily for countries outside the European Union. IAH also has that strain for research and diagnostic purposes; as the global FMD reference center, it maintains a large collection of strains.

Several groups are investigating the outbreak, including an independent panel led by Imperial College molecular epidemiologist Brian Spratt; researchers familiar with the effort say Spratt's panel is awaiting the full genome sequence of the virus found on the farms. Comparing that to strains at IAH and Merial should help pinpoint the culprit, says Martin Hugh-Jones of Louisiana State University in Baton Rouge. But Ferguson says if both labs happened to have the exact same strain and if there aren't other signs of biosafety problems—such as virus outside high-containment areas—” we may never find the smoking gun.”

Pirbright has been the source of an FMD outbreak before. In January 1960, animals at a single farm close to what was then called the Animal Virus Research Institute became infected with a South African strain of the virus, “which had apparently escaped through the Institute's ventilation system,” according to a 1969 report on FMD by a panel of experts. Improvements in containment technology and procedures were supposed to make such accidents a thing of the past, however. At the safety level required for FMD work, labs operate under negative pressure so that air flows in, not out, through any leaks. All outgoing air is filtered twice, wastewater is sterilized, and garbage incinerated. Workers must shower and scrub before going home.

A 2001 review did raise questions about the state of facilities at IAH, however. Although the review didn't specifically warn about safety, it did conclude that “some of the laboratories and other areas of the Pirbright estate are not close to the standard expected of a modern biomedical facility.” The report helped pave the way for an expansive building project that started in 2003; construction of a new high-containment lab is still under way, an IAH spokesperson says.

On Monday, U.K. Chief Veterinary Officer Debby Reynolds said that the recent floods may have carried the virus to the farm after it was released through a drain. Even that scenario would still imply a technical or human error, however, and some infectious-disease researchers worry that the incident will cause public distrust. In the United States, for instance, the FMD outbreak could trigger worries among the five communities that may host the new National Bio and Agro-Defense Facility, which will also be home to FMD work. “It's obviously a concern. It's a situation we're going to monitor very closely,” says David Lee, vice president for research at the University of Georgia, Athens, one of the five sites being considered.

2. HUMAN EVOLUTION

# New Fossils Challenge Line of Descent in Human Family Tree

1. Ann Gibbons

Ever since the famous fossil hunter Louis Leakey found a skull of Homo habilis in Olduvai, Tanzania, in 1960, researchers have thought that this 2-million-year-old hominid was the first member of our own genus, Homo. This “handyman's” relatively big brain and association with flake tools eventually convinced many paleoanthropologists that H. habilis gave rise to H. erectus between 2 million and 1.6 million years ago, in a neat line of descent that led to modern humans.

Now, this gradual succession that dominated textbooks for decades is being challenged by none other than Leakey's daughter-in-law and granddaughter, Meave and Louise Leakey. This week in Nature, the Leakeys and their international collaborators describe the discovery of a surprisingly recent upper jawbone of H. habilis in Kenya that persisted until 1.44 million years ago. The team also found an older skull of H. erectus in the same region, which, taken together with earlier discoveries of this species, extends the time that the two types of humans lived in the same Lake Turkana basin to half a million years. “Their coexistence makes it unlikely that H. erectus evolved from H. habilis,” says paleontologist Meave Leakey, an associate of the National Museums of Kenya in Nairobi.

Some other researchers agree. “Half a million years suggests that we are dealing with two lineages, not one with a bit of overlap,” says paleoanthropologist Bernard Wood of George Washington University in Washington, D.C. But others question the identification of the jawbone as H. habilis, given that it depends on three worn teeth. When it comes to possible ancestors, “Homo habilis is all we've got,” says paleoanthropologist Philip Rightmire of Harvard University. “I don't see any compelling reason to reject this species as the antecedent to Homo erectus.”

H. habilis arose during a time, 2 million to 3 million years ago, when there is a gap in the fossil record. As a result, no one knows where it came from or how it is related to the smaller-brained, more apelike australopithecines such as the fossil Lucy, whose species Australopithecus afarensis lived 3 million to 3.6 million years ago.

H. erectus appeared about 1.8 million years ago in Africa and Asia, in both places with a larger brain and other more modern features. The lineage of H. habilis to H. erectus had seemed straightforward, even though earlier discoveries showed overlap between them. But the new discoveries on the east side of Lake Turkana in Kenya suggest the two coexisted for so long that they must have adapted to different niches, says Leakey. If so, the team concludes, it's unlikely that H. habilis gave rise to H. erectus. “The unilineal picture, where you start with this smaller, more primitive thing and it gradually gets bigger brains, bodies, and limb proportions—that really doesn't work,” says co-author Susan Antón of New York University.

A more likely scenario, Leakey says, is that both species arose from another, yet-to-be-identified ancestor. Several other fossils have been proposed as candidates for that role, but so far the evidence is “not satisfactory” to nail down a connection, says paleoanthropologist William Kimbel of Arizona State University in Tempe.

But Rightmire defends an early “habilis-like creature” as the most likely ancestor of early H. erectus. Fossils of early H. erectus that date to 1.7 million years from Dmanisi, Georgia, show affinities with H. habilis and lack some traits that appeared later in H. erectus in Africa, suggesting that H. erectus arose from one group of H. habilis in Asia and later migrated to Africa, Rightmire says (Science, 5 July 2002, p. 26).

Meanwhile, the new skull of H. erectus from the Ileret area east of Lake Turkana is revealing that this ancestor came in many sizes. “What is truly striking about this fossil is its size,” says co-lead author Fred Spoor, a paleontologist at University College London. With a cranial capacity of just 691 cubic centimeters, it is the smallest H. erectus ever found and is almost as small as some skulls of H. habilis. Yet it is not primitive or transitional from H. habilis: The new skull dates to 1.55 million years ago, which “nicely shows that there were big H. erectus and little ones for a long time,” says Antón. Because the worldwide variation is greater than that between living male and female humans or chimpanzees but less than that between male and female gorillas, some researchers suspect that male H. erectus might have been significantly larger than female H. erectus.

The skull also shows features that had previously been seen only in Asian fossils of H. erectus, such as a keeling (or ridge) on its frontal and parietal bones. These traits had persuaded a growing number of researchers in recent years to split the fossils of H. erectus into two species, with H. erectus from Asia and H. ergaster from Africa. But the skull's mix of traits shows H. erectus cannot be “easily divided between two species from Africa and Asia,” says Spoor. Kimbel and Arizona State graduate student Claire Terhune reached a similar conclusion after studying the temporal bones of 15 H. erectus skulls, in a paper published in the July issue of the Journal of Human Evolution.

Others who have championed H. ergaster are taking note. “The new cranium blurs the distinction between H. erectus and H. ergaster,” says Wood. “I am not willing to sell my shares in H. ergaster just yet, but I am not relying on them for my retirement!”

3. GENETICS

# High-Risk Glaucoma Gene Found in Nordic Studies

1. Jean Marx

Glaucoma can be an insidious disease. It often develops painlessly, robbing its victims of their sight so gradually that they barely notice at first. Conventional wisdom holds that a buildup of pressure in the anterior chamber of the eye causes the vision loss by damaging the optic nerve. But why that pressure increases for the most part remains a mystery. Now, researchers have a new clue to the cause of a common form of the eye disease, one that's particularly tough to treat.

