# News this Week

Science  06 Apr 2001:
Vol. 292, Issue 5514, pp. 24
1. AIDS RESEARCH

# Merck Reemerges With a Bold AIDS Vaccine Effort

1. Jon Cohen

KEYSTONE, COLORADO—Over the past few years, scientists from Merck & Co. have quietly built an AIDS vaccine research program that has fundamentally altered the landscape of this beleaguered field. In separate presentations at a scientific meeting* here this week, Merck researchers Emilio Emini and John Shiver described some of the first results of this ambitious effort: a comparison of various AIDS vaccine approaches in more than 100 monkeys. The work indicates that Merck is banking more heavily than any other vaccine maker to date on the so-called “monkey model” to select the most promising strategy for human tests. But what most dazzled researchers here is the sheer scale of the company's AIDS vaccine effort, an endeavor that has attracted scant interest from other big pharmaceutical companies.

As Merck scientists and others stressed, huge obstacles stand between monkey results and a vaccine that works in humans. Merck's successes in monkey experiments also closely resemble the positive results reported recently by several other groups. Still, Merck's single-minded pursuit of vaccines that ignore antibodies and instead boost what is known as the “cellular” arm of the immune system impressed many of the 300 researchers who attended the gathering. “I think their studies are terrific and very energizing,” says David Watkins, a primate researcher at the University of Wisconsin, Madison. “I'm delighted that they've made such a comprehensive effort.” Douglas Richman, a virologist at the University of California, San Diego, emphasizes that academic groups simply don't have the resources to conduct such extensive, systematic studies.

Shiver first described a head-to-head comparison of five different vaccines that represent an about-face for the company. In 1986, Merck launched what became a leading AIDS vaccine program based on the idea that antibodies, which prevent invaders from infecting cells, would hold the key to a successful AIDS vaccine. Disappointed with the difficulty of stimulating potent antibodies, Merck scuttled that approach in 1992 and all but disappeared from the field. Shiver explained how the company has since designed vaccines to stimulate cellular immunity, which eliminates those cells the virus has managed to infect.

Specifically, these five vaccines exclude the gene that codes for the envelope protein of the AIDS virus—the focus of Merck's earlier effort—because it stimulates production of antibodies and it also varies greatly among viral strains. Instead, these vaccines each contain one gene from SIV (the simian cousin of HIV) called gag, which codes for an internal protein of the virus that is highly conserved in different strains. The comparison essentially asked which carriers, or “vectors,” best deliver gag and stimulate the highest levels of “killer cells.”

Three of the vectors in this study were variations of a bacterial plasmid, a ring of naked DNA. Another vaccine stitched gag into a version of the smallpox vaccine, modified vaccinia Ankara (MVA). The fifth vaccine used a crippled version of adenovirus, Ad5. After immunizing 15 animals, three with each vaccine, the researchers found the best killer cell response with Ad5 and a DNA vaccine that included a novel potentiator, or adjuvant, polyoxyethylene. They then “challenged” the vaccinated animals by injecting them with SHIV 89.6P, a hybrid strain of SIV and HIV that quickly causes immune destruction and death in monkeys. Six unvaccinated controls also received an injection of SHIV 89.6P.

The challenge virus infected all of the animals; 8 months later, five of the six controls had AIDS-like illnesses, and several of the vaccinated animals also had high levels of virus in their blood. In contrast, the animals that received Ad5 and the DNA vaccine with the novel adjuvant had low viral loads and suffered no immune damage.

Other groups have reported comparable protection with similar strategies, including the authors of a paper published in this issue (see p. 69). But Merck has taken these leads a step further. Emini described how the Merck team—which includes no fewer than 48 lab chiefs—analyzed HIV-infected humans to see which viral proteins triggered the strongest killer cell responses. This led them to add the genes pol and nef to their vaccines. Next, they injected dozens of monkeys with different vectors and at different doses to optimize killer cell production.

Merck now intends to challenge monkeys that have been immunized with their best DNA vaccine followed by two shots of the Ad5 vaccine. One possible problem is that roughly 50% of humans have antibodies against adenovirus, which might hamper the vector's ability to deliver HIV genes. Several researchers also cautioned that SHIV 89.6P might not accurately reflect how HIV behaves in humans.

View this table:

HIV typically causes AIDS after 10 years, while SHIV 89.6P can destroy the immune system of monkeys in as little as 3 weeks. “People picked that because they thought that it was setting the bar high: If you could protect against this, you knew your vaccine was good,” explains Mark Feinberg of Emory University in Atlanta. But paradoxically, SHIV 89.6P “may be easier to contain,” says Feinberg. Answering this question with certainty, however, is tough because researchers are using a dizzying array of challenge strains, making it nearly impossible to compare experiments from different groups (see table). In addition, no one has yet tested the same vaccine against SHIV 89.6P and other strains. Merck's Shiver says company scientists now plan to do just that.

Small human studies have begun with Merck's DNA and Ad5 vaccines; even so, the best guess is that figuring out whether this approach works will take at least 5 years. Either way, says University of Pennsylvania virologist Neal Nathanson, the recently retired head of the Office of AIDS Research at the National Institutes of Health, Merck's comprehensive studies represent a “landmark.” “For those of us who have followed the field, we're beginning to see light at the end of the tunnel.”

• *“AIDS Vaccines in the New Millennium,” 28 March to 3 April.

2. CLINICAL RESEARCH

# Fred Hutchinson Center Under Fire

1. Eliot Marshall

One of the most respected U.S. clinical research centers—the Fred Hutchinson Cancer Research Center in Seattle—has been engulfed for the past month in a media investigation of alleged conflicts of interest and ethical problems in clinical trials conducted there in the 1980s. Now, partly as a result of this news coverage, “the Hutch” has been hit with a class-action lawsuit by the husband of a cancer patient who volunteered for experimental therapy in 1985.

The controversy began when The Seattle Times ran a five-part investigative series on 11 to 15 March charging that the Hutch had exposed subjects to undue risks in bone marrow transplantation trials in the 1980s and 1990s. The Times report claimed that researchers had failed to inform subjects properly about alternative therapies and neglected to tell them of potential financial conflicts of interest among the staff. Members of the Hutch, who were testing monoclonal antibodies in cancer therapy, had invested in a biotech company that was trying to develop monoclonal antibodies for biomedical use. Hutch officials insist, however, that the monoclonals developed and used in the clinic were not of interest to the company.

Center president Lee Hartwell, who was not in charge when these trials were done, immediately rejected the Times' allegations in a series of newspaper ads and accused the Times of spreading “blatantly false” information. Two weeks later, the Hutch was rattled by an aftershock. William Lee Wright Sr., the husband of a patient who had died in a bone marrow transplantation experiment, sued the center and named families of other participants as fellow plaintiffs. Hutch officials say the suit has no merit but declined comment while the litigation is pending.

The suit follows on the heels of a similar case handled by the same attorney who is representing Wright—Alan Milstein of the Pennsauken, New Jersey, firm of Sherman, Silverstein, Kohl, Rose & Podolsky. Last year, Milstein won a significant settlement from the University of Pennsylvania (the amount is undisclosed) on behalf of the father of Jesse Gelsinger, a young man who died in a gene therapy trial in 1999.

Milstein says he learned of the Seattle case “from the newspapers.” The Wright suit, filed on 26 March in Kitsap County court, names as defendants the Hutch, a co-founder, several physicians, and a biotech company, alleging that they violated federal guidelines, committed fraud, and subjected patients to “battery” in the pursuit of a clinical breakthrough. The suit focuses on “protocol 126,” a series of experiments begun at the Hutch in 1981 and modified seven times over the following 12 years. The protocol's objective, according to comments the Hutch has posted on its Web site, was to improve the survival rate of leukemia patients receiving bone marrow transplants by blocking a dangerous graft-versus-host immune response (www.fhcrc.org). The experiments sought to do this initially by using monoclonal antibodies to target and deplete T cells in donor marrow.

The experiments did not lead to a successful therapy, and Hutch officials concede that about 17 of the 82 patients appear to have died of graft failure. In retrospect, they say, it was clear that T cell-depleted marrow did not engraft as well as untreated marrow. The Seattle Times—and the lawsuit—claims that patients who enrolled in later stages of protocol 126 were not adequately informed of earlier failures and might have fared better on “standard” therapy (which was also pioneered at the Hutch). The Hutch insists that each stage of protocol 126 was a unique trial, “conducted separately,” with specific risks and benefits—and that patients were fully informed and gave proper consent at each stage. In addition, the Hutch points out that the experiments were peer-reviewed at the National Cancer Institute twice, in 1981 and 1986. Hartwell has appointed an outside panel—chaired by Seattle University chancellor Father William Sullivan—to take another look at all these issues.

Milstein, meanwhile, appears to be targeting other clinical research projects. He says he represents more than 10 clients in a suit against the University of Oklahoma's Health Sciences Center in Tulsa. Outside investigators faulted members of the Tulsa staff for errors in obtaining consent from human subjects, including being too optimistic in descriptions of the possible benefits of an experimental cancer vaccine (Science, 4 August 2000, p. 706). Milstein says he plans to announce another big suit involving clinical research “in about a week.”

3. ASTROPHYSICS

# Farthest Supernova Yet Bolsters Dark Energy

1. Mark Sincell*
1. Mark Sincell is a science writer in Houston.

If the idea that the universe is flying apart at ever-increasing speeds makes you seasick, better stock up on Dramamine. A star exploding in another galaxy has just given that theory a fresh boost.

Until recently, the queasy could hope that the evidence for the acceleration—the systematic dimming of distant supernovae—was really due to something else. Maybe intervening dust clouds were sopping up some of the light. Or maybe some quirk of cosmic evolution made ancient dying stars as different from today's supernovae as Donald Johanson is from the Lucy skeleton he found in Africa. One test could easily settle the issue: If dust or evolution were at work, more distant supernovae should become progressively fainter. If, however, unseen “dark energy” were pushing the universe apart, cosmologists predicted that the dimming with distance should eventually stop.

Now, through a combination of inspired detective work and plain old good luck, a team of astronomers led by Adam Riess of the Space Telescope Science Institute (STScI) in Baltimore has identified the most distant supernova ever. As Riess and colleagues announced on Monday at a press conference in Washington, D.C., supernova SN1997ff is so bright that it rules out both dust and evolution as explanations for the dimming, bolstering the case for dark energy.

“This is tantalizing evidence,” says Robert Kennicutt, an astronomer at the University of Arizona in Tucson. “They have done a very careful job with both the measurement and the error analysis, and that is very important in this game.”

The game is dissecting the light of a special class of supernova called a type Ia. A type Ia supernova erupts when enough ambient gas falls back onto the snuffed-out core of an old star to raise the star's mass to 1.4 times the mass of the sun, making the star collapse and explode. Because they start with nearly the same amount of combustible fuel, all type Ia supernovae reach nearly the same peak brightness before fading. That allows astronomers to determine exactly how far away a supernova is: The fainter the measured peak, the farther away the supernova. “They are nature's cosmic mile markers,” says Riess.

