News this Week

Science  06 Aug 2004:
Vol. 305, Issue 5685, pp. 760
1. ELECTION 2004

The Calculus of Making Stem Cells a Campaign Issue

1. David Malakoff*
1. With reporting by David Grimm and Constance Holden.

Most scientists predict that it will be at least several years before human embryonic stem cells are used to treat disease. But Democratic presidential candidate John F. Kerry is betting that the political payoff from his support for stem cell research will be much quicker.

Last week, the Kerry campaign took the unusual step of elevating a complicated bit of science policy to a top-tier election issue. Kerry used his televised nomination speech to attack the Bush Administration's handling of science and promised to lift restrictions on government-funded stem cell research that his opponent, President George W. Bush, imposed in 2001. “What if we have a president who believes in science, so we can unleash the wonders of discovery like stem cell research to treat illness and save millions of lives?,” Kerry asked in the 29 July address to the Democratic National Convention in Boston, Massachusetts. Two days earlier, Ron Reagan, the son of the late Republican president, addressed the convention to extol the promises of embryonic stem cell research.

Kerry's barbed rhetoric drew a quick response from Bush campaign officials. “Ridiculous. … We have a commitment to science,” said deputy policy director Megan Hauck. She noted that the Administration has overseen increased funding for research and relied on input from both scientific and religious leaders to craft a “compromise” that provides federal funding for some embryonic stem cell research.

Many science and patient groups welcomed Kerry's remarks, saying they signaled success in attracting attention to their key concerns. “For science and stem cells to make it [into Kerry's speech] shows that these issues have made it to the political major leagues,” says Kevin Wilson, public policy director of the American Society for Cell Biology in Bethesda, Maryland. But, Wilson and others warned, the high-profile embrace could also create problems, from unrealistic public expectations for quick stem cell cures to strained relationships with Republican allies. “I had hoped that we could keep stem cell research separate from election-year politics. … Politicization of this critical issue will only serve to alienate more potential supporters,” predicted Senator Orrin Hatch, a Utah Republican who has led efforts to reverse the White House policy.

Many polling experts, however, say Kerry's move is smart electoral politics, given surveys showing that more than two-thirds of voters—including many conservatives—support loosening Bush's 3-year-old stem cell policy, which limits federally funded researchers to using just a few dozen existing stem cell lines. The White House has held firm against relaxing the restrictions, in part for fear of alienating conservative Christian voters who oppose destroying human embryos to harvest stem cells.

Such complicated science issues rarely rise to prominence in national elections. But the death of former president Reagan, along with public criticism of Bush's policy from his widow Nancy and son, helped focus public attention on the issue. And that spotlight presented Kerry—who has long opposed the Administration's restrictions on stem cell research and raised the issue in his stump speeches—with an opportunity to make a “double-edged” case, says Matthew Nisbet, a communications professor at Ohio State University in Columbus who has studied public opinion on stem cell research. “It allowed Kerry to highlight a major policy difference between the candidates on a health issue that is relevant to millions of Americans,” he says. It also allowed him to reinforce reservations that undecided voters may already have about Bush being “an ideologue who doesn't listen to experts who hold other views.”

Still, Nisbet warns that many voters are “queasy” about the moral issues raised by stem cell research. And the Bush campaign believes those voters will be reassured by the current policy, which Hauck says “balances our need to respect human life and move ahead with research.”

Other analysts say Kerry's claim that Bush's policy is delaying cures may appeal to sought-after suburban women voters, while the suggestion that Bush doesn't believe in science could appeal to white males with technical training. “This is a message crafted with an eye toward demographics,” says one Democratic strategist.

Amid the sound bites, some researchers worry that public expectations for stem cell therapies will become too great. Kerry's speech “was electrifying,” says cell biologist George Daley of Harvard Medical School in Boston, Massachusetts. “But it puts a heavy responsibility on scientists to provide accurate information and not overhype.” Voters, meanwhile, are expected to have plenty of opportunity to make up their own minds. Analysts on both sides expect the candidates to be asked questions about their stem cell policies in the upcoming debates.