In work published online this week in Science (www.sciencemag.org/cgi/content/abstract/1146554), a team led by Kari Stefansson of deCODE Genetics Inc. in Reykjavik, Iceland, and Fridbert Jonasson of the University of Iceland reports the discovery of a gene variant that confers an extremely high risk of developing exfoliation glaucoma. This form of glaucoma accounts for perhaps as many as 10% of all cases in the United States, yet it responds poorly to the current treatment of eye drops that lower pressure in the eye. The genetic find might lead to better ways to diagnose and prevent the slow descent into blindness. “I think it's a great paper. … People with this glaucoma have a much higher risk of going blind,” says Mary Wirtz, an expert in glaucoma genetics at Oregon Health and Science University in Portland.

Stefansson and his colleagues found the gene using a genomewide association study, a method that is fast becoming the standard way to track down disease genes (Science, 11 May, p. 820). This technique identifies small variations in gene sequences known as single-nucleotide polymorphisms (SNPs) that occur in greater frequency in people with the disease under study—in this case, 195 Icelandic glaucoma patients—than in unaffected persons. One SNP variant stood out as being associated with glaucoma, but only in the 75 people who had the exfoliation type. A subsequent study of a Swedish population confirmed the association.

This particular SNP turned out to be only indirectly related to glaucoma risk, however. It's located in a gene that makes an enzyme called lysyl oxidase-like protein 1 (LOXL1), but the SNP is in a so-called intron that doesn't encode any part of the enzyme. Still, the enzyme made sense as a possible contributor to exfoliation glaucoma, which develops when tiny flakes slough off the lens and iris of the eye. These eventually deposit in the trabecular mesh-work, a small structure that allows fluid to drain from the anterior eye chamber. Blocking this drainage presumably produces the very high intraocular pressures. The exfoliated material contains tiny fibrils of a protein called elastin, which may be where LOXL1 comes into play. The enzyme helps form elastin fibrils, so its malfunction might well lead to exfoliation glaucoma.

In a closer look at the gene, Stefansson and his colleagues turned up two more SNPs associated with exfoliation glaucoma, neither of which was examined in the original screen. These two do appear to play a role in glacuma risk. They reside in the protein-coding portion of LOXL1, and a person carrying both of the highest risk variants is up to 700 times more likely to develop exfoliation glaucoma as persons with low-risk variants. The analysis showed, Stefansson says, that “the variant accounts for … all or most cases of exfoliation glaucomas.”

Exactly how the changes to the LOXL1 gene lead to exfoliation glaucoma remains to be determined. Studies of animals genetically engineered to have the high- and low-risk versions of the gene should help clarify this issue, Stefansson says. Once that issue is resolved, it might be possible to develop ways to correct the problem given that the eye is so accessible to treatment. And that could mean a brighter day for some glaucoma patients.

4. U.S. SCIENCE POLICY

# Congress Passes Massive Measure to Support Research, Education

1. Jeffrey Mervis

In 2005, a U.S. National Academies' panel drew up a blueprint for sustaining economic growth by strengthening the country's research and educational systems (Science, 21 October 2005, p. 423). Last week, Congress adopted nearly all of its recommendations in a bill that prescribes new policies and programs at six federal agencies.

The academies' report, titled Rising Above the Gathering Storm, named 20 priorities, putting more and better science and math teachers at the top of the list. It also called for a sustained boost in federal spending on research, especially for the physical sciences and engineering, and increased support for those planning to become scientists. Congress folded most of those proposals into the America COMPETES (Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science) Act, a 407-page leviathan that authorizes $43 billion over 3 years for dozens of research and training programs. It passed the House by a vote of 367-57 on 2 August and, a few hours later, the Senate by unanimous consent. Part of the reason for the overwhelming support was that America COMPETES is not a spending bill that appropriates money for the next, or any, fiscal year. Instead, it's an authorization bill that describes broad policies an agency should follow, specifies programs to achieve those goals, and endorses a desired spending level. It is the job of the appropriations committees to decide how much money will be spent in any particular year. Appropriators are still working on the 12 spending bills for the 2008 fiscal year that begins 1 October. The preliminary signs are good for the three agencies—the National Science Foundation (NSF), the Department of Energy's Office of Science, and the National Institute of Standards and Technology (NIST)—that are included in the president's American Competitiveness Initiative (ACI), itself a response to the academies' report. Still, the new legislation gives appropriators lots of suggestions. It puts NSF on a 7-year doubling track, for example, compared with 10 years under ACI, and increases many of its education programs, including a huge jump in a$10-million-a-year program to give scholarships to science, math, and engineering undergraduates who promise to teach. It declares that an NSF program partnering universities and local school districts is complementary to one at the Department of Education, rather than redundant, as the Bush Administration has argued. It greatly expands DOE's role in elementary and secondary school education, giving it the authority to create new science and math academies affiliated with its network of national labs. It authorizes a new version of an industrial research program at NIST that Republicans have long sought to eliminate, converting the Advanced Technology Program to the Technology Innovation Program and starting it off with $100 million. It also creates grants for young scientists who have failed in their first NSF submission, in hopes of bolstering their chances of success the next time around. The most controversial element is a new agency within DOE (see sidebar, p. 737). In addition to beefing up current efforts and creating a cornucopia of new programs, the legislation ties up some loose policy ends. It enshrines the social and behavioral sciences as an essential element in NSF's research portfolio, a rebuff to attempts last year by Senator Kay Bailey Hutchison (R-TX) and others to downplay their importance. And it orders the White House Office of Science and Technology Policy (OSTP) to come up with a standard policy for all agencies on the dissemination of research results, a reaction to a spate of reports that federal scientists have been hindered in publicizing studies that appear to contradict Administration policies on global warming and other hot-button issues. That will happen, promises OSTP director and presidential science adviser John Marburger. “We're a science policy shop, and we'll do what Congress tells us to do,” he says. Legislators portray the bipartisan support for science as a matter of enlightened self-interest. “This bill will help us keep our brainpower advantage,” trumpeted Senator Lamar Alexander (R-TN), who shepherded the bill through three Senate panels. “Securing a brighter future for our children is simply not a partisan issue,” noted Alexander's Tennessee colleague, Representative Bart Gordon (D-TN), who as chair of the science committee played a similar role in the House. Even so, only three Republicans voted in favor of moving the measure to the House floor, expressing their ire over how the Democratic majority handled the procedural steps leading to the final vote. Why was the academies' report so influential when similar proposals to bolster science have fallen short in the past? The trick this time around, says Norman Augustine, former CEO of Lockheed-Martin and chair of the panel that produced the report, was to argue in terms that the public would understand. “We quit talking about the virtues of science in the abstract and started talking about its impact on jobs,” he explained about the 2-year lobbying effort by university and industry leaders. “Everybody understands jobs.” Even one-time critics say that the final legislation provides a useful road map for managing the country's scientific enterprise. “It's good for Congress to say that STEM [science, technology, engineering, and mathematics] education and research are important,” says Marburger. “But we have to pay for this stuff, and this bill is way over the top in terms of authorized spending and the number of new programs. My concern is that when the time comes for Congress to appropriate the money for each of these agencies, what will they choose to support?” Gordon praised university and business leaders for being effective “cheerleaders” for the new legislation. But Augustine cautioned that their work is far from over. “Our biggest challenge is to sustain this coalition for the next 10 to 15 years, because it will take that long for the new jobs to appear,” he predicts. “Still, you can't finish if you don't start, and that's what this bill does.” 5. U.S. SCIENCE POLICY # New DOE Agency Sparks an Energetic Debate 1. Eli Kintisch Can a new agency within the Department of Energy (DOE) give the country a technological boost to develop new energy sources? Last week, as part of a mammoth innovation bill (see main text, p. 736), Congress created the Advanced Research Projects Agency-Energy (ARPA-E) that would, as the legislation explains, identify and fund “transformational technological advances that industry by itself is not likely to undertake.” To do that, the new agency's rotating program managers will fund risky projects with aggressive performance targets and timetables, an approach modeled on the Pentagon's DARPA. Supporters say that it's important to keep ARPA-E at arm's length from the rest of the department by keeping its funding separate from the$4 billion Office of Science. But critics say the new agency will be, at best, a redundant layer of bureaucracy and, at worst, a drain on the agency's ability to fund basic research in the physical sciences.