The color of a type Ia supernova also reveals how much the universe has grown since the star exploded. As the universe expands, the wavelength of light traveling through space also stretches by the same amount. Astronomers call this effect a redshift, because the increase in wavelength changes blue light to red. The more the universe has grown in the time it takes light from a distant supernova to reach Earth, the larger the redshift.

In the early 1990s, while assembling the redshifts and peak brightness of hundreds of supernovae, two international teams based at the Lawrence Berkeley National Laboratory in California and Mount Stromlo Observatory in Australia made a surprising discovery. At larger redshifts, type Ia supernovae become progressively fainter than predicted by the simplest model of a steadily expanding universe. “They are dimmer than we expect for a universe that is expanding at a constant rate or slowing down,” says Saul Perlmutter, a leader of the Berkeley group. To explain the dim supernovae, both teams concluded that the expansion of the nearby universe has to be accelerating. And to drive the acceleration, the universe must be filled with dark energy.

The hitch was that, on a cosmic scale, the supernovae astronomers had seen weren't very far away—merely a few billion light-years or so. As a result, the universe hadn't picked up enough speed since the stars exploded to make much difference in their brightness. “You could say, ‘That's not very much,'” says cosmologist Michael Turner of the University of Chicago. “ ‘Maybe it's just dust blocking the light, or maybe supernovae are just dimmer in the early universe.'”

SN1997ff has dealt those ideas a potential death blow. When astronomers spotted it in a follow-up observation of the Hubble Deep Field in 1997, they knew it was far away. To tell how far, though, they needed the peak brightness—information that one image could not reveal. Digging in the Hubble Space Telescope archives, Riess and his collaborators spotted SN1997ff in the corner of a series of infrared images taken during an unrelated research project. “There were nearly 35 days of data in the archives,” says Riess. That was more than enough to show that SN1997ff was a type Ia supernova in a galaxy over 10 billion light-years away. And it was brighter than it would have been if either dust or evolution were responsible for the apparent dimming.

Does this supernova prove that the universe is filled with dark energy· Cosmologists say they would like to see a few more examples before they decide. “Extraordinary results require extraordinary scrutiny,” Turner says. But at the least, the discovery of SN1997ff gives cosmologists a useful new tool. “The way to understand the nature of dark energy is by studying supernovae like this one,” says Turner, “and this discovery shows that they are out there.”

4. VENICE PRESERVATION

# Climate Change Data Prompt New Review

1. Susan Biggin*
1. Susan Biggin writes from Trieste, Italy.

TRIESTE, ITALY—The Italian government has put another hurdle in the way of a controversial plan to control the flooding of Venice. Last month, the government sent the plan—which has been under development for almost 30 years—back for reworking under its water authority in Venice. The move leaves open the question of exactly what will be done.

On 15 March, the Council of Ministers agreed that the city's proposed $2 billion mobile floodgate scheme, called MOSE (Modulo Sperimentale Elettromeccanico, or experimental electromechanical module), should be reviewed once again to factor in potential rises in sea level caused by global climate change (Science, 25 August 2000, p. 1301). The ministers also directed that MOSE should be integrated with small-scale measures such as raising pavement levels. The review is expected to begin immediately. But details remain unresolved, as does the role of the Consorzio Venezia Nuova, which has designed and assessed the project and is also expected to lead construction of the floodgates. Willer Bordon, head of the Environment Ministry (which has opposed MOSE in its present form), emphasizes that the review is not a green light for MOSE itself. Nerio Nesi, head of the Ministry of Public Works—which has backed the project and will oversee the review—is more positive. “Venice needs [both] MOSE and the small-scale measures,” he says. “The MOSE project only needs updating in view of the predicted changes in climate.” The idea for MOSE arose after a 2-meter flood in 1966. Its central feature is a system of inflatable mobile barriers that would close off the three lagoon outlets when tides exceed 1 meter. Planning began in the 1970s, and the project was finally endorsed in 1998 by the Veneto region, as well as an international panel. The ministries of environment and cultural heritage rejected the assessment, however, but the Veneto Court annulled their decree last July. With two ministries warring over the project, the issue was handed over to the Council of Ministers to resolve. Last month's decision comes 10 weeks after a deadline set last year and 2 months before general elections. Members of environmental groups, who say that MOSE could turn the ecosystem into a “stinking marsh,” worry that projected global warming will exacerbate the problems by requiring greater use of the floodgates. Instead, they pin their hopes on such small-scale operations as raising pavement, which is already under way, and proposals to reconfigure the port outlets, strengthen the shorelines, and rebuild the quays. Officials for the Green Party say that such projects could reduce the effective tide level by up to 40 cm, safeguarding the lagoon for the next 50 years and permitting a reanalysis of MOSE that is based on more recent scientific findings. Nesi says that the planning effort should be completed within “a few months.” Bordon and the environmentalists hope for a formal reassessment of MOSE's environmental impact then, before the Council of Ministers takes final action. In the meantime, the European Community is looking into whether the Consorzio's role in the project represents an infraction of community regulations on open competition. 5. BUSH APPOINTMENT # Venture Capitalist to Lead Science Panel 1. David Malakoff The Bush Administration has made its biggest science-related job appointment so far. President George W. Bush last week named Floyd Kvamme, a former computer industry executive and Republican stalwart, to lead his science advisory panel. The post of presidential science adviser, a full-time position typically held by a prominent scientist from academia, remains empty. Kvamme, 62, is a partner in the California venture capital firm of Kleiner Perkins Caufield & Byers, which provided early backing for such prominent high-tech companies as Genentech and America Online. He becomes co-chair of the President's Committee of Advisors on Science and Technology (PCAST), a volunteer panel stocked with prominent researchers and industry chiefs whose other co-chair is the science adviser, who also heads the White House Office of Science and Technology Policy. PCAST meets periodically to offer its thoughts on hot science policy topics, although past presidents, including Bill Clinton, have paid scant attention to the group. In naming Kvamme on 28 March, Bush said that “science and technology have never been more essential to the defense of the nation and the health of our economy.” He called Kvamme “a risk taker” who “knows the players.” Kvamme's background includes stints at computer giants Apple and National Semiconductor. He is an electrical engineer by training. Kvamme was unavailable to comment, but science community leaders familiar with his résumé predict that he will be a strong advocate for science and technology. John Yochelson, president of the Washington, D.C.-based Council on Competitiveness, says Kvamme understands the link between government research spending and economic growth, and he is close enough to Bush to gain his ear. But some science policy veterans were surprised that the PCAST appointment preceded the selection of a science adviser. D. Allan Bromley, former engineering dean at Yale University and science adviser to the first President Bush, called the timing “a little peculiar.” 6. GERMANY # A Big Boost for Postgenome Research 1. Robert Koenig BERN—Germany may have been a minor player in the human genome sequencing project, but it is making a bid for the big leagues in the next wave of functional genomics research. Last week, the nation's research ministry said it will channel$175 million over the next 3 years into a National Genome Research Network involving at least 16 universities, several Max Planck institutes, and four national research centers. German research minister Edelgard Bulmahn, who announced the initiative on 30 March in Berlin, said the new program is intended to “put Germany in the forefront of public support for the systematic functional analysis of genes and the use of those research results in the fight against widespread diseases.”

The new Genome Research Network— financed by government revenues from last year's licensing of communications frequencies—has three main parts (see table): a “core area” consortium of big nonuniversity research centers, a “disease- oriented genome network” that links research at 16 universities with other centers, and a separate category to fund proteomics and bioinformatics research. In addition, $10 million will be spent to study the ethical, social, and legal impacts of genomics research. Bulmahn said a high-level group of academic and industrial researchers will serve on a panel that will help set overall directions for the network and give advice on which projects to fund. View this table: The core area consortium will get about 38% of the money for functional genomics projects. Funding will be divided among four national research centers—the German Cancer Research Center in Heidelberg, the German Research Center for Biotechnology (GBF) in Braunschweig, the Max Delbrück Center for Molecular Medicine in Berlin, and the National Research Center for Environment and Health in Munich—and the Max Planck Institute for Molecular Genetics in Berlin. Rudi Balling, a prominent mutant-mouse researcher who became the GBF's scientific director earlier this year, said the$10 million in extra funding that the center will receive from the program will help him reorient GBF's research to focus on the genetic basis of infectious diseases. He said the grants will also help the GBF play a role in the rat genome sequencing project.

A nearly equal share of the money will go to a disease-oriented genome network that will include an array of research institutes at 16 universities. The main focus will be on functional genomics related to five types of disease: cardiovascular disorders, cancer, problems of the nervous system (including Alzheimer's disease), infectious diseases, and environment-related illnesses such as asthma. Those university networks are to cooperate with the core area research institutions for specialized work, such as help with sequencing.

For example, seven research groups at the University of Bonn will share about $4.5 million in genome network funds to help identify the genes and mutations that lead to diseases of the central nervous system, including schizophrenia, epilepsy, and manic depression. At the University of Kiel, about$5 million in grants will fund research on inflammatory and environment-related diseases.