2. RESEARCH PROTESTS

Britain Unveils a Plan to Curb Animal-Rights 'Extremists'

1. Fiona Proffitt

CAMBRIDGE, U.K.—Britain is weighing tough new measures to crack down on intimidating tactics used by a radical minority of animal-rights activists. In a report* published on 30 July, the government proposes new criminal penalties for protests that cause “harassment, alarm, or distress,” to be enforced by a newly created special police unit and network of 43 prosecutors. The move comes in the wake of animal-rights campaigns that contributed to the University of Cambridge's decision to abandon a primate research facility this year and now threaten to derail construction of a building at the University of Oxford.

Leaders of the research community welcomed the plan: “It's great that the Home Office is doing something about this at long last,” says neuroscientist E. Barry Keverne, chair of the Royal Society's Committee on Animals in Research. But antivivisection groups suggest that ratcheting up penalties won't deter their protests.

In addition to outlawing harassment of people at home, the government seeks to make it an offense for protesters to return within 3 months to a place they've been ordered to leave. The government also plans to extend antiharassment laws to apply to all employees of an organization rather than specific individuals and may outlaw acts that cause economic damage to research-related operations. The government did not seek—but is considering—a single law targeting animal-rights extremists.

Scientists hope the new measures will be more effective than past efforts at deterring threatening behavior. Personal intimidation, such as calling researchers “torturers” in letters to neighbors, has increased in the last 18 months, says Mark Matfield, executive director of the Research Defence Society (RDS), which represents scientists engaged in animal research. RDS reports that 50 suppliers for animal research facilities have pulled out of contracts this year alone. Over the past year, instances of damage to property—mostly involving corrosive substances thrown at vehicles—have doubled, and protests at the homes of company directors have increased by 45%, according to the Association of the British Pharmaceutical Industry. “It does make it difficult to get anything done,” says Keverne.

Matfield says protesters have turned their attention from heavily guarded private facilities to “softer targets”: the universities. In January, a planned primate research facility at Cambridge University was abandoned after protests led by the group Stop Primate Experiments at Cambridge escalated security costs (Science, 30 January, p. 605). “It gave the activists a victory they hadn't had for 5 years,” says Matfield. The university is now seeking to carry out primate studies at existing laboratories, an official says.

The animal activist group, now calling itself Speak, has since set its sights on an animal research facility being built at Oxford University. Construction of the $33 million laboratory ground to a halt last month when the main contractors pulled out following threats to staff and shareholders and damage to property (Science, 23 July, p. 463). Speak co-founder Robert Cogswell says that the group was not involved in any illegal acts. A spokesperson for the university describes the delay as a “temporary hiccup.” “The government has pledged to support the project; we just hope that that would include financial support,” she says, adding that there are no plans to use troops to assist the project, as some newspaper reports have suggested. A recent Royal Society survey (Science, 18 June, p. 1731) found that security against animal-rights extremism was costing universities$320,000 per year on average. The National Association of Pension Funds, whose members control about 20% of the U.K. stock market, are considering establishing a $46 million fund to reward information on extremists. Seeking to offset the impact of protests, three big drug companies—GlaxoSmithKline, AstraZeneca, and Pfizer—last week announced a$7.3 million fund for animal research in U.K. universities over the next 4 years.

The protesters say they're unimpressed. Cogswell sees the tougher measures as a “knee-jerk reaction” to complaints from pharmaceutical companies. “The government needs to think carefully why people are engaging in actions,” he says, arguing that many are disappointed over its failure to deliver a promised inquiry into animal research. “The more people feel disempowered, the more they're going to take the law into their own hands.” However, he's confident that opponents can stop the Oxford facility “by legal means.”