Representative Bart Gordon (D-TN), who as chair of the House Science and Technology Committee has pushed hard for the new agency, hopes ARPA-E will catalyze partnerships among universities, companies, and national laboratories. “ARPA-E will foster a much more distributed base of energy researchers and technology developers than you see today, with the result being a vibrant domestic energy technology industry and work force,” Gordon explained shortly after last week's successful vote. Last year, Steve Chu, director of DOE's Lawrence Berkeley National Laboratory in California, said the new agency could improve DOE science by funding “activities more applied than DOE basic-research programs and too basic for its applied-research programs.”

But others, noting current DOE efforts to patch such holes, are skeptical that ARPA-E is needed. “[It's] completely pointless,” says Joseph Romm, head of DOE's renewable energy office during the Clinton Administration and no fan of the agency's current performance. “I don't know what DOE isn't doing that ARPA-E would be doing.” Some observers also doubt that the new agency will help bring new discoveries to the market. “What it can do to further commercialization is harder to see,” says Robert Fri, a former deputy secretary of energy who has led several National Academies' studies of DOE's activities. “DOE's skills in managing large science programs and large applied-technology programs are not necessarily the right ones for the [new] job.”

The COMPETES Act authorizes up to $300 million for the new agency in 2008 and “such sums as are necessary” for the next 2 years. But congressional appropriators haven't been enthusiastic about making more money available, and the current Administration may well drag its feet appointing a director, who must then be confirmed by the Senate. Earlier this year, President George W. Bush objected to a smaller and less independent entity that was part of the Senate bill (S. 761), expressing “serious doubts about the applicability of the national defense model to the energy sector.” 6. AIDS RESEARCH # Feud Over AIDS Vaccine Trials Leads Prominent Italian Researchers to Court 1. Jon Cohen Impassioned debates have swirled around several AIDS vaccines, with proponents aggressively pushing for larger trials in humans and detractors contending that little evidence suggests that the given approach will succeed. If no serious safety concerns exist, the issue typically comes down to money; peer-review committees, blue-ribbon panels, or deep-pocketed pharmaceutical companies ultimately decide whether the trial receives the many millions of dollars needed. But a dispute about the merits of an AIDS vaccine being developed by a leading Italian researcher, Barbara Ensoli of the Istituto Superiore di Sanità (ISS) in Rome, has wound up in a different venue: the courtroom. Ensoli is suing another prominent Italian investigator, immunologist Fernando Aiuti of the University of Rome “La Sapienza,” for what she contends is damage to her reputation. Aiuti, a former collaborator of Ensoli's, has assailed what he sees as critical flaws in the early clinical trials of the vaccine. The feud raises serious questions about the boundaries of academic debate and the conduct of clinical trials, as well as how the Italian government sets its HIV/AIDS research priorities. HIV co-discoverer Robert Gallo, in whose lab Ensoli worked for many years, says her battle with Aiuti has caught the attention of many Italian AIDS researchers who are frustrated that their government has committed tens of millions of euros to Ensoli's project while they struggle to find funding for their own work. “It's disproportionate to the money available to other scientists,” says Gallo, who now directs the Institute of Human Virology at the University of Maryland School of Medicine in Baltimore. “That's the background to all of this.” And there's a dash of soap opera in the mix, too, given that Aiuti was once Ensoli's mentor, employed her brother, collaborated with her former husband and former sister-in-law, and ran one of the centers that helped test her AIDS vaccine. “It's a classic Roman infight,” says one Italian AIDS researcher who did not want to be quoted by name. “We are all refusing to be dragged into this.” Ensoli has taken an unusual approach to developing an AIDS vaccine. Most AIDS vaccines in development combine several HIV genes or their proteins, but Ensoli has focused on one HIV protein, Tat, that helps the virus produce more copies of itself. Ensoli hopes that bolstering the immune response to Tat can prevent infections and also help people who are already infected. Although Ensoli has reported some success in monkey studies with her Tat vaccine, studies by several other labs that used different conditions have not had the same success. “There's no body of data that suggests this vaccine will work,” says retrovirologist Genoveffa Franchini of the U.S. National Cancer Institute (NCI) in Bethesda, Maryland. Franchini, who collaborated on a monkey study of a Tat vaccine that failed and once worked with Ensoli in Gallo's lab, adds, “I don't think it has any chance.” Gallo, who says Ensoli was a tireless worker in his lab, similarly believes her Tat vaccine has dim prospects, and he has long cautioned that the form of Tat in her vaccine could actually suppress some immune responses. The saga began in January 2004 when ISS launched phase I trials of Ensoli's Tat vaccine to test for toxicity in both HIV-infected and uninfected people. Researchers conducting the two studies aimed to recruit 88 volunteers in 3 months. Few people initially volunteered, and Aiuti and investigators running other sites were allowed to continue enrolling until the end of the year. But in November 2004, over Aiuti's objections, ISS decided to stop enrolling people into both trials, which then had a total of only 47 participants. Although the trials were placebo-controlled and the investigators were not told who received the actual vaccine, Ensoli backed the decision, she says, because ISS determined that the trial had met its endpoints: No serious safety issues had surfaced, and blood tests showed that a significant number of participants had developed immune responses to Tat. “When you reach the endpoint, it's not ethical to continue the trial,” says Ensoli. On 11 July 2005, inspectors at the Agenzia Italiana del Farmaco (AIFA)—Italy's equivalent of the U.S. Food and Drug Administration—wrote a harsh report about the conduct of the clinical trials, highlighting several “critical deviations” from the original protocol. In addition to noting that researchers had not enrolled the number of people specified and had failed to seek amendments to change the protocols, AIFA's inspectors reported that clinicians had difficulty removing all of the vaccine solution from the vials, making it technically impossible in 70% of the cases to administer the specified dose. Aiuti, who says he received a copy of the document from several sources including the hospital he works with, raised the issues identified by the AIFA investigators in letters to several university and government officials. Ensoli charges in her lawsuit that he had no right to share this confidential document with them. Aiuti counters that no one told him it was confidential and that it was his duty to report the serious findings to officials. In a 26 July 2005 letter, AIFA Director Nello Martini accepted ISS's explanations, writing in a letter addressed to Ensoli, ISS officials, and a company hired to oversee the studies that neither the change in enrollment nor the problem with the vaccine itself compromised the trials, which he wrote indeed hit their endpoints. Aiuti stepped up his efforts to inform the media, public officials, and colleagues about what he saw as the shortcomings of the trials. “It's not enough to say there are no problems,” insists Aiuti, who says he believes that Martini too readily dismissed the deviations that his inspectors found. “Just the word of the AIFA director is not enough. All the data of the four inspectors were very specific. There is not a single reply from any of the inspectors.” Ensoli says the assertion that Martini does not speak for his inspectors is ludicrous. “It's totally untrue,” she says. Martini did not respond to e-mailed questions about Aiuti's allegation. Ensoli was particularly perplexed that Aiuti suggested in a letter to the health minister that conflicts of interest compromised the study. Ensoli's brother was appointed to run the core lab, and her brother's ex-wife helped run the clinical trial. “We all come from [Aiuti's] lab, which is funny,” says Ensoli. “When we were all working in his lab, everything was okay. When we left, it was a conflict of interest, which is totally crazy.” Despite Aiuti's complaints, Italy's Ministry of Health and, separately, Ministry of Foreign Affairs decided to invest heavily in staging larger phase II studies of the vaccine in both Italy and Africa. In a December 2005 press release quoted in Ensoli's lawsuit, Italy's then-minister of health claimed “there has never been an AIDS vaccine, as we can see in research from the whole world, which has seen such success during research.” In all, the Italian government committed €21 million for expanded trials in Italy and another €31 million for an extensive AIDS program in South Africa that includes phase II trials of Ensoli's vaccine. None of this funding was subject to peer review, though Ensoli notes that the decisions were based on results from the phase I studies and that a scientific committee at ISS reviewed the data. Aiuti, not surprisingly, thinks the funding is a mistake. “I don't think this vaccine should move to phase II trials,” he says. Ensoli filed suit against Aiuti this May. She alleges that he “went beyond the limits of his legitimate right to criticize” and damaged her reputation, citing a newspaper article that is headlined “Aiuti: AIDS Vaccine a Trick to Find Funding.” (Aiuti denies he said any such thing, and the article does not directly quote him making that statement.) Ensoli