The third main category of funding—amounting to about $32 million—is proteomics and bioinformatics research, which will fund work at several university and nonuniversity institutes. Although many scientists welcomed the initiative, some worry that its 3-year time frame—with no clear guarantee of long-term research money—might limit its impact. Germany's main opposition party, the Christian Democrats, has called for even more funding for functional genomics research, as has the nation's main basic research granting agency, the Deutsche Forschungsgemeinschaft. 7. GERMANY # Old Guard Battles Academic Reforms 1. Robert Koenig BERN—The war of words over efforts to reform Germany's hierarchical university system ratcheted up a level last week. The latest salvo is a 4-page advertisement in the nation's top newspaper, signed by 3759 professors, that criticizes the research ministry's plans to create “junior professors,” phase out the Habilitation requirement—a kind of extended postdoc needed to secure academic tenure—and change some work rules that favor professors. Under the headline “Protect Universities From the Departure of Their Top Talent,” the ad urges the German Parliament to reject the proposed reforms. It says they would degrade the quality of professorships under the guise of promoting more independence for younger researchers. Hartmut Schiedermair, a law professor at the University of Cologne, warns that presenting the reforms as “cost neutral” is misleading and that the likely result will be pay cuts that will drive many new professors into industry or abroad. Schiedermair is also president of the main organization of German university professors, the Deutscher Hochschulverband (DHV), which placed the ad in the Frankfurter Allgemeine Zeitung newspaper. The signatories represent nearly 12% of the country's 32,000 professors. The chief target of the DHV's wrath is research minister Edelgard Bulmahn, who has championed the reform package. A ministry spokesperson calls the campaign “unserious and full of errors.” For example, she rejects the DHV's assertion that salaries for new professors would fall substantially under the new system. Although it sets a minimum salary, she says, the best professors would likely receive significant pay hikes based on merit. Supporters of the reforms include the HRK German conference of university rectors and presidents and Ernst-Ludwig Winnacker, president of the DFG (Deutsche Forschungsgemeinschaft) basic research granting agency, who says that the professors' letter is “unfortunate if not counterproductive.” They and others argue that the best way to promote the independence of young scientists is to create “junior professorships”—roughly equivalent to U.S.-style assistant professor slots—and to phase out the post-Ph.D. Habilitation requirement, which puts young researchers under the thumb of senior professors for years. The reforms were supported last year by a high-level commission (Science, 21 April 2000, p. 413) and more recently by a petition signed by 646 German scientists working abroad. The lobbying from all sides is converging on Germany's Parliament, which appears likely to make its decision later this year. With one of Germany's leading newspapers describing the fight as “The Bulls Against Bulmahn,” the debate promises to be one of the nation's liveliest in years. Many scientists also consider it to be one of the most important to the future of German research. 8. JAPAN # Court Backs Lab's Safety Practices 1. Dennis Normile TOKYO—A Japanese court has rejected claims by a citizens' group that a major biomedical research facility poses a safety threat to downtown Tokyo. But the plaintiffs aren't finished: They hope that the government's poor record on several health and safety issues will fuel a nationwide campaign against other research facilities. The suit was brought by some 200 people who live or work near Japan's National Institute of Infectious Diseases (NIID) in central Tokyo. A part of the Ministry of Health, Labor, and Welfare, the NIID is the government's main facility for studying and tracking infectious diseases, including such deadly pathogens as dengue virus and hantavirus. The suit was originally filed in 1989, 3 years before NIID's predecessor moved to the present site. The plaintiffs enlisted European biosafety experts, who detailed numerous violations of World Health Organization (WHO) biosafety standards. The NIID marshaled its own outside experts, who found no problems (Science, 9 October 1998, p. 213). Last week the Tokyo District Court sided with the NIID, finding “no illegality” in the facility's operating practices. The court said that the WHO recommendations have no standing under Japanese law and that the plaintiffs' claims lacked supporting evidence and were based only on a “vague fear of the unfamiliar.” “It is surprising that the court found not a single safety violation,” says the plaintiffs' lawyer, Syuichi Shimada. The decision, he adds, appears to endorse an institution's right to both set safety standards and then decide whether those standards are being met. NIID officials failed to respond to requests for comment. Although most in the scientific community believe that the neighbors' fears are overblown, many feel that the NIID and the Health Ministry mishandled the situation. Ken-Ichi Arai, director of the University of Tokyo's Institute of Medical Science, says that residents living near research facilities should be given adequate explanations of an institute's mission and safety precautions regardless of the level of biohazards involved. The government's slow and clumsy response to the threat of contaminated blood products, which resulted in thousands of hemophiliacs being infected with the AIDS virus, has weakened its credibility, adds Arai, whose institute recently held “many, many meetings” to sooth neighborhood qualms over its expansion plans. NIID's neighbors are appealing the ruling, although a reversal is unlikely. But although they appear to have lost this battle, they and their supporters plan to fight on. They have set up an organization to aid other grassroots groups who want to combat similar facilities, and some plaintiffs have published a book about their experience as a guide for future legal actions. “I think citizen activism regarding biohazards is likely to increase,” says Kenji Urata, a law professor at nearby Waseda University. 9. REPRODUCTIVE SCIENCE # Human Cloning Plans Spark Talk of U.S. Ban 1. Gretchen Vogel U.S. lawmakers have renewed their efforts to ban human reproductive cloning after hearing last week from two groups that say they intend to produce a human clone. Several bills were introduced 2 years ago after a physicist, Richard Seed, made a widely publicized claim that he would attempt to clone a human. But scientists warned that loosely worded legislation could stifle a broad range of important health research, and no bill was passed (Science, 20 February 1998, p. 1123). More recently, the U.S. Food and Drug Administration (FDA) has said it would prohibit any attempts at cloning because the procedure is unsafe. But at a 28 March hearing of the House Energy and Commerce Subcommittee on Oversight and Investigations, lawmakers worried that FDA's authority could be struck down in court, or that it might not be able to prevent secretive efforts to clone a child. “It is my view that the risk is so grave … that we will have to act,” said panel chair Representative James Greenwood (R-PA). The hearing featured several experts on animal cloning as well as representatives from two groups that say they are attempting to produce a human baby using nuclear transfer techniques. That's the technology used to create the sheep Dolly as well as cloned goats, cattle, mice, and pigs. Scientists remove the nucleus of an egg cell, replace it with a nucleus from the animal they wish to clone, and then jump-start embryo development with an electric shock or chemical signals. Chemist Brigitte Bossilier of Clonaid, an organization founded by the Raëlian religious movement, spoke about the company's plans to transfer the nucleus of a frozen cell taken from a baby that died after surgery. Bossilier testified that the company's scientists, working in a secret location in the United States, had been practicing removing nuclei from cattle eggs but have not yet begun to work with human cells. She told the panel that the developmental problems seen in animal clones would not necessarily occur in humans. Infertility researcher Panos Zavos of the Andrology Institute of America in Lexington, Kentucky, who has announced his intention to produce clones for infertile couples, told the committee that he and his colleagues would carefully screen embryos for abnormalities during gestation. “We would not step on dead bodies or deformed babies” to pursue the technology, said Zavos, who is leading work in an undisclosed country. But developmental biologist Rudolph Jaenisch of the Massachusetts Institute of Technology's Whitehead Institute told lawmakers that Zavos's and Bossilier's description of the risks was “totally irresponsible and misleading.” He said he suspects that all animal clones so far—even those that seem normal—have subtle defects in the brain and other organs. Although scientists are not yet sure, Jaenisch thinks a gene regulation process called DNA methylation goes awry in the cloning process. Currently there is no test for methylation abnormalities, he said. FDA's Kathryn Zoon testified that her agency has jurisdiction over human cloning as part of its oversight of biological products. But several lawmakers worried that her argument sounded similar to the FDA's justification for regulating tobacco, which courts struck down. Several members also questioned the agency's ability to act quickly. Despite extensive coverage of Clonaid in the press, it wasn't until 2 days before the hearing that the FDA told Bossilier in a letter that Clonaid must obtain FDA approval before proceeding with its cloning efforts. Bossilier has not yet responded. The testimony “has raised our level of interest in legislating in this area,” said Representative Billy Tauzin (R-LA), chair of the parent Commerce committee. Greenwood said that he and Tauzin would soon introduce legislation to regulate attempts at human cloning. On the day of the hearing, Representative Brian Kerns (R-IN) introduced a bill that would impose fines or prison terms for anyone who undertook human nuclear transfer experiments “with the intent of implanting the resulting cellular product into a uterus.” Tim Leshan of the American Society for Cell Biology says that Kerns's bill is narrow enough not to hobble mainstream research. But he warned scientists to monitor its path closely. The wording “may seem fine in the beginning,” Leshan says, “but you never know what could happen in committee or on the floor.” One scientist who testified said that he would favor a carefully worded ban on reproductive cloning. “We don't know how far human clinics have gone,” explained developmental biologist and cattle cloning expert Mark Westhusin of Texas A&M University in College Station after the hearing. “For now … it looks like we're going to need these types of regulations to get some control over it.” 10. STEM CELL POLICY # Canadian Panel Aims for Middle Ground 1. Wayne Kondro* 1. Wayne Kondro writes from Ottawa. OTTAWA—New guidelines proposed last week by a blue-ribbon committee would allow Canadian scientists to derive stem cells from embryos left over from fertility treatments or fetal tissue obtained from elective abortions. The proposal is less restrictive than U.S. guidelines currently under review by the Bush Administration. Alan Bernstein, president of the Canadian Institutes of Health Research (CIHR), which formed the panel, says that the proposed guidelines would allow researchers to explore such questions as what makes a cell commit to becoming a particular type of tissue and whether stem cells can be used “to actually cure diseases.” Adds Mick Bhatia, who works with blood stem cells at the John P. Robarts Institute in London, Ontario, “we certainly would be happy if the CIHR would fund research in this area.” U.S. policy, which is being reviewed by Health and Human Services Secretary Tommy Thompson, requires government-funded scientists to obtain embryonic stem cells from private sources. The Canadian panel took a more lenient approach, but it didn't go as far as U.K. rules, which allow scientists to create embryos for research purposes. “In developing the [final] guidelines, the question is whether the benefits outweigh the controversial aspects of using embryos for research of this sort,” says panel chair Janet Rossant of Mount Sinai Hospital's Samuel Lunenfeld Research Institute in Toronto. In weighing that balance, the 10-member panel opposed the donation or sale of gametes to create embryos for the sole purpose of generating stem cell lines. It also urged a moratorium on creating human embryos by somatic cell nuclear transfer, saying that the underlying science is flimsy and that the practice would inevitably lead down a slippery slope to human cloning. It suggested forming a national advisory body to oversee stem cell research, both public and privately funded, and possible licensing of researchers. Such an oversight body is expected to be part of long-promised federal legislation on reproductive technologies. Antiabortion groups have already lined up against the guidelines. “We're well aware of the utilitarian argument, that [fetal tissue from elective abortions and embryos from fertility treatments] are going to be discarded anyway,” says Tim Bloedow, spokesperson for the Campaign Life Coalition. “But we do not feel it's right to use that tissue for this kind of research.” The guidelines will go before the CIHR governing board this fall. Issues still to be resolved include whether to allow donors to select a particular research lab and whether to require consent from the woman who had an abortion or the individuals whose gametes were used during in vitro fertilization. Those gametes usually come from an anonymous donor, notes committee member and Dalhousie University bioethicist Françoise Baylis. If the CIHR board approves the guidelines, Bernstein foresees a boom in stem cell research once money becomes available. Bhatia agrees that interest is high, but he also hopes that the final guidelines will satisfy an ethical “comfort level” among the general population. 11. ASTRONOMY # Comet's Course Hints at Mystery Planet 1. Govert Schilling* 1. Govert Schilling is an astronomy writer in Utrecht, the Netherlands. A supercomet following an unexpectedly far-flung path around the sun suggests that an unidentified planet once lurked in the outermost reaches of the solar system, an international team of astronomers reports. What's more, the scientists say, the mysterious object may still be there. “This is the first strong evidence that somewhere out there, there once was something big,” says Hal Levison of the Southwest Research Institute in Boulder, Colorado. “It's a very important result.” The giant comet, known as 2000 CR105, measures some 400 kilometers across. It is one of the hundreds of known trans-Neptunian objects (TNOs)—icy leftovers from the early solar system that populate the Kuiper Belt, a flattened region beyond the orbit of Neptune, the outermost giant planet. According to most planetary scientists, distant Pluto is the largest member of this population. Some TNOs move in vast, elongated orbits. Current wisdom holds that they have been scattered into their eccentric trajectories by the gravitational pull of a giant planet, probably Neptune. If so, basic orbital mechanics dictates that these “scattered disk objects” should swing nearest the sun at perihelion points close to Neptune's orbit, some 4.5 billion kilometers from the sun. But comet 2000 CR105, first discovered in February 2000, doesn't follow this script. Brett Gladman of the Observatoire de la Côte d'Azur in Nice, France, and his colleagues have discovered that the giant comet's orbit is much larger and more distant than astronomers had assumed. Their observations reveal that 2000 CR105 orbits the sun in 3175 years and never comes closer than 6.6 billion kilometers—well beyond Neptune's orbit. The farthest point of the highly eccentric orbit lies 58.2 billion kilometers from the sun—13 times as far as Neptune. “[This is] the first [scattered object] beyond the dynamical influence of the giant planet system,” Gladman and his colleagues write in a paper submitted to the journal Icarus. So how did it get there· One possibility is that 2000 CR105's orbit evolved into its freakish shape gradually, due to small, periodic gravitational nudges from Neptune. Computer simulations imply that such a “diffusive chaos” scenario is unlikely, Levison says, but Gladman says it can't be ruled out. “It's hard to quantify,” he says. “There's even disagreement about this among the co-authors of the paper.” The alternative is that the supercomet was hauled into its present orbit by some massive object still farther from the sun. The object might have been Neptune itself: According to some theories, the planet once resided in a much more eccentric orbit and could have created havoc in the distant parts of the solar system. Or maybe there has been a transient population of massive planetary “embryos,” formed in the early days of the solar system and expelled later on. The most exciting possibility is that a planet-sized body still hides in the outer solar system. “A Mars-sized body [at an average distance of some 15 billion kilometers] could scatter a body like 2000 CR105 to its present orbit,” Gladman and his colleagues write in their Icarus paper. Unlike Mars, the planet would consist mainly of ice. Because its high mass would protect it from orbital disruptions, the astronomers say, it could still be around. “I'd love to find proof that this is true,” says Alessandro Morbidelli, a colleague of Gladman in Nice who is not on the team. “Unfortunately, this object [2000 CR105] doesn't constitute a definitive proof yet.” On the other hand, Morbidelli stresses, a Mars-sized body 15 billion kilometers away would not measurably affect the orbits of the known planets, so it could well have passed unnoticed. “There's no direct or indirect observational evidence that these objects can't exist,” he says. But Levison doesn't like the idea of an undiscovered Mars out there. “It's not clear how it would have formed,” he says. “I would be surprised if anything much larger than Pluto would be found. But of course I could be wrong.” Large or small, astronomers agree that whatever nudged 2000 CR105 into its large, distant orbit is bound to have done the same to other TNOs. “Finding more would give us a better idea of how they got there,” Levison says. 12. ECOLOGY # Words (and Axes) Fly Over Transgenic Trees 1. Jocelyn Kaiser The battle over genetically modified crops is being replayed as transgenic trees enter field trials Forest geneticist Steve Strauss just lost some of his idealism. He thought he was making the world a better place when he began working on genetically engineered trees 16 years ago at Oregon State University (OSU). If transgenic tree farms could help meet demand for pulp and paper, he thought, then natural forests might be spared. But 2 weeks ago, vandals attacked more than 800 young trees at Strauss's experimental plots near Corvallis, either hacking them down or condemning them to death by stripping off a ring of bark. A shadowy antibiotech group at OSU issued a letter claiming responsibility for destroying what it called “a dangerous experiment.” “It feels absolutely terrible,” says Strauss. “We're doing research we regard as a net environmental good.” Fortunately, he adds, his team had finished studying most of the trees, some of which were transgenics. Tree-chopping fringe activists aren't the only threat to transgenic tree research. Forest biotechnologists are also coming under fire from influential environmental groups such as the World Wildlife Fund (WWF), which claim that genetically engineered trees may wreak havoc on natural ecosystems and want a moratorium on their use. Indeed, transgenic trees may well be the next battleground in the war over biotechnology. Unlike genetically modified (GM) crops, which are already widely planted by farmers and consumed in foods, GM trees are still at least 5 years from commercialization in North America. Their developers say these trees, with traits ranging from fast growth to herbicide tolerance, could help solve environmental problems such as chemical pollution and the loss of wild forests. Critics, however, say the altered trees could do more harm than good—especially because they live much longer than crops. “I think this is a very risky approach,” says Faith Campbell of American Lands, a conservation organization in Washington, D.C. Although it's still early days, debate is flaring up worldwide: in New Zealand, where the government has been holding hearings on GM trees and other plants, to Canada and the United Kingdom, where experimental trees have also been vandalized. Hoping to avoid the brouhaha over GM foods, some researchers and companies are reaching out to their critics, inviting them to a meeting in Oregon in July. And industry groups, led by a nonprofit organization funded by the state of North Carolina, are launching a new think tank to debate and try to defuse societal issues before they explode. “I have to be optimistic that we're going to get past this phase,” says Strauss, who helped plan the think tank. ## The next battleground Forest biotechnology has taken off in the past decade despite scientific hurdles such as the slow growth rate of trees and their giant genomes, ranging up to 10 times the size of the human genome (Science, 9 February 1996, p. 760). Much work focuses on gene mapping and function, but plant molecular biologists have also added foreign genes for herbicide tolerance and the production of a bacterial insecticide called Bt to such mainstays as poplar, pine, and fruit trees. Working within labs and greenhouses, researchers are also developing trees that yield more energy when burned, and others with lignin modified so that the trees are easier to break down for paper. Plans afoot to sequence the first tree genome—the poplar, the model organism of forestry—should spur more such work. Like Strauss, many academic researchers say they got into this field because of its environmental benefits. Trees with less lignin should save on chemicals in paper factories, they say, while Bt trees could reduce the use of pesticides, and fast-growing trees could produce more wood on less land. At the same time, they were well aware of the ecological risk of these introduced traits spreading to natural forests. “We in the community talked about that from the get-go,” says David Neale of the U.S. Department of Agriculture (USDA) Institute of Forest Genetics in Berkeley, California. So research has also gone into developing sterile trees to minimize the risk; such sterile trees could also offer the bonus of faster growth, because they don't devote energy to flowering or producing seed. And even if sterilization isn't perfect, proponents argue that GM trees are unlikely to invade wild ecosystems, because their new traits won't give them a long-term advantage. A combination of government and private funds has supported GM tree development, with the dozen or so companies involved worldwide often collaborating with academic researchers such as Strauss. The reasons for commercial interest are clear: Traits such as faster growth and insect resistance could reduce the cost of growing trees on plantations. The industry heavyweight is Arborgen, a joint venture of International Paper, Fletcher Challenge Forests, and Westvaco Corp. formed in 1999. Arborgen is putting$60 million over 5 years into developing GM trees. All told, more than 300 field trials have been approved by the USDA, as well as a dozen or more by other countries, according to Campbell of American Lands, who checked public databases last year. But so far, nobody in the United States has applied to grow trees on a commercial scale, aside from virus-resistant GM papaya trees that are credited with saving the industry in Hawaii.