further charges that Aiuti “overstepped the line in criticism” in other statements to the press that derided the decision to stop enrollment. She alleges that his “inappropriate use” of the AIFA report was a “malicious diffusion of false information,” and she charges that he spread “false information about her supposed use of privilege to involve members of her family in the research program.” The suit concludes with an allegation that Aiuti, in a “wholly arbitrary and unlawful fashion,” wrote the ministries of health and foreign affairs to “denigrate” her work. Ensoli is seeking €2.5 million for damages to her reputation and the resultant loss of income from speaking engagements. “If you're in science, you're very well used to getting criticisms,” says Ensoli. “But scientific criticism based on science is one thing and defamation is another.” Aiuti, she charges, is not making a good-faith attempt to critique these studies. “There was an intention to sabotage here,” claims Ensoli. Aiuti says he has “nothing personal” against Ensoli and was surprised that she sued him, but he emphasizes that he has not changed his opinions. “Criticism is less tolerant” in the Italian scientific community than elsewhere, he says. “The Latin mentality is in part responsible.” Glenda Gray, who heads a unit at Chris Hani Baragwanath Hospital in Soweto, South Africa, that is considering conducting phase II studies of the vaccine, contacted Ensoli after learning of Aiuti's concerns to inquire about enrollment and other issues. Ensoli replied in an e-mail that she thought Gray was “acting like a court of law.” Gray wrote back that she construed this as “threats of legal action” and decided to forward the matter to her institutional review board, which she told Science will now try to get to the bottom of what she sees as the biggest outstanding question: Why was enrollment stopped so abruptly? Ensoli says phase II therapeutic studies will start in Italy during the next few months, and she's now making a second-generation preventive vaccine that will contain the HIV envelope protein as well as Tat. The court case against Aiuti is slated to come to trial in October, and ISS leaders urged its board of directors in a 17 July memo to file a separate suit against Aiuti to “defend its own image and professional reputation and seek payment of the damages it has suffered.” Aiuti says he may countersue. 7. PALEOANTHROPOLOGY # The Fellowship of the Hobbit 1. Elizabeth Culotta Adversaries in a debate with momentous implications—whether a tiny human fossil found in Indonesia is a new species—mulled fresh data on hallowed ground. But the hobbit remains an enigma to many FLORES, INDONESIA—Liang Bua cave, as big as a concert hall, with a domed ceiling and a giant stalactite for a chandelier, thrums with the din of a portable generator and excited conversation in many languages. Fifty anthropologists plus a retinue of villagers, police, and curious children mill about in cool air that smells faintly of damp rock and cigarettes. The researchers are on a pilgrimage to ground zero of one of the most contentious debates in human evolution. Here, in 2003, the skull and skeleton of a meter-tall adult woman were unearthed. Ever since, experts have sparred over the “hobbit”: Is it an astonishingly primitive species with a tiny head, dubbed Homo floresiensis, or a diseased member of our species, H. sapiens? The stakes are high. A new species shakes to the core ideas about the defining role of big brains in our genus and about relations among hominids. The hobbit bones are dated to as recently as 12,000 years ago, so the diminutive hominid must have lingered on Flores for thousands of years while modern humans colonized nearby islands. The tiny human suggests that big brains aren't required for making tools—and, according to a theory proposed by the hobbit's discoverers, may imply that the first hominid migrated out of Africa far earlier than anyone had thought. “Flores is the thorn in the flesh. [It implies] that we have to rethink everything,” says anthropologist Marcia Ponce de León of the University of Zurich in Switzerland. The visit to Liang Bua cave was the culmination of an unprecedented gathering* of the hobbit's discoverers and their critics, several of whom had battled fiercely in print and on film but had never met in person. For the most part, adversaries were on their best behavior, like feuding relatives gathered for a reunion. Conference organizer Teuku Jacob of Gadjah Mada University in Yogyakarta has argued that the hobbit is a diseased H. sapiens. Two years ago, he borrowed the bones for study over the objections of co-discoverer Mike Morwood of the University of Wollongong, Australia; some of the bones were broken upon return (Science, 25 March 2005, p. 1848). But Jacob was unfailingly smiling and polite to all, and Morwood made a point of speaking to each critic. Still, divisions run deep, among both Indonesians and foreigners. At the meeting, funded generously by businessman and philanthropist Hashim Djojohadikusumo, who paid for the travel and five-star accommodations for all presenters, researchers heard much of the latest thinking on crucial aspects of hobbit science and lore, from cave geology to an (unsuccessful) hunt for living “orang pendek,” mythical humanlike creatures that legends say once roamed Flores. The critics, most of whom were in attendance, were unshaken in their belief that the hobbit is a pathological modern human, perhaps one who suffered from microcephaly, a disorder that results in a tiny head, or from a growth hormone insensitivity called Laron syndrome. Meanwhile, a growing number of those working on the bones, several of whom were not invited or chose not to attend, are convinced that they are dealing with a new phenomenon in human evolution. “This is a different species for sure,” says William Jungers of Stony Brook University in New York, who is working on the skeletal bones but was not invited. “There is no pathology that recapitulates early hominid morphologies and proportions.” Others haven't made up their minds, perhaps in part because the bones themselves were deemed by the Archaeological Institute in Jakarta to be too fragile to send to the conference for viewing. “It was a pity we didn't see the fossils,” said Zhao Lingxia of the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing, as she picked up her baggage after the last trip. “I am not sure what [the hobbit] is.” ## Reading the bones Even for scientists steeped in the mysteries of the hobbit, the seminar offered surprises. One was from archaeologist Carol Lentfer of the University of Queensland in Brisbane, Australia, who analyzed residues and polish on the edges of stone tools found in Liang Bua. Under the microscope, substances such as animal hide, wood, and plant materials leave telltale traces on stone. Because the tools were found near animal bones, especially baby pygmy elephants called Stegodon, researchers had inferred that the little people used the tools to process meat. But to Lentfer's surprise, most of the tools she examined were used for working with woody and fibrous plants, perhaps to craft spear shafts of wood or bamboo or items like traps. “It looks like a tool kit for making other tools,” she said in her talk. Whatever the tools were for, some experts aren't sure that hobbits made them. James Phillips of the Field Museum in Chicago, Illinois, has argued that long, narrow blades removed sequentially from blade cores are too sophisticated to have been made by anyone other than a member of our species. That means that the hobbit must have been part of a H. sapiens population, he said. Harry Widianto of the Centre for Archaeology in Jakarta also believes that the tool kit belonged to our species. The tools were made with “very high skill,” he said, and resemble artifacts found in other Indonesian caves, including those occupied more recently. But every shred of hobbit evidence has conflicting interpretations. Morwood and two colleagues—hobbit excavator Thomas Sutikna of the Centre for Archaeology and archaeologist Mark Moore of the University of New England in Armidale, Australia, who did his Ph.D. on the artifacts—don't agree that they are sophisticated. Moore, who was not invited to the meeting, told Science that although “blades”—flakes twice as long as they are wide—are found at Liang Bua, there is no evidence that they were flaked deliberately, as seen in classic H. sapiens tools. “These are simple stone artifacts,” agrees Sutikna. When it was Morwood's turn at the podium, he emphasized the evidence against the theory that the hobbit was a modern human. His voice crackling with intensity, Morwood reminded colleagues that the famous skull and skeleton known as LB1 is not alone. To date, the team has found an additional jawbone plus various bones of the leg, arm, and shoulder, all petite, from different layers. “We have a minimum of 12 individuals … going back to 95,000 years ago,” he said. “That's twice the accepted date for H. sapiens in Southeast Asia and Australia. Twice the accepted date, okay?” He adds that the hobbit layers show no traces of pigments, ornaments, or formal burial—all signs of H. sapiens that are found in the cave's upper levels. Morwood also underscored the similarities among the hobbit bones. “The radius and leg bones in the deeper deposits have the same unique characters as seen in the higher levels,” he said. Because it's highly unlikely that only diseased individuals died in the cave over thousands of years, the additional specimens rule out pathology, he said. But critics have argued that, except for the tiny brain, some hobbit traits are also seen in living Southeast Asians and so aren't signs of either pathology or a new species (Science, 25 August 2006, p. 1028). ## Not the brainiest For others, no trove of skeletal bones can compensate for the puzzle of that puny brain. Short stature alone does not mean that it is a distinct species, as small stature is known from living pygmies, including those in the village of Rampasasa near Liang Bua, say Jacob and others. But pygmies have brains nearly the same size as those of other modern humans. The minute brain that would have fit inside LB1's skull was only 400 cubic centimeters, compared to the roughly 1350 cubic centimeters seen on average in living humans (see graph). “Flores falls outside the range of anything I have seen before,” said Robert D. Martin, a paleoanthropologist at the Field Museum. Martin and other presenters suggested that LB1 was diseased, perhaps suffering from microcephaly, Laron syndrome, or both. The Laron's hypothesis debuted in the hobbit debate on 27 June, in a paper published online in the American Journal of Physical Anthropology by a trio from Tel-Aviv University who were not at the meeting: Israel Hershkovitz, Liora Kornreich, and Zvi Laron, discoverer of the disease. Their paper lists Laron's symptoms—although with few measurements—that are also seen in hobbits, including pillars of bone near the nose, a short clavicle, a curved tibia, and an upper arm bone whose top end is not twisted. Some of these traits have been considered signs of a primitive ancestry for H. floresiensis. “All [Laron's] patients share a battery of traits, which they also share with Homo floresiensis,” Hershkovitz and Laron told Science. At the meeting, Dean Falk of Florida State University in Tallahassee, who has concluded from computed tomography (CT) scans of the skulls of LB1 and microcephalics that the hobbit is a new species, tackled the Laron's hypothesis head-on. Hershkovitz and colleagues note that many Laron's patients also lack the sinuses of a normal human head. And although in most people the texture of the mastoid process—the bony bump behind the ear—is spongy and air-filled, in Laron's patients this bone is dense. CT scans of LB1's skull show that it has normal sinuses and a porous mastoid process, Falk said. “We don't think LB1 comes close to looking like their description of Laron's,” she said firmly. Hershkovitz responds that some Laron's patients do have normal sinuses, and so their presence does not disprove the hypothesis. ## Island living If the hobbit is a new species, who were its ancestors? Morwood's team once postulated that H. floresiensis evolved from H. erectus, the first human ancestor known to have left Africa. Dozens of H. erectus specimens have been unearthed on the nearby island of Java. But the team now argues for a more radical idea of the hobbit's origins: a “pre-erectus ancestor”—a small-bodied, small-brained, primitive hominid, which shrank further once on Flores. In her talk analyzing the skull and jawbones, Debbie Argue of Australian National University in Canberra proposed that the hobbit shared an ancestor with 2-million-year-old H. habilis (see p. 733). When asked by colleagues, Morwood referred to unpublished work presented at recent meetings that unites H. floresiensis with early Homo or with the even more ancient australopithecines. He ticked off a few key features: an odd shoulder joint (Science, 19 May 2006, p. 983), a wrist like that of an ape (Science, 6 April, p. 34), and primitive feet. Jungers agrees that the hobbit “has australopithecine limb proportions and australopithecine/ape wrists and tarsals.” Given these primitive traits, Morwood argues for a very ancient ancestor. “I believe now that they split from us 2 to 3 million years ago,” he said. That would imply that an australopithecine or very early Homo, rather than H. erectus, was the first hominid to leave Africa. Skeptics are unimpressed. For starters, they point out that there is no evidence of the hobbit lineage for those millions of years. “If you go back that far, where are all the intermediates?” asks Martin. Other scientists, including those convinced that the hobbit is a new species, think it may be premature to eliminate H. erectus as a possible ancestor. To date, the most complete H. erectus skeleton published is much larger than H. floresiensis, but there are other, smaller skulls of the species, particularly from the 1.7-million-year-old site of Dmanisi, Georgia. And evolving into a smaller form on an island is a common phenomenon in other mammals. In his talk, paleontologist John de Vos of the National Museum of Natural History in Leiden, the Netherlands, gave a whirlwind tour of such island dwarfing. On islands from the Mediterranean to Southeast Asia, some large species such as elephants and hippos shrank while others such as rats and hedgehogs evolved into giant forms, depending on the available ecological niches. “On islands, we get relict lineages,” de Vos added—lineages that hark back to primitive ancestors. In his view, animal and hominid bones from Flores fit this pattern. Dwarf island forms are also often pedomorphic, in that they retain childlike traits into adulthood, de Vos said. Thus on islands, adult elephants, hippos, and deer retain short snouts and short legs. This could be what happened to a H. erectus-like ancestor on Flores, he speculated, for many of H. floresiensis's peculiarities appear to be pedomorphic: the lack of twisting at the top of the arm and leg bone, a flat face, and short legs. Christoph Zollikofer of the University of Zurich, who works with Ponce de León on the H. erectus fossils from Dmanisi, compared them to the Flores bones and independently came to the same idea: “Homo floresiensis can be understood as a pedomorphic, dwarf erectus,” Zollikofer said. Some degree of island dwarfing makes sense, even if starting from a smaller ancestor, said Morwood. Yet skeptics aren't swayed by the dwarfing evidence. Martin argues that mammalian brains are unlikely to shrink to the same degree as their bodies during dwarfing. “Weird things happen on islands, but not that weird,” he said. He and de Vos are considering a joint project to probe dwarfing and brain size. The controversy may rage until more fossils emerge—and new specimens may not all come from Liang Bua. Given ocean current patterns, Morwood thinks that H. floresiensis might have originally been swept to Flores from Sulawesi, and he's planning to dig there to find out. On many Southeast Asian islands, says de Vos, excavations stopped at layers dated to the beginning of our current Holocene Epoch, about 11,000 years ago. Morwood found the hobbit “because he dug deep,” says de Vos. “The message for the future is, dig a very deep hole.” Eusebio Dizon of the National Museum of the Philippines in Manila, for one, is eager to excavate. “In the Philippines, we have the right fauna: Stegodon, giant rats, and turtles,” he said. “It is perhaps just a matter of time until such species [as the hobbit] appear.” Researchers on both sides are also pinning their hopes on DNA. Genetic data could establish or rebut the existence of a new species, test the Laron's hypothesis, and perhaps even identify a mechanism of dwarfing. Previous attempts at retrieving DNA from hobbit bones failed, but clean sampling will be done immediately at the site if more bones are found, Morwood says. “The issues won't be resolved here at the meeting,” he adds. Nor were they resolved on the brief visit to Liang Bua cave, where Morwood and Sutikna recounted this year's excavations to a handful of colleagues, pointing to two pits the size of telephone booths, shored up with wood and with stratigraphic layers neatly revealed on the sides. In one excavation, the team had just struck a layer of a whitish volcanic tuff dated to 12,000 years ago that they say runs through the cave. Yet skeptics such as the Field Museum's Phillips say cave stratigraphy is notoriously hard to decipher, and they aren't ready to accept the dates. Later, after the visiting scientists troop out of the cave, Sutikna and other excavators welcome one more group: a priest and a few dozen of his flock who have come to sing and pray for the excavation's success. After the last hymn, the worshippers file out, and Sutikna and the crew clean up. The next day they will dig deeper, continuing their quest for more tiny bones with big implications. • *International Seminar on Southeast Asian Paleoanthropology, 22-29 July, Yogyakarta, Indonesia. 8. MEDICINE # The Big Chill 1. Jennifer Couzin Lowering the body's temperature improves the chances of surviving a cardiac arrest and other types of trauma; but as cold therapy expands, researchers are struggling to understand why and for whom it works PITTSBURGH, PENNSYLVANIA—In the first frantic minutes after a trauma victim rolls through the emergency room double doors at the University of Pittsburgh Medical Center, the medical team employs an arsenal to keep the patient's temperature up. The trauma rooms hold warm blankets and heated saline fluid in a small silver cabinet. Blood often runs through a warming device before a transfusion. Heat lamps glow next to a bulky x-ray machine. Keeping warm helps protect the immune system and sustain blood clotting, but for the most grievously wounded, that's often not enough. More than 90% of patients with massive bleeding who lose a pulse will die—a figure that has remained stubbornly high. “What we do doesn't work” to save these people, says Samuel Tisherman, a soft-spoken, goateed surgeon at the medical center. And so, as a last-ditch effort, Tisherman, who has spent nearly all his life in this industrial city, wants to try something radical: Jettison warming, and put the critically injured who have lost circulation into a deep freeze of sorts, giving surgeons time to repair the wound. Infusing and draining up to 20 liters of cold saline fluid will plunge a patient's body temperature from 37°C to less than 10°C, “pickling” him, in the words of one researcher, in order to bring him back to life. As drastic as it sounds, hypothermia—albeit not normally this profound—has had a lengthy, bumpy history in emergency medicine. At its core, the aim is to push the outer limits of survival. “When I was training, I learned [that] after 4, 5 minutes [without oxygen], the brain would die,” says Lance Becker, director of the Center for Resuscitation Science at the University of Pennsylvania. With hypothermia, he says, “many of us are beginning to think it's possible to shift that” to 