Until 1999, this work attracted little attention outside scientific circles. But in July of that year, demonstrators picketed a forest biotech conference at Oxford University, and activists hacked down a nearby field of lignin-modified poplars being tested by AstraZeneca. The WWF, followed last year by American Lands, then put out scathing reports calling for more research on risks and a moratorium on commercialization. Perhaps the biggest blow to forest biotechnologists is opposition from a coalition that certifies timber as sustainably harvested. The Forest Stewardship Council, which includes companies such as Sappi Forest Products and activists such as Greenpeace, refuses to certify any GM plantations, Strauss notes.

Environmentalists' main concern parallels that about GM crops: They're worried that pollen containing Bt proteins may harm nontarget insects such as monarch butterflies, and they're concerned that sterility won't work perfectly, resulting in gene “leakage.” In this scenario, transgenic trees might pollinate natural relatives and pass on traits such as pest resistance or modified lignin that could alter ecosystems in unpredictable ways. “Trees live a lot longer [than crops], and they're more integrated into natural systems,” Campbell says, so they pose a much greater threat. She also predicts that companies will abandon fields if they don't perform as expected. Because many GM plants are no longer regulated once they've been approved for commercial use, there's little to prevent that from happening, Campbell asserts. Stewart Maginnis of WWF also fears that plantations of fast-growing GM trees could add to environmental problems caused by some nontransgenic tree farms, such as depleted water tables and fertilizer runoff, while there's no evidence that they will do anything to slow global forest loss.

As the debate heats up, it is attracting attention from the broader community of ecologists. Peter Kareiva of the National Oceanic and Atmospheric Administration says he started to take notice when a European study of ornamental woody plants showed that although they spread very slowly, over the course of 150 years they had made substantial progress. “These woody plants could look harmless for 50 to 100 years and then become a pretty severe problem,” Kareiva says.

Strauss, who says the activists' two reports are “hysterical in places” and contain “scientific distortions,” argues that the ecological threat from GM trees is actually less than that posed by many of the trees already grown on plantations, which include exotic species that can become invasive weeds if not managed properly. “These things are not mortally dangerous compared to everything else we're doing,” he says. In a commentary in the December 1999 issue of Nature Biotechnology, endorsed by members of the International Union of Forestry Research Organizations (IUFRO), Strauss and several colleagues argued that GM trees would be unlikely to infiltrate natural forests because they could be made highly infertile and would be planted on managed farms and harvested after 3 to 25 years. The commentary also laid out the benefits of transgenic trees for meeting wood demand. “I'm not proposing that GM trees are a panacea, but I think they're part of the solution,” says Malcolm Campbell of Oxford University, a co-author.

Still, GM tree backers agree that gene escape is impossible to prevent entirely, and several groups are investigating the risk. For example, Steve DiFazio of Strauss's group has looked at gene spread from commercial plantations of nontransgenic hybrid poplar to nearby wild poplars. When DiFazio analyzed the DNA of seeds from wild trees growing close to the hybrids, he found that on average 0.2% of the seeds had been fathered by the hybrid trees, suggesting that the risk of pollen spread is real, although low. And insect ecologist Kenneth Raffa of the University of Wisconsin, Madison, has found that insect pests could develop resistance to Bt trees if the trees are not interspersed with a buffer zone of non-GM trees that would harbor populations of insects without resistance. The risks of GM trees, says Raffa, “depend on how they're used.”