10 minutes and beyond. “We don't really have a fix on what death is” or when it's irreversible, says Becker. Although it's still not clear exactly how and why hypothermia works, physicians are using it against an assortment of maladies. Mild hypothermia improves survival of people experiencing cardiac arrest and infants deprived of oxygen before birth. Clinical trials are testing it in head injury and stroke, and a vast European study is gearing up to refine hypothermia's effects in cardiac-arrest victims. Tisherman hopes that his much colder, profound-hypothermia trial will open within a year or so. But there have also been high-profile failures and some safety concerns, a reminder of how much is left to learn. Once considered especially promising for those with brain trauma, hypothermia has proven unexpectedly fickle in this population. It has also proven exceptionally difficult to test in people, especially in the United States, where strict informed-consent guidelines mean that emergency-medicine trials are developed at what researchers contend is a glacial pace. ## Beginnings “I remember as a resident, we had patients in hypothermia for a week or longer,” says Patrick Kochanek, a pediatric critical care specialist who directs the Safar Center for Resuscitation Research at the University of Pittsburgh. In those days in the early 1980s, Kochanek was at Children's Hospital San Diego in California, and youngsters with devastating head injuries were routinely cooled to 30°C, and sometimes less, for days, a trend that began in the 1950s. Pediatricians led the hypothermia charge, inspired by stories of children who had drowned in ice-cold water and been revived. “Everyone had their one miracle case of an amazing recovery,” says Kochanek. But cooling in brain injury was largely abandoned after life-threatening complications surfaced, including pneumonia, cardiac arrhythmias, and blood-clotting problems. Hypothermia continues to be used in many heart and brain surgeries to protect cells. But in the operating room, “we apply cooling before we deprive the system of oxygen,” not after, which has different effects, says Hasan Alam, a trauma surgeon at Massachusetts General Hospital in Boston. The controlled conditions in surgery are also a world apart from the chaos in the emergency room. The hypothermia field revived when a number of labs made a fortuitous discovery. For neurosurgeon Guy Clifton, now at the University of Texas Health Science Center in Houston, the insight came one winter in the mid-1980s while he was testing drugs in gerbils to prevent cell death during stroke. Animals in the control group, whose brains ought to have been seriously damaged, kept throwing off the experiments by staying healthy. The building in which Clifton was working was 100 years old and drafty. He found that the gerbils' body temperature had dipped 2°C—enough, it turned out, to protect them. “It was better than any drug we ever looked at,” he says now. A group in Miami made the same chance observation in rats, and another in Pittsburgh found similar responses in dogs. It dawned on the community that hypothermia need not be deep to be potent. “It wasn't just one laboratory showing that this works, it was almost everybody,” says W. Dalton Dietrich, a neuroscientist at the University of Miami in Florida, one of the discoverers. Cooling a few degrees kept brain cells from dying. It's far from clear why. Hypothermia slows metabolism and lowers the body's demand for oxygen, which is especially useful in cases of ischemia, in which blood supply stops and there's little oxygen to be had. Hypothermia may also inhibit a destructive cascade of molecules that surge through brain cells after someone is resuscitated. Starting the heart up after a minutes-long pause can do serious harm to the brain, causing inflammation and damage from free radicals—a process called reperfusion injury. Reperfusion “adds a great insult to the injury” of ischemia in cardiac arrest and stroke, killing brain cells over many days, says Stephen Bernard, a critical-care specialist at Alfred Hospital in Melbourne, Australia. It is precisely this type of cellular death some scientists believe hypothermia can prevent. But scientists are now finding that mild hypothermia, defined in humans as cooling from 37° to about 33°C, has more nuanced effects. “The assumption for many years was that hypothermia was primarily downregulating metabolism” and downregulating gene expression, says David Beiser, an emergency-medicine physician and biomedical engineer at the University of Chicago in Illinois. “But there's another aspect of this that is kind of puzzling.” In a survey of 45,000 genes, Beiser and his colleagues found that when cooling clumps of cells or mice in shock from massive bleeding, just as many genes increased expression as decreased it. Beiser presented his findings at a June meeting and is preparing them for publication. ## When the heart stops As happens often in medicine, clinicians are concentrating more on how to use hypothermia than on understanding why it might work. “Our focus has always been on outcomes, not on what various molecules are doing,” says Tisherman. This goal-driven mentality runs deep in the field, in part because of the man who shaped it: Peter Safar, widely considered the father of CPR and a believer in hypothermia long before it was in vogue. The animal studies showing benefits from mild hypothermia immediately prompted clinical trials. One of the first was led by Fritz Sterz, a paramedic turned emergency-medicine doctor who had spent 3 years at Pittsburgh with Safar. Cooling at Vienna General Hospital in Austria, where Sterz returned after his Pittsburgh sojourn, was a decidedly low-tech enterprise. Sterz invited over the local firefighters, who agreeably carted mammoth ventilators into his emergency room and blasted ice-cold air onto unconscious cardiac-arrest victims. That lowered body temperature 2° to 3°C. Sterz later graduated to a mattress blowing cold air, which dropped temperature by up to 5°C for 24 hours. Simple as it was, the technique saved lives. In a clinical trial run by Sterz with 273 patients, 41% of those in the hypothermia group died within 6 months, compared with 55% in the control group. A second cardiac-arrest trial in Australia led by Bernard found that 49% of patients given hypothermia survived with minimal disability, compared with 26% in the control group. (Bernard wedged ice packs around his patients.) Both studies appeared in 2002 in The New England Journal of Medicine. A 2005 study described equally compelling outcomes for babies deprived of oxygen before birth—a condition that affects the body much like a cardiac arrest. Among more than 200 newborns in the study, half were cooled to 33°C for 72 hours. Forty-four percent of those treated with hypothermia died or survived with significant disabilities. As grim as that sounds, the number was worse in the group that received standard treatment: 62%, or a difference of 19 babies. “I was astonished that they were able to show a beneficial effect,” says Kochanek. Some of the infants could have been deprived of oxygen for a day or two before birth. The cardiac-arrest studies, furthermore, suggested that doctors had been wrong in thinking brain damage was inevitable after more than 5 minutes without oxygen. ## A knottier test The next frontier, treating brain injury, has been far more difficult to cross. This is surprising, because it's brain cells that seem to benefit most when hypothermia is used against ischemia. Pediatric clinical-care specialist Jamie Hutchison of the Hospital for Sick Children in Toronto, Canada, concedes disappointment that his trial of 225 children with serious head injuries detected no benefit from hypothermia, a finding he first presented at a June meeting in Switzerland. This is consistent with an earlier head-injury trial of almost 400 adults, led by Clifton, which also flunked the hypothermia test. The failures are of special concern because hypothermia is not harmless. The larger of the two cardiac-arrest trials, for example, saw more sepsis among treated patients (hypothermia depresses the immune system), more bleeding, and more cardiac arrhythmias. These were not considered significant, but they have long been associated with cooling. Perhaps the greatest risk comes not from cooling itself but from rewarming, which can sink blood pressure to life-threatening lows. Why the dispiriting results in the head-injury trials? One possibility is that, whereas ischemia from a cardiac arrest briefly shuts down oxygen to the entire brain, “trauma's a dirty disease,” says pediatric neurosurgeon P. David Adelson of Children's Hospital of Pittsburgh. Traumatic brain injury can mean multiple injuries to different parts of the brain, or be combined with trauma elsewhere in the body. That variability is not reflected in lab studies, in which hypothermia has performed so impressively. There, “you hit a group of animals in the same place with exactly the same force,” says Hutchison. Another theory is that different injuries provoke different forms of cell death, and hypothermia may be more suited to preventing one form than it is another. For example, the apoptotic death of cells observed after a cardiac arrest, in which cells “self-destruct,” may be more amenable to hypothermia than the necrotic cell death seen in head injury, says Kochanek. None of these ideas persuaded Clifton, who was baffled by hypothermia's lackluster showing in his head-injury trial. But parsing the data, he noticed that younger people whose bodies cooled spontaneously right after injury—a common effect of head trauma—and who then received hypothermia fared better. This suggested that early cooling could be key. Narrowing his focus, Clifton has launched a second head-injury trial with$15 million in funding from the National Institutes of Health (NIH) in Bethesda, Maryland. He aims to enroll 240 people under age 45 and cool them within 2 hours of injury. Where possible, paramedics infuse chilly IV fluids in the helicopter en route to the hospital.