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One of the few points of agreement among advocates and critics is that there aren't enough of these kinds of studies. USDA funds some work through its $1.5-million-a-year Biotechnology Risk Assessment Research Grants Program; a new USDA extramural grants program has supported studies of GM tree risks as well. That's small potatoes compared to the tens of millions being spent on tree development. Besides, review panels tend to reject proposals on “more complex questions” such as effects of Bt trees on a whole array of insect species, says Raffa. Companies are just beginning risk studies, and the public tends to distrust industry trials anyway, he notes. But Strauss argues that companies need to co-sponsor risk studies if they're to be done on a large enough scale to be meaningful. The problem, Strauss and others say, is whether field tests will escape the axes of the eco-terrorists, who have attacked at least a half-dozen experimental tree plots in the past 2 years. ## In search of consensus To explore such issues and reach out to their critics, Strauss and other forest biotechnology researchers hope to bring all sides together at a July symposium to be held in conjunction with a meeting of the IUFRO. The list of questions ranges from whether research should be put on hold, to whether allowing the public to monitor commercial plantations would make them more acceptable, to how best to study ecological risks. “We want to get as wide a group as possible to sign off on a scientific agenda,” says co-organizer Toby Bradshaw of the University of Washington, Seattle. Representatives from a few environmental groups will be there, along with ecologists and company scientists. The National Academy of Sciences' standing committee on ag biotech is expected to launch a study of the ecological risks of trees, ornamental grasses, and shrubs. And the forestry industry is reaching out to critics as well, motivated by a desire to save transgenic trees from the fate of GM crops. “A world with transgenic trees raises an entire range of very complicated issues,” concedes Steven Burke, senior vice president of the North Carolina Biotechnology Center, a state-funded nonprofit that promotes biotech. “This has been a big wake-up call to the forestry companies to say, ‘What can we do to make this palatable·'” notes Malcolm Campbell. The North Carolina biotech center is launching a new institute this year that will bring together respected representatives from companies, government, academia, and environmental groups. “We will only commercialize these technologies if there is a clear agreement to doing such,” says Daniel Carraway of International Paper, who was also on the planning task force. But some environmental groups are not convinced. Companies haven't indicated they'll take a precautionary approach and weigh the pros and cons before deploying trees, asserts Rebecca Goldburg of Environmental Defense: “It's not if, it's when.” Not necessarily, counters Strauss, who worries not only about the activists but also about how restrictive upcoming regulations on GM trees will be. “Nearly all the scientists I know believe that GM trees have a lot of potential,” Strauss says. “But if the whole process of moving them to the field is too expensive and legally risky, then scientists are going to walk away from this. … It would be a shame to foreclose the possibilities.” 13. GREENHOUSE EFFECTS # High CO2 Levels May Give Fast-Growing Trees an Edge 1. Laura Tangley* 1. Laura Tangley is an editor at National Wildlife and International Wildlife Loblolly pines may reproduce earlier—and more abundantly—in a future environment pumped up with carbon dioxide, according to a new study Take a walk through a southeastern U.S. forest half a century from now, and it may look, or at least smell, a lot like Christmas: Loblolly pines, fed by rising levels of carbon dioxide, fill the air with their scent. Spurred to early maturity, the pines are challenging slower growing species such as oak and hickory. As forest composition shifts, it affects animals, too, making life more difficult for some seed-eating birds and mammals while providing a boon to others. Although the scenario is hypothetical, it could happen, suggests a new study of CO2's effects on tree fecundity, reported on page 95. The research, conducted by Duke University biologists Shannon LaDeau and James Clark, shows that loblolly pines (Pinus taeda) grown for 3 years at the CO2 levels expected by 2050 are twice as likely to be reproductively mature, and produce three times as many cones and seeds, as trees in today's environment. This work marks the first time that a CO2 experiment has resulted in forest trees grown all the way to reproductive maturity. The conclusions are among several now beginning to emerge from an ambitious, decade-long project—launched 5 years ago in loblolly stands within a North Carolina Piedmont forest—that aims to predict the effects of high CO2 levels on both the trees and the ecosystem as a whole (Science, 5 May 1995, p. 654). Already, the project has confirmed one key result of earlier small-scale experiments—that high CO2 levels can spur faster photosynthesis and growth. As the first such experiment to look at forest tree fecundity, the new report is an “elegant demonstration that CO2's stimulatory effect on photosynthesis and growth carries over to reproduction,” says Peter Curtis, a biologist at Ohio State University in Columbus. Predicting the effects of high CO2 levels on natural ecosystems is more than an academic exercise, though. The answers are likely to fuel public policy debates on global warming. Because CO2 is a plant nutrient as well as a greenhouse gas, some researchers argue that faster growing trees of the future will absorb and sequester increasing amounts of CO2, making it unnecessary to impose new controls on the gas. Other scientists warn that the effects may not be benign and could include dramatic changes in the composition of ecosystems worldwide. Although heated debate continues over how much, or even if, the globe is warming, no one disputes the fact that atmospheric CO2 has increased—from about 270 parts per million (ppm) in 1870 to about 370 ppm today—and that it will continue to rise in the future. For more than 2 decades, biologists have been working to understand how plants respond to increasing CO2 levels—focusing first on crops (which clearly respond with faster growth and higher yields), then moving on to plants in natural ecosystems. But these experiments, conducted in greenhouses or growth chambers, have been hampered by artificial conditions. According to James Teeri, an ecologist at the University of Michigan, Ann Arbor, scientists discovered early on that “pot effects” skewed their results. That realization led to the development of outdoor open-top chambers, in which plants surrounded by polyvinyl chloride cylinders are fed extra CO2 but receive natural sunlight and grow freely in the soil. Yet these chambers hold only about a dozen small, immature trees. By contrast, the Duke experimental system can test the responses of an entire stand of adult trees. It relies on a technology—called Free Air Carbon Enrichment, or FACE—designed in the early 1990s by scientists from Brookhaven National Laboratory on Long Island. At Duke, large vertical pipes that release CO2 tower over six plots of mature loblolly pine, each 30 meters in diameter. Half grow at ambient CO2 levels and the other half at the 560-ppm concentration expected by 2050. Except for this extra CO2, conditions in the experimental and control stands are identical, and all trees are exposed to whatever Mother Nature decides to dish out. “If a deer wants to run through a plot and eat something, so be it,” says William Schlesinger, co-director of the Duke project. He adds that all the plots have experienced drought, record-level snowfall, and even a hurricane since they were established in August 1996. Today, there are 12 FACE sites up and running worldwide. Duke's is the oldest of three forest sites. The most important result to date, says Schlesinger, is that trees in the high-CO2 plots grew 25% faster than controls did during the first three growing seasons of the experiment (Science, 14 May 1999, p. 1177). Last year, however, the difference between the experimental and control stands “was not as great” as it had been from 1997 to 1999, suggesting that the initial boost CO2 gives to the growth rate of trees may not be sustained once other nutrients such as nitrogen begin to run out. By November, Schlesinger expects to have results from this year's growing season—and a much better idea of how at least one forest tree species will respond to high CO2 levels over the long run. The answer is critical to ongoing policy debates. Some partisans argue that faster growing forests will provide a sink for the excess CO2 humans produce, but “our experiments are suggesting that forests will soak up some of the excess carbon dioxide but nowhere near all of it,” says Schlesinger. And Harvard University biologist Fakhri Bazzaz, who also studies vegetative responses to CO2, estimates that higher levels of the gas will boost the growth rate of the world's plants by only about 10%—far less than what would be needed to balance the global carbon budget. High CO2's impact on pine fecundity turned out to be even more dramatic than its impact on growth—onset of reproductive maturity at smaller sizes and 300% more cones and seeds than controls. In addition, trees in the high-CO2 plots were producing more seeds than were trees of the same size in control plots, suggesting that they were putting a higher percentage of their carbon currency into reproduction. Early reproduction could also cause the trees to grow old and die sooner, reducing the amount of carbon they sequester. But for Pinus taeda, the study's results may be good news—and spell trouble for its competitors. Scientists have hypothesized that faster growing species such as pine will respond more to elevated CO2 levels than will slower growing hardwoods. If this turns out to be true, “we would expect to see dramatic changes in forest community composition,” says LaDeau. According to Bazzaz, simulation models predicting the effects of elevated CO2 levels 150 years from now do show a trend of decreasing species diversity over time. And in a still-unpublished meta-analysis of 170 studies of reproduction in herbaceous plants, mostly crops, Curtis found that fast-growing, high-yielding species—equivalent to loblolly pines—profited more from high CO2 levels than did slow-growing plants. “My suspicion is that forest communities will become less diverse as aggressive, fast-growing trees become more abundant,” he says. Such shifts in tree composition would have cascading effects throughout the ecosystem. Some pollinating insects and birds, for instance, may end up with more food and others with less, changing the abundance and distribution of these animals as well as other species that rely on them. It is way too soon, of course, to say whether any of this actually will happen. Among the Duke researchers' next steps is to examine the viability and quality of the seeds their experimental pines produced. They also are waiting for a handful of hardwoods growing in each plot to reach maturity—as well as those at an all-hardwood FACE site in Tennessee—so they can examine these trees' reproductive responses to CO2. But even following through on FACE experiments may never reveal how real forests will react to high CO2 levels. The Duke plots “are pine plantations, not forest ecosystems,” says Bazzaz. Teeri agrees that “what we really need are long-term studies of significant expanses of natural forest.” Researchers had hoped to conduct such mega-experiments soon, but Congress last year did not fund a$12 million request from the National Science Foundation to launch a National Ecological Observatory Network. For now, Duke's loblolly pine experiment—and others like it—may offer the best evidence of how forests will respond to CO2 buildup in the next half-century.

14. SCIENCE IN BRITAIN

# Science Centers Blossom, But How Many Will Survive?

1. John Pickrell

Hands-on science exhibits are springing up across the U.K. Now, they're all part of an unplanned experiment: survival of the fittest

BRISTOL, U.K.—Inside a huge, five-story greenhouse on the waterfront of downtown Bristol, tropical birds and butterflies flit above a botanist's wonderland. Glistening in the humid enclosure are species representing key events during 500 million years of plant evolution—from primitive liverworts and velvety mosses through horsetails, ferns, and conifers, on up to the flowering plants. Scientists laud the “Wildscreen” exhibit, saying that it vividly brings science to life. It's “a marvelous project,” says Thomas Eisner, an ecologist at Cornell University. “It's exactly what is needed to kindle an interest in nature and the spirit of conservation.”

Wildscreen is part of a phenomenon that's sweeping the United Kingdom. Fueled by $1.4 billion in national lottery revenues and matching funds, 10 science centers—including @Bristol, which houses Wildscreen—have opened their doors to the public since July 1999, and another seven are scheduled to get going in the next year. Created to mark the new millennium, the gleaming new edifices are replacing such urban chancres as derelict steelworks and neglected quays. From the National Space Science Centre featuring a Soyuz rocket to the model ecosystems inside the Eden Project's multiple linked geodesic domes—tall enough to enclose the Tower of London—the science centers offer much more than inner-city renewal, says @Bristol chief executive John Durant. “This is an amazing opportunity to change the scientific culture of a country and connect the community closely … to the world of science and technology,” he adds. But the science centers must count on a healthy patronage if this budding British renaissance in bringing science to the public is to succeed. The Millennium Commission, a quasi-governmental body that has funded the start-up of the 17 interactive science and technology centers (see table), has stated from the get-go that it will not provide operating money for its progeny. Once the initial funding has been exhausted, the centers are vulnerable to collapse—and that's not necessarily a bad thing, some argue. “Only the better schemes will survive,” says David King, chief scientific adviser to the U.K. government. “That's what survival of the fittest is all about.” ## Millennium fever Mandated to spend$3.2 billion in profits from the U.K. lottery, the Millennium Commission ended up doling out 21% ($390 million) to science-based projects, with commercial sponsors—a requirement—kicking in more than$1 billion more. The United Kingdom hasn't had an investment in science communication on that scale since proceeds from the Great Exhibition in 1851 were used to set up several major British institutions, including the precursors to London's Science and Natural History Museums, says John Beetlestone, founder of Techniquest, one of the few U.K. science centers started before the lottery bonanza.

Distinguished from museums by their emphasis on hands-on exhibits and lack of specimen collections, science centers first got going in the late 1960s, when the San Francisco Exploratorium and the Ontario Science Centre in Toronto were created. “The U.K. has been a relative latecomer in this area,” Beetlestone says. The concept took root in the United Kingdom only in the 1980s, with the launch of three centers aimed at elementary school children: Techniquest in Cardiff, the Exploratory in Bristol, and Launchpad, a hands-on exhibit in London's Science Museum.

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The lottery funds have shaken up the status quo. “The movement has changed from being a tiny crusade amongst a lonely group of enthusiasts, to something of a national movement,” says Durant.

In general, the new centers are receiving high marks for science content. Many have links to universities. For example, the Institute of Human Genetics at the University of Newcastle-upon-Tyne has moved its entire faculty (150 researchers) into new labs down the road at the International Centre for Life. And the National Space Science Centre, designed with the help of researchers at the University of Leicester, will house mission control for CATSAT, a satellite built partly by students under supervision from Leicester researchers.

“The initial quality of the centers looks high,” says Peter Cotgreave of the Save British Science Society. Not all scientists are impressed, however. “I'd like to see a lot more science in the new centers,” says University of Bristol neuropsychologist Richard Gregory, founder of the Exploratory, which was replaced by @Bristol.

## Financial uncertainty

Like young salmon, not all the hatchlings are expected to survive. Casting a shadow over the lottery-funded projects is the much-panned Millennium Dome, a nearly $1 billion exhibition in Greenwich that drew far fewer visitors than expected. But the dome is not the only 2000 baby to flounder: The National Centre for Popular Music in Sheffield has gone bankrupt, while the Earth Centre in Doncaster—the first science center driven to the financial brink—has closed temporarily, apparently to save money through restructuring after the number of projected visitors was cut by half. Many observers worry that the Earth Centre's woes are only the beginning of a wave. Part of the problem is that the commission funded each proposal on its merits, without judging how many science centers a single island nation might support. “The Millennium Commission didn't have any experience with science centers, so they really didn't know how to rationally decide which proposals to fund and which not to fund,” says Techniquest's Melanie Quin. “I fear visitor numbers will not be met simply because the centers conducted feasibility studies in ignorance of all the others.” And some of the feasibility plans are considered suspect. “In some cases, business plans were the product of market researchers sticking a wet finger in the air,” Quin says. “There has been an underestimation of what is needed to run and what is needed to invest,” adds Goéry Delacote, chief executive of San Francisco's Exploratorium. Whatever their initial promise, all the science centers now face a huge fund-raising challenge. “I don't know of a science center anywhere in the world that is meeting 100% of its running costs from commercial sources,” says Durant, who notes that visitor revenue covers 20% to 75% of a center's operating costs. “Education costs money and does not pay its way.” Some centers have done well in luring corporate sponsors; for instance, @Bristol's stable includes the European telecom giant Orange, which put up$5.7 million over 5 years for the Orange Imaginarium, an immense steel-hulled planetarium.

Another financial hurdle is that, in order to remain fresh, science centers must change their exhibits every 3 to 5 years—a considerable expense beyond running costs. The Millennium Commission may be poised to help out, however: It is discussing a set-aside of \$35 million for the development of new exhibits at existing science centers. “The proposal is still at an embryonic stage at the moment, but the idea and the willingness are there,” says the commission's Nina Baxter.

Rather than compete with one another, the science centers have banded together to lobby for more money. With start-up funding from The Wellcome Trust, they have formed a U.K. branch of the European Collaborative for Science, Industry, and Technology Exhibitions.

“I would be surprised if all the centers turn out to be a major success,” says Cotgreave. “But even if only some turn out that way, then it will all have been well worth it.”

15. LUNAR AND PLANETARY SCIENCE CONFERENCE

# Rethinking Water on Mars and the Origin of Life

1. Richard A. Kerr

HOUSTON—Last month, planetary scientists gathered here at NASA's Johnson Space Center to consider the rocky (and icy) bodies of the solar system, from motes of dust to the terrestrial planets. Mars got the lion's share of attention, including second thoughts on whether water has shaped gullies and layered sediments there, but the prospect of interstellar travel—by bacteria on bits of rock blasted from the planets—also came up.

## Not-So-Wet Martian Gullies?

Hopes for life on Mars got a boost last summer—at least in the public imagination—with the release of dramatic pictures of gullies carved into martian cliffs. The images, sent back by the orbiting Mars Global Surveyor, evoked water gushing from the rock, perhaps in recent times. And where there's been liquid water there could be life, or at least the remains of ancient living things (Science, 30 June 2000, pp. 2295 and 2330). But now that Mars researchers have had a chance to reconsider such a possibility, some are pouring cold water on the idea.

Although several presentations at the meeting suggested ways that aquifers beneath Mars's frigid surface might create the gullies, others pointed to strikingly similar features on Earth that are produced by nothing more than ephemeral patches of melting snow. This “suggests you don't need water seeping from underground” to explain the features, says planetary scientist Michael Hecht of the Jet Propulsion Laboratory in Pasadena, California. Without water remaining liquid underground, prospects for life or fossils within easy reach would be greatly dimmed.

In their Science paper presenting the gully images, planetary scientists Michael Malin and Kenneth Edgett of Malin Space Science Systems Inc. (MSSS) in San Diego suggested water from a permeable, water-filled layer of rock—an aquifer—exposed in a cliff face as a likely explanation. (MSSS designed, built, and operates the camera on the Mars Global Surveyor.) The cold, they argued, would freeze an outer carapace of the aquifer, but building water pressure behind it could eventually break through, excavating an alcove in the cliff face, cutting a channel down the slope, and depositing the debris in an apron at the base of the cliff. That scenario, however, didn't fly with some planetary scientists. The surface of Mars is so cold—on average −70° to −100°C—that any water within 2 or 3 kilometers of the surface, never mind a meter or two, should be permanently frozen, they noted.

At the meeting, a number of researchers offered ways to make a seeping aquifer work. Perhaps many subterranean intrusions of magma, too small to be detectable, keep near-surface water liquid; a thick surface layer of insulating “soil” might hold in enough of the planet's internal fires; or the water could be too briny to freeze. But the most striking presentations were new images of gullies, not from Mars but the high Arctic of Earth. Geomorphologist François Costard of the University of Paris-South in Orsay and colleagues hauled out slides from field trips in the late 1980s to Jameson Land in East Greenland, where they studied geologic features formed around glaciers. There they saw what looked for all the world like martian gullies—alcoves high on a cliff, channels running down from each, and aprons of debris at the end of each channel. There were even low levees of debris bordering each channel, just as on Mars. But there was no aquifer emerging from the cliff, no seeps of any kind. Geologist Pascal Lee of the SETI Institute in Mountain View, California, and colleagues reported finding similar, though smaller, gullies in far northern Canada on Devon Island.

Seepless gullies on Earth draw on the past winter's snow, not aquifers, say Costard and Lee. Snow caught in an alcove melts in the spring, saturating the steep surface beneath it with water and weakening the rock until a chunk collapses and a mixture of water and debris flows downslope. “It's a classic process,” says Costard. The same simple explanation might work on Mars, he says, if climate there has changed enough—perhaps through the periodic tilting of Mars's rotation axis—to bring frost, which now forms around the poles, or even snow, which may fall today, to the midlatitudes of Mars where most of the gullies are now found.

Edgett doubts, however, that a purely surface process would work on Mars. He notes that the channels tend to originate at the same layer of rock in a formation, suggesting that something about that rock—presumably an aquifer—controls the formation of gullies. On the other hand, Edgett has noted a central peak of an impact crater replete with gullies. Where would the water come from to feed a seep high on a central peak, he wondered? Snow might work. A closer look at the 65,000-plus Mars Global Surveyor images already back from Mars, as well as more Earth analogs, seems in order.

## Layered Mars Not Always Wet?

While gullies on Mars got much of the attention in the conference's sessions on the Red Planet (see above), last year's other big martian splash—layered sediments said to be laid down in lakes or even shallow seas (Science, 8 December 2000, p. 1879)—kept a lower profile. The basic issue was the same, however: How much water, if any, do layered sediments imply existed on the martian surface?

Layering by itself doesn't tell planetary geologists much; layers of fine-grained material could be wind-blown dust or ash spewed by volcanoes, for example. Without being able to put eyeball to sediment grain, Mars geologists must decipher the origin of layered terrains from the shape of the landscape. At the meeting, one suite of layered terrains set in the huge impact crater Hellas got strong support as the bed of an ancient, ice-covered lake. But in discussions of other terrains, volcanic ash and water-lain deposits generally got equal billing.

The Hellas basin would certainly make a fine lake. Formed perhap. 4 billion years ago by a planet-rocking impact, it spans 2000 kilometers of the martian southern hemisphere, plunges 8 kilometers below its surroundings, and would potentially drain 20 million square kilometers of the planet. In order to find out if water ever did flow into Hellas, carrying sediment with it, planetary geologists Jeffrey Moore of NASA's Ames Research Center at Moffett Field, California, and Don Wilhelms, retired from the U.S. Geological Survey's (USGS's) Astrogeology Branch, inspected images and topographic data that the orbiting Mars Global Surveyor returned in recent years.

By their analysis, deposits in Hellas do display the shapes of an ancient lake bed. Wind erosion has partially cut away Hellas sediments, exposing a layered structure in the rock all across the crater. One distinctively layered band of sediment nearly circles the crater margin like a bathtub ring. This discontinuous band has shelflike and scarp structures of the sort that ice-covered lakes in the Dry Valleys of Antarctica produce at their margins, say Moore and Wilhelms. If the climate about 3.5 billion years ago—when the sediments were laid down—was anything like today's, they note, a Hellas lake would have been covered by hundreds of meters of ice that could have shaped the margins of the deposits by blocking sediment inflow and piling it at the margins. To judge by the valleys that flow into Hellas on the east and south, much of the sediment may have flowed in after the heat of nearby volcanic activity melted ice-rich sediments. And one area, the low point of the basin, has a unique “honeycomb” structure (see figure), as if blocks of the last ice of a vanishing lake had sunk into the soft bottom mud. As a consistency check, Moore and Wilhelms determined that the altitude of the margin deposits around the crater remains constant, as a good bathtub ring should.

Listeners at the meeting took the layered sediments of Hellas to be promising as remains of an ancient lake. “We also see evidence for water and standing water deposits in Hellas,” says planetary geologist James Head of Brown University in Providence, Rhode Island, who has looked at much the same data with Bradley Thomson of Brown.

But participants often associated layering elsewhere on Mars with volcanic ash deposits rather than waterborne deposits. Baerbel Lucchitta of the USGS in Flagstaff, Arizona, pointed to new images of layered deposits in the bottom of Valles Marineris, the great crack in the planet's midsection, that are closely associated with small fissures resembling volcanic vents, all of which reminded her of the explosive, ash-producing portions of the 1783–84 Laki fissure eruption in Iceland. Elsewhere on Mars, the layered deposits near the volcano Arsia Mons look very much like the layered ash from the 1790 eruption of Hawaii's Kilauea rather than lava, noted planetary geologist Laszlo Keszthelyi of the University of Arizona, Tucson.

Proving that particular martian deposits are ash fallen from the sky rather than material carried in by water is difficult, but “a lot of us are more comfortable with a volcanic explanation,” says Peter Mouginis-Mark of the University of Hawaii, Honolulu. “I just look at these deposits and think, ‘Boy, that looks like a pile of ash,'” says Keszthelyi. “Many if not most [of the] layered deposits could be ash deposits.”