This time constraint presents a sticky problem: It's rarely possible to obtain informed consent so quickly from a patient's family. Relatives might be difficult to locate, or, in the worst case scenario, they might have died or been badly injured in the same accident. Many countries allow researchers to waive consent in emergency situations, though to do so in the United States, researchers must alert the community to their trial in advance. Clifton ran newspaper advertisements and met with community groups to describe the potential benefits and risks of cooling and how his study would be conducted. One man he met in Houston asserted that “only a Nazi would do this,” says Clifton, adding, “but the majority of people ask a lot of questions and don't have a problem with it.”

In Pittsburgh, Adelson also received an emergency waiver of informed consent from the university's Institutional Review Board (IRB) for a \$15 million hypothermia study on head injuries in children, also funded by NIH. Although Hutchison's trial in Canada failed, Adelson says his trial, which he hopes to start this fall, will cool patients for longer: 48 hours instead of 24. And it will treat children within 6 hours rather than 8 hours of injury. Adelson is heartened by hints from a pilot trial he published 2 years ago that found that 44% of children treated with hypothermia were still showing improvements in cognition and behavior 6 months later, compared to 36% of those given standard care.

Tisherman is working toward approval and funding for his trial of trauma victims, the first that will cool injured patients dramatically, to 7° or 10°C. Alam of Mass General hopes to participate as well. Some consider this strategy especially risky because hypothermia is known to inhibit blood clotting, and these patients are already enduring massive internal bleeding. But “there really is no good alternative” treatment, says Jeannie Barone, assistant director of the Pittsburgh IRB.

## Spotty execution

Clinicians say that trials like these, as well as at least a half-dozen others in Europe, Asia, North America, and Australia, are crucial to learning how hypothermia might help. But the field is fragmented. Already the treatment is being used in situations not backed by clinical data and not used in situations that are. Frustration creeps into Adelson's voice as he describes how some centers refused to join his head-injury trial because they are reluctant to randomize their young charges. Instead, physicians are treating brain-injured patients as they come in, without the rigors of a clinical trial, says Adelson: “That's despite data showing it's not effective in probably 65% of patients.”

View this table:

SOURCE: CLINICALTRIALS.GOV

Meanwhile, hypothermia's impressive ability to boost survival after a cardiac arrest prompted professional societies, beginning in late 2002, to recommend its use. Yet a 2006 survey of more than 2200 physicians in the United States, the United Kingdom, and Finland found that 74% in the United States and 64% in Europe had never used hypothermia to treat patients after a cardiac arrest. Often, hospitals don't adopt hypothermia unless it's foisted upon them. In Norway, Kjetil Sunde, an anesthesiologist at Ullevaal University Hospital in Oslo, spent 2 years pressing for the treatment. At first, many doctors, he says, “didn't believe in this.” Now more than 90% of the country's hospitals use hypothermia in cardiac-arrest cases, he notes.

One reason hypothermia hasn't caught on is money, says James Grotta, director of the Stroke Program at the University of Texas Health Science Center. Drug companies don't develop it. The pharmaceutical industry provides “a substantial impetus for teaching, education, and practice patterns,” says Grotta, who is studying hypothermia in stroke. When it comes to cooling, “nobody's pushing this. … There's nothing really patentable here.”

Still, “it's almost, to me, scandalous” that the treatment remains so rare, says Clifton. “There are not that many cities where a patient can expect to get it.”

9. CLIMATE CHANGE

# Humans and Nature Duel Over the Next Decade's Climate

1. Richard A. Kerr

Rising greenhouse gases are changing global climate, but during the next few decades natural climate variations will have a say as well, so researchers are scrambling to factor them in

For a century or more, meteorologists have known the secret to weather forecasting: To glimpse tomorrow's weather, one must know today's. And lately they have realized that the same precept applies to predicting climate years or decades ahead. Stirrings in the North Atlantic Ocean today that have nothing to do with the strengthening greenhouse—just natural jostlings of the climate system—could lead to drought in Africa's Sahel in a decade or two, they recognized. Ignore today's ocean conditions, and your 2020 global-warming forecast could be a bust. And such natural variability can be far-reaching. In a recent study, researchers found that when the Atlantic Ocean swung from one state to another, it apparently helped trigger a decade-long climate shift in the late 1960s that sprang from the Atlantic and reached as far as Australia.