Kenneth Edgett of Malin Space Science Systems Inc. in San Diego, who with Michael Malin of MSSS caused the stir last year by advancing an aqueous origin for layered sediments, concedes that from orbit “there's no way to know” whether water was involved in most of the layered deposits. To be sure about it, rovers will have to check them out up close, he says, and pretty smart ones at that.

## No Life From the Stars

The origin of life on Earth, just half a billion years after Earth formed, seems so incredibly unlikely that some scientists have wondered about an alternative: Perhaps life arose in a single improbable event somewhere else in the galaxy and then drifted from one solar system to the next until it arrived here. Now planetary physicist Jay Melosh of the University of Arizona, Tucson, has put the statistical kibosh on that scheme. He reported at the meeting that he's done the numbers on interstellar panspermia, and the chance that life in another solar system may have hitched a ride on a bit of rock that fell to Earth is vanishingly small. “It appears solar systems are biologically isolated,” says Melosh. “It looks like we'll have to find the origin of life in our own solar system.”

Ironically, it was Melosh's work in the 1980s that provided theoretical support for the transfer of life among the planets of a single solar system. Rocks from Mars and the moon were being identified among meteorites collected on Earth, but it wasn't clear how that could be. Melosh showed that rock at or very near the surface of Mars, say, could be blasted to escape velocity by a nearby large meteorite impact without being melted or vaporized by the shock. Then it would be just a matter of time and luck before the rock could collide with Earth. The inner solar system must be adrift with bits of all the rocky planets, enough in the case of Mars that roughly 15 martian meteorites fall to Earth each year.

Melosh has now done calculations of the chances that a rock launched from a terrestrial planet in one solar system will land on one in another system. Using a Monte Carlo technique that simulates how the orbits of launched rocks evolve, Melosh found that Jupiter slings about as many martian rocks out of the solar system each year as fall on Earth. He then followed the ejected rocks toward the stars, where another version of the Monte Carlo orbit program calculates “that about one meteorite ejected from a planet belonging to our solar system is captured by another stellar system every 100 million years.” But he's not done yet. Another calculation shows that only 1 in 10,000 rocks captured in orbit about another star hits a terrestrial planet in that system. So, according to these calculations, you'd have to wait 1 trillion years for an Earth-to-extrasolar planet transfer.

Even so, “I was pretty liberal in estimating a probability,” says Melosh. He assumed all stars were liable to have habitable planets, and that every rock would be launched carrying viable life that would survive the vacuum, cold, and cosmic rays of deep space for the tens of millions if not hundreds of millions of years required for the trip. “We don't have to worry about extrasolar panspermia,” Melosh concludes.

Geophysicist Norman Sleep of Stanford University has made similar calculations. “Given that impact ejection and travel over interstellar distances are not likely to be good for microbes,” he says, “the chances of life getting transferred into our solar system in this way are essentially nil.” Earth's neighboring stars probably were closer and moved more slowly when our solar system formed in a star cluster, he notes, but conditions on any newly formed planets back then were not very conducive to life. Melosh has entertained other suggestions for upping the odds, such as a close encounter of stellar systems, “but so far no one's come up with anything that seems plausible.” Origin of life researchers may have to settle for the least implausible of improbable events.

16. LONGEVITY

# Growing Old Together

1. Evelyn Strauss

Simple evolutionary arguments don't demand that organisms share mechanisms of aging. But new work is strengthening the case that common processes control the life-spans of biology's favorite model systems

At the Retirement Home for Aging Model Organisms, each creature might have rocked on the front porch complaining about its own species' particular way of growing old. Now a spate of new papers suggests that these organisms in fact break down in similar ways as they pass their primes. And it's seeming more likely that mammals, too, will pull up a chair and swap stories about similar failing molecular pathways.

In the past decade, researchers have discovered an array of genes that control aging, but it was questionable whether one organism's methods for dipping into the fountain of youth would apply to any other. Yet reports on pages 104 and 107 show that a signaling pathway that tunes the worm life-span also operates in flies. A third article, published online today by Science (www.sciencexpress.org), reports that a gene related to a member of this pathway likewise influences aging in yeast. Other recent work suggests that an aging gene discovered several years ago in yeast also controls life-span in worms. And researchers speculate that mammals share similar aging pathways.

“It's all coming together,” says molecular geneticist Cynthia Kenyon of the University of California, San Francisco (UCSF). “This aging system that we know about in the worm is out there in other animals, regulating their aging. Maybe not in the same exact form, but it's there. It's unbelievable, simply unbelievable.”

This congruence is surprising because natural selection acts on genes that influence reproductive success, so those that accelerate or decelerate aging might be expected to lie beyond the reach of evolution's mighty arm. As molecular geneticist Gordon Lithgow of the University of Manchester in the United Kingdom points out, “If aging is a collection of nonadaptive deleterious events, why on Earth should they be conserved across a wide variety of species?”

## Aging gracefully without reproducing

No Hollywood star has grown old under as much scrutiny as the roundworm Caenorhabditis elegans. Extensive studies have revealed a detailed picture of a molecular signaling pathway that controls the worm's longevity. At the heart of the pathway lies the daf-2 gene, which encodes a member of the insulin family of cell surface receptors. Upon binding an insulin-related hormone, daf-2 receptors trigger the activation and repression of a suite of other genes. Certain mutations in daf-2 allow worms to wriggle into ripe old ages that greatly exceed those of their normal counterparts. Other genes in the pathway also affect longevity, and signals from both the reproductive and sensory systems feed into it as well. For example, genetically pinning a clothespin to a worm's nose by disrupting olfactory signaling appears to extend life via the daf-2 pathway.

Now, two teams report that a related insulin-like pathway shapes life-span in flies as well. Female Drosophila melanogaster that carry only defective copies of the daf-2 equivalent (InR) buzz around long after normal flies keel over, according to a group led by Marc Tatar, an evolutionary geneticist at Brown University in Providence, Rhode Island. Similarly, animals with inactive versions of another member of the pathway called chico (see diagram, p. 43) flit into extreme dotage, report geneticists Linda Partridge and David Gems of University College London and colleagues. In both cases, adding back an operational version of the appropriate gene returns life-span to almost normal. Together, these results suggest that functional InR and chico genes accelerate aging. The work is “tremendously exciting,” says John Tower, a molecular biologist at the University of Southern California (USC) in Los Angeles. “To see [the aging pathway] conserved in two such different species makes you hypothesize that the pathway may be more general.”

How these mutations confer longevity is a puzzle, however. Other work has shown that stalling or blocking reproduction in flies enhances longevity. Such findings bolster conventional wisdom about how animals allocate limited resources: If they make lots of babies, they burn through the energy that would otherwise preserve their own bodies. The newly described chico mutant females are almost sterile, so the Partridge and Gems team tested whether another mutation that prevents Drosophila from making eggs would also lengthen life to the same extent.

They found that sterility apparently isn't the only factor that sets back the clock in chico mutants: chico flies survived longer than the other sterile and long-lived mutant, called ovo. Furthermore, flies that carry one good and one bad copy of chico outlive ovo flies, even though these heterozygotes are more fertile than ovo mutants. The commonly observed trade-off between reproductive capacity and longevity might arise not simply because of energy investments, suggests Gems, but because a single system normally controls both processes. He cautions that the new results do not rule out a direct connection between fertility and life-span: The flies might be making the critical energy investment in reproductive activities before the mutation halts egg production.

InR mutant flies, which are also sterile, provided another way to explore the relation between aging and reproduction—or at least fertility hormones. Normally, flies put reproduction on hold during the winter by tapering off levels of juvenile hormone (JH). It turns out that the long-lived InR mutants produce abnormally small amounts of this hormone, suggesting that low JH levels may mediate the mutants' life-span extension. To test this, the researchers exposed flies to a chemical that mimics JH.

The results indicate that JH might indeed be driving InR mutants' longevity, at least partially. The chemical didn't alter the life-spans of wild-type flies much, but it pushed mortality in InR flies back toward normal. This work “makes a leap from the genetic pathways to the hormonal signals that may be affecting life-span,” says Lithgow, adding that the finding “begs the question of what endocrine signals in mammals might be involved in determining longevity.”

## Handling stress with maturity

Both fly papers examine another possible explanation for the staying power of chico and InR flies: resistance to stresses such as heat and oxidative damage. Long-lived mice, worms, and flies tolerate these and other physical and chemical insults better than do normal organisms. Furthermore, treatments that defend against damage from free radicals, such as overproduction of the enzyme superoxide dismutase or exposure to chemicals that perform a similar detoxifying reaction, confer long life on flies and worms. The researchers therefore wanted to know whether the mutants displayed unusual hardiness when subjected to harsh conditions. The results were inconclusive, but neither team conducted exhaustive tests. “These data don't move that argument either way,” says Lithgow. “There's a lot of supportive evidence that there's a relationship between stress and aging.”

Indeed, the work on yeast reported today advances the claim that stress resistance lengthens life. Valter Longo, a molecular geneticist at USC, and colleagues battered a population of yeast mutants with heat or paraquat, a chemical that creates reactive oxygen molecules. Among the survivors, they found two strains that endured both treatments. These mutants also lived longer than wild-type yeast and mutants that tolerated only heat or paraquat, but not both. One of the mutants carries a defect in Sch9, which resembles Akt1 and Akt2, genes that act in the C. elegans daf-2 pathway. When the researchers engineered a deletion of Sch9, they found that the resulting strain survived three times longer than did wild-type cells.

Both Sch9 and the other yeast gene that emerged from both the heat and paraquat screens, adenylate cyclase (Cyr1), are know to participate in pathways that decrease stress resistance. Indeed, the two mutant strains tolerate not only heat and paraquat, but also hydrogen peroxide. And Longo's group found that genes that protect against heat shock increase survival in Cyr1 mutants. He suggests that resistance to multiple stresses promotes extended longevity.

Other researchers previously implicated the adenylate cyclase pathway in yeast staying power. Several years ago, Leonard Guarente of the Massachusetts Institute of Technology and colleagues established that overproduction of the yeast protein Sir2 increases a different measure of longevity, the number of times a mother cell produces a daughter cell. Last September, his team showed that SIR2 allows yeast to live longer via the adenylate cyclase pathway (Science, 22 September 2000, p. 2126). And Guarente recently extended the relevance of his work with SIR2 by implicating a homologous gene in the process of worm aging. Overproducing the worm relative of Sir2 increases average life-span by up to 50%, he reported in the 8 March issue of Nature. Furthermore, he gathered genetic evidence that Sir2 operates in the daf-2 pathway.

Guarente suggests that SIR2 and its kin mediate life-span by the same mechanism in many creatures: They remove an acetyl chemical group from DNA-binding proteins, allowing them to halt gene expression. But the targeted genes perform a variety of physiological roles. “Deacetylation of some protein is important for longevity, but how that plays out in different organisms is likely to be very, very different,” Guarente says. His team found that nutrient deprivation spurs Sir2 to extend life-span, and this ability to respond surroundings, he says, “allows an organism to hang around longer when food is scarce. When things get better, you're still there and your neighbor's not.”

This link between environmental conditions and aging pathways also provides an explanation for how “aging” and “antiaging” genes might have evolved. In worms, the daf-2 pathway controls life-span, fertility, and entry into a semidormant state that allows prepubescent worms to wait out rough times. Crowding and lack of food, for example, trigger this “dauer” state; the trade-off is that dauer worms can't reproduce. The life-span genes “all seem to be allowing these animals to survive periods of food deprivation and harsh conditions,” says UCSF's Kenyon. “Now we're learning that by tinkering with this system, it's possible to change life-span in a healthy way. You don't have to be a dauer to do it.”

## Hungry but wizened

The connection between limited food and longevity is reminiscent of the one well-established treatment that stalls aging in mammals: calorie restriction. Calorie-restricted mammals have low levels of both insulin and insulin-like growth factor-1 (IGF-1). Several receptors respond to such hormones in mammals, including separate insulin and IGF-1 receptors, both of which resemble the single daf-2 receptor that underlies the aging pathway in C. elegans.

“You can make a very strong case that there is a link between IGF signaling and aging” in mammals, says Gems. Some of the best evidence comes from previous research on three strains of long-lived mice. They carry mutations in different genes that affect growth hormone signaling, and all have low levels of IGF-1 in the blood, as well as alterations in the amounts of other hormones. Like many long-lived fly mutants, these mice “are small, have reduced reproductive function, mutations in what looks like a similar pathway, and more of a life-span effect on females than males,” says Andrzej Bartke, a mammalian endocrinologist at Southern Illinois University in Carbondale. “To what extent the [fly and mouse] genes have corresponding functions, it's hard to know. But these papers are very exciting because they add an enormous amount of evidence that the parallelism does indeed exist.”

The parallels among flies, worms, and yeast are falling into place, but connecting these pathways with mammalian aging will take more work. Other pathways are out of whack in the mouse mutants, warns William Sonntag, an endocrinologist at Wake Forest University School of Medicine in Winston-Salem, North Carolina, so it's too early to draw solid connections between IGF-1 and aging pathways in C. elegans and Drosophila. But he is cautiously optimistic. “The fly and nematode results make us more enthusiastic that similar mechanisms are working in vertebrates and mammals,” he says. “If it transfers [from worms] to flies, there's the possibility that it will transfer to mammals.”

17. COMPARATIVE GENOMICS

# Gene Expression Differs in Human and Chimp Brains

1. Dennis Normile

Greatly elevated levels of gene expression compared with chimpanzees and rhesus macaques could shed light on how our brains developed

TOKYO—Genetic variation may explain why humans differ from their primate cousins, but not in the way one might expect. Although the human genome differs only slightlyan estimated 1% to 2%from those of the great apes, there are significant differences in how genes are expressed and regulated. New research suggests that those differences are most marked in the brain, a finding that offers possible clues to how humans developed their prodigious mental capacity.

“I'm not interested in what I share with the mouse; I'm interested in how I differ from our closest relatives, chimpanzees,” says Svante Pääbo, a geneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. Such comparisons, he argues, are the only way to understand “the genetic underpinnings of what makes humans human.”

With the human genome virtually in hand, many researchers are now beginning to make those comparisons. At a meeting here last month,* Pääbo presented work by his team based on samples of three kinds of tissuebrain cortex, liver, and bloodfrom humans, chimps, and rhesus macaques. Pääbo and his colleagues pooled messenger RNA from individuals within each species to get rid of intraspecies variation and ran the samples through a microarray filter carrying 20,000 human cDNAs to determine the level of gene expression. The researchers identified 165 genes that showed significant differences between at least two of the three species, and in at least one type of tissue. The brain contained the greatest percentage of such genes, about 1.3%.

It also produced the clearest evidence of what may separate humans from other primates. Gene expression in liver and blood tissue is very similar in chimps and humans, and markedly different from that in rhesus macaques. But the picture is quite different for the cerebral cortex. “In the brain, the expression profiles of the chimps and macaques are actually more similar to each other than to humans,” Pääbo said at the workshop. The analysis shows that the human brain has undergone three to four times the amount of change in genes and expression levels than the chimpanzee brain since the two split off from a common ancestor. “Among these three tissues, it seems that the brain is really special in that humans have accelerated patterns of gene activity,” Pääbo says.

The 200 workshop participants also heard about a biochemical difference that sets humans apart from our close cousins and, perhaps, influenced human brain development. “Beyond genomics and transcriptomics and proteomics, there is glycomics,” says Ajit Varki, a glycobiologist at the University of California, San Diego (UCSD). Varki and his colleagues are looking at how the loss of an enzyme may have given humans an evolutionary advantage (Science, 23 March, p. 2340).

The enzyme makes one form of a family of cell surface sugars called sialic acids. The UCSD team found that all mammals except humans have on their cell surfaces two variants, known as N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). The researchers traced the lack of Neu5Gc in humans to a small mutation in a gene that, in other mammals, codes for an enzyme called CMP-Neu5Ac hydroxylase. This hydroxylase catalyzes the conversion of CMP-Neu5Ac into CMP-Neu5Gc by adding an oxygen atom. Without it, humans have none of the Gc variant and an excess of Ac.

Luckily, the acids are well preserved in bones. And the group found that whereas modern ape bones have a mixture of Neu5Gc and Neu5Ac, Neandertal fossilsand modern human bonesprimarily have Neu5Ac. So the gene inactivation “appears to predate the common ancestor of humans and Neandertals but postdates the common ancestor with the great apes,” Varki says. Because Neu5Gc is a binding target for certain pathogens, Varki speculates that the loss of Neu5Gc in early humans may have strengthened their immunity to certain diseases.

The connection to the brain comes in because even in mammals where Neu5Gc is common in most tissue, it is nearly absent in the brain. It is, of course, entirely absent in the human brain. In what Varki emphasizes is “pure speculation,” he posits that getting rid of Neu5Gc may somehow have fostered improvements in the brain. Naruya Saitou, an evolutionary geneticist at the National Institute of Genetics in Mishima, Japan, calls the theory “a very provocative idea … worth examination.”

The next step is to look at the effect of eliminating or overexpressing Neu5Gc in knockout and transgenic mice. Varki's group has also been studying a family of lectins called siglecs (for sialic acid-binding immunoglobulin-like lectins) that offer further clues. Although their function is not completely understood, siglecs are found in a wide variety of cell types, and all have an arginine residue that is needed to bind sialic acids.

One of Varki's postdocs stumbled onto something in human cells that looked very much like a siglec, but it was missing the arginine residue indispensable for sialic acid recognition. A comparison with great apes found that the ape version, which they provisionally named siglec zz, had the arginine residue, and it prefers to bind Neu5Gc. A single base-pair mutation is responsible for the loss of this arginine residue in the human version of siglec zz. “It is hard to imagine that these two [genetic differences] in sialic acid biology are not evolutionarily connected,” Varki says.

But which one came first, and when? Varki suggests that it is unlikely the genetic mutation occurred first in Neu5Gc, followed by a precise “surgical strike” that hit the siglec zz arginine residue and left the rest of the molecule intact. Instead, he believes the first mutation was probably the loss of the arginine residue on human siglec zz, and that reduced, but did not eliminate, Neu5Gc binding sites. This may have then set the stage for the subsequent mutation in the hydroxylase.

For Caro-Beth Stewart, a molecular anthropologist at the University at Albany in New York, the research raises the possibility that what humans lost during evolution might be just as important as what they gained. Maybe, she quips, “we're just apes with lost functions.”

• * Genes and Minds Initiative Workshop on Ape Genomics, Tokyo, 14–15 March.

18. SOLID-STATE PHYSICS

# Nanotube 'Peapods' Show Electrifying Promise

1. Robert F. Service

Take a microscopic buckytube, stuff it with buckyballs, and what do you get? Just possibly room-temperature superconductivity

SEATTLE, WASHINGTON—Materials that lose their electrical resistance at a whisper above absolute zero are too common to grab much attention nowadays. But when a French and Russian team reported that carbon nanotubes perform this trick, other researchers at the March meeting of the American Physical Society took notice.

The transition temperature—a measly 0.55 kelvin—isn't likely to entice engineers to spin the tiny all-carbon cylinders into superconducting wires. But calculations show that nanotubes filled with other materials could do much better, perhaps even superconduct at room temperature.

“It's impressive work,” says David Tomanek, a nanotube expert at Michigan State University in East Lansing. “This is the first direct evidence that nanotubes superconduct.” That's important, he continues, because other teams have already shown that crystals of fullerenes—carbon spheres informally known as buckyballs—can superconduct at temperatures as high as 52 K. And theory suggests that lining fullerenes up in wirelike rows would raise the threshold dramatically. Researchers in Japan and elsewhere have aligned fullerenes by packing them inside nanotubes like peas in a pod. Electronic interactions between the tubes and the fullerenes could further boost the superconducting temperature of fullerene wires, Tomanek says. Now the race is on to see if these peapods will superconduct at a high temperature.

Detecting superconductivity in empty nanotubes has been tough. In 1999, a group led by Mathieu Kociak and Helene Bouchiat at the University of Paris-South in Orsay reported in Science (28 May 1999, p. 1508) that ropes of 100 or so nanotubes could carry supercurrent between two superconducting electrodes. In superconductors, electrons pair up and travel through conductors without any electrical losses. In this earlier study, the electrons traveled in pairs through the nanotubes, but poor contact with the electrodes caused electrical losses that kept the experiment from confirming that superconductivity was taking place.

To prove that the nanotubes were truly superconducting, the researchers had to show that the electron pairs were not due to superconductivity in the electrodes. Kociak and his colleagues at the French national research agency CNRS and the Russian Academy of Sciences in Chernogolovka started with an array of metal pads made from a nonsuperconducting sandwich of aluminum oxide, platinum, and gold. After placing a batch of nanotube ropes atop a wire mesh suspended above the array of metal pads, the researchers blasted the ropes with a brief laser pulse. That shook loose some of the ropes, which fell atop the contacts below, in certain cases creating a bridge between two electrodes.

Then, using additional laser pulses, the researchers soldered the nanotubes to the metal pads to make clean electrical contact. Finally, they ran currents between selected metal pads to test the nanotubes' behavior.

The painstaking work paid off: Measurements of both the electrical and magnetic behavior reported at the meeting and in the 12 March issue of Physical Review Letters show that the nanotube ropes were indeed superconducting.

Now the question is whether Kociak's team can pull off the same feat with nanotubes packed with fullerenes. The all-carbon spheres themselves became a big story in superconductivity last year when Bertram Batlogg and colleagues at Lucent Technologies' Bell Laboratories in Murray Hill, New Jersey, raised their superconducting temperature from about 9 K to 52 K by putting the spheres in the middle of a transistor. Turning on an electrical voltage between metals on either side of the transistors swiped electrons from the fullerenes in between. That opened up space for superconducting pairs of electrons in the material to hop around more easily, thereby raising the temperature at which it could superconduct.

According to Tomanek, theory suggests that placing the fullerenes in a wirelike arrangement could do even better: Lowering the number of immediate fullerene neighbors increases a quantum mechanical property known as the density of states—a situation favorable to a higher temperature superconductor.

“Fullerene peapods should give you room-temperature superconductivity,” says Tomanek. However, he says, it could also lead to a type of magnetic behavior in the materials that would undermine superconductivity completely. The winner will likely be known in the next few months.