But until now, climate forecasters who worry about what greenhouse gases could be doing to climate have ignored what's happening naturally. Most looked 100 years ahead, far enough so that they could safely ignore what's happening now. No more. In this week's issue, researchers take their first stab at forecasting climate a decade ahead with current conditions in mind. The result is a bit disquieting. Natural climate variability driven by the ocean appears to have held greenhouse warming at bay the past few years, but the warming, according to the forecast, should come roaring back before the end of the decade.

“This is a very valuable step forward,” says meteorologist Rowan Sutton of the University of Reading, U.K. “It's precisely on the decadal time scale and on regional scales that natural variability and anthropogenic effects have comparable magnitudes.” So improved climate forecasting of the next few decades could help decision-makers focus on where and when the most severe climate change will be happening. Or, conversely, they could recognize when the looming threat of global warming will be masked—temporarily—by natural variability.

## Jiggly climate

No one ever said Earth's atmosphere was a boring place. Air is in continually shifting motion, from the wafting of innumerable summer breezes to a few roaring jet streams. But forecasters have long recognized that certain parts of the chaotic atmosphere are better behaved than others. Over the North Atlantic, for example, atmospheric pressure over Iceland and Portugal tends to “seesaw” over the weeks and months, rising at one site while it falls at another. This North Atlantic Oscillation (NAO) in turn switches winds to and fro across the Atlantic, guiding storms into or away from western Europe. Other modes of natural variability—atmospheric jigglings that lack an external cause such as added greenhouse gases—tend to cause atmospheric reorganizations over the North Pacific and the high latitudes of both hemispheres. The tropical warmings and coolings of the El Niño-La Niña cycle can also hold sway in various regions around the globe.

Once meteorologists recognized that natural variability offered hope of predicting out a few months, climate researchers began to see that the same or similar modes might improve forecasting a decade or more ahead. On a regional scale, the NAO seesaws over the decades as well. Its dramatic strengthening in winter between the 1960s and 1990s pumped extra heat into Northern Europe on top of greenhouse warming, according to a new analysis in press at the Journal of Geophysical Research by climate researcher David Parker of the Hadley Centre for Climate Prediction and Research in Exeter, U.K., and his colleagues.

On a broader scale, natural variability over decades is clearly rooted in the oceans. A warm-cool cycle that spans the Pacific, both North and South, has lately swung back and forth on a time scale of 30 to 50 years. By Parker and his colleagues' data and model analysis, this so-called Interdecadal Pacific Oscillation seems to be driven by interactions between the tropical ocean and atmosphere much like those that drive El Niño; the IPO could be the multidecadal expression of the El Niño cycle, they say.

Over in the Atlantic, there's the Atlantic Multidecadal Oscillation (AMO) of sea surface temperature. It is apparently driven by the acceleration and slowing of the great ocean conveyor that carries warm surface water into the northern North Atlantic (Science, 1 July 2005, p. 41). The AMO's vacillations have been linked to everything from triggering drought in the Sahel and the central United States to alternately suppressing and—in the past decade—firing up hurricanes (Science, 10 November 2006, p. 910).

## A global reach

Lately, researchers are finding that the AMO may have a stronger influence and a longer reach than they once thought. They knew that the oscillation affected climate around the Atlantic, but some suspected it had also caused a mid-century warming of the Northern Hemisphere or even the globe.

This past January in Geophysical Research Letters, climate modeler Rong Zhang and colleagues at the Geophysical Fluid Dynamics Laboratory in Princeton, New Jersey, showed how the AMO might have warmed at least the one hemisphere. They varied the warmth of the North Atlantic in their model to mimic the way the temperature of the real North Atlantic varied under the AMO during the 20th century. In the model, the Northern Hemisphere warmed to midcentury and then cooled slightly through the 1950s and 1960s, as it did in the real world.

In work accepted at the Journal of Climate, climate researchers Sergey Kravtsov and Christopher Spannagle of the University of Wisconsin, Milwaukee, extract what looks like an AMO temperature signal from not just the hemispheric but the global record as well. To gauge the effect of natural variations, they took 20th century temperature records from around the globe and subtracted the warming due to rising greenhouse gases, as simulated by 16 climate models. The difference—a strong warming over southern Greenland, a warming North Atlantic, a cooling South Atlantic, and a weak warming in the far North Pacific—looks like the pattern and timing attributed to the AMO. Kravtsov and Spannagle conclude that the shifting ocean circulation behind the AMO has global effects on global warming.

The AMO may have had a hand in a more dramatic global climate event, according to meteorologist Peter Baines of the University of Melbourne, Australia, and climatologist Chris Folland of the Hadley Centre, writing in the 15 June issue of the Journal of Climate. Their climate shift rattled the circum-Atlantic region over a decade starting in the early 1960s and reached around the globe.

First, Baines and Folland pulled together a range of regional changes in temperature, rainfall, and atmospheric circulation around the Atlantic that could all be tied back to a cooling of the North Atlantic. The AMO presumably cooled the ocean—perhaps with the help of sun-shielding pollutant hazes—as the warm conveyor slowed. Greenland cooled, Brazilian rainfall swelled, hurricane activity dropped, and the Sahel dried to the most catastrophic drought in more than a century. These changes, which are most evident in the northern summer, can all be linked to the reduction and relocation of the ocean's transfer of heat into the atmosphere, Baines and Folland say. Those shifts, in turn, led to changes in atmospheric circulation and precipitation over adjacent continents.

Searching for the most remote limits of this climate shift, Baines and Folland looked out along the atmospheric circulations ultimately driven by tropical ocean heating in the Atlantic. There they found changes in subtropical jet streams in both hemispheres and poleward shifts in storm paths. In southwest Australia, for example, the shift reduced the rains and brought long-term drought. Baines and Folland's explication of a globe-girdling late-'60s climate shift only reinforces the view that “the AMO does affect global climate,” says meteorologist Mojib Latif of the University of Kiel, Germany. “It's not just regional climate.”

## Anticipating nature

Appreciating the power and reach of natural climate variations is a major step. To put that information to use, however, climate forecasters must find a way to model the future course of the variations themselves, starting from current conditions. Climate researchers from the Hadley Centre, led by Douglas Smith, are the first to try that, as they report on page 796.

The Hadley group tested the usefulness of their new prediction model by “hindcasting” the climate of two past decades. Starting from the observed distribution of ocean heat content, the model outperformed its own forecasts that lacked observed initial conditions. Errors in predicting global temperature declined by 20% or 36%, depending on the type of error. The model successfully predicted the warming of El Niño and the effect of unusually warm or cold waters around the world. An actual forecast starting in June 2005 correctly predicted that natural variability—the appearance of cooler water in the tropical Pacific and a resistance to warming in the Southern Ocean—would offset greenhouse warming until now. But beyond 2008, warming sets in with a vengeance. “At least half of the 5 years after 2009 are predicted to be warmer than 1998, the warmest year currently on record,” the Hadley Centre group writes.

“Smith et al. is an important first step in setting out the method,” says meteorologist Tim Palmer of the European Centre for Medium-Range Weather Forecasts in Reading, U.K. Now researchers need to amass more computing power, more past observations to test the method better, and more future observations to feed the models, he says. And time is of the essence. If the AMO in fact played a substantial role in the rapid warming and enhanced hurricane activity of the past decade or two, says Sutton, “there will in all probability be a turnaround [of the AMO], possibly in the next decade.” It would be nice to know for sure.