Ian Gibson, chair of the U.K. Parliament's science and technology committee, doubts that the new measures will stop the most determined extremists, but he hopes they'll “give some breathing space” for debate. Matfield and Aisling Burnand, CEO of the BioIndustry Association, suggest that the government may need to adopt even stronger measures. To move quickly, the government has opted primarily to amend existing legislation, but the new law banning protests at individuals' homes will require approval by Parliament.

3. NEUROBIOLOGY

Untangling Alzheimer's by Paring Plaques Bolsters Amyloid Theory

1. Mary Beckman*
1. Mary Beckman is a writer in southeastern Idaho.

Consider it a potential biomedical bargain—two therapies for the price of one. New research in mice suggests that targeting one of the two molecular aggregates gumming up brains with Alzheimer's disease also rids tissue of the other, as long as treatment starts early enough. This finding and a recent analysis of an interrupted Alzheimer's vaccine trial in people have brought new life to the idea of immunotherapy for the debilitating disease.

An ongoing debate within the Alzheimer's disease community centers on the importance of brain plaques, extracellular clumps of a protein fragment called β amyloid, and tangles, filaments of the protein tau that form inside neurons. In the 5 August issue of Neuron, a team led by neuroscientist Frank LaFerla of the University of California, Irvine, reports that antibodies against β amyloid can wash mice brains free of amyloid plaques—and mutant tau before it tangles. Some researchers have argued that plaques instigate the formation of tangles, but there's been little solid evidence for that. “This is the most complete confirmation that accumulation of β amyloid can lead to accumulation of tau and eventually to tangles,” says neuroscientist Michael Hutton of the Mayo Clinic College of Medicine in Jacksonville, Florida.

Researchers have had difficulty testing the relative roles of plaques and tangles, because until last year, no one had generated mice that develop both. LaFerla and his colleagues recently endowed mice with a triple threat: a mutant copy of the gene for amyloid precursor protein (APP), a mutated gene for presenilin-1, which helps chop APP into β amyloid, and a mutant form of the tau gene. These rodents develop plaques and tangles in the cortex, amygdala, and hippocampus, just as people with Alzheimer's disease do. The plaques precede tangles, consistent with the idea that β-amyloid buildup starts brains off on the road to dementia.

In the new work, the team injected antibodies against β amyloid into the hippocampus of their transgenic mice once the animals were 1 year old. Three days after the injection, plaques in the injected animals had disappeared. Between 5 and 7 days after the injection, tau, which in the mice had aggregated within neurons but not yet formed tangles, also had melted away.

LaFerla's group tested the antibody treatment on another set of triple-mutant mice; these animals have two copies of each mutant gene and develop tangles in under a year. The antibodies erased plaques in 6- and 12-month-old animals. They also cleared pretangle tau aggregates in the 6-month-old animals but couldn't budge the tangles in year-old mice. “Once tau forms tangles, it can't be removed,” says LaFerla.

The rodent work seems to mirror recent findings in autopsies of brains from people involved in a vaccine trial for Alzheimer's disease. In 2000, investigators showed that immunizing mice with amyloid itself could rid mouse brains of plaques. In 2002, however, clinicians abruptly halted a human study of the vaccine when a small percentage of patients developed brain inflammation. Last month, at the 9th International Conference on Alzheimer's Disease and Related Disorders in Philadelphia, Pennsylvania, Sid Gilman of the University of Michigan, Ann Arbor, described the brains of four people with mild to moderate Alzheimer's disease who had received the vaccine and subsequently died from unrelated causes. Each brain showed an almost complete lack of β amyloid; the tangles remained, however.

LaFerla's work “goes hand-in-hand with the vaccine trial,” says neurobiologist Virginia Lee of the University of Pennsylvania in Philadelphia. The mouse and human data suggest that a vaccine would be most therapeutic if researchers treat patients in very early stages of the disease, before tau forms tangles.

Still, Lee admits, that remains a bit of a “pipe dream,” because such patients can't yet be identified. Nevertheless, biotech companies are redesigning amyloid vaccines to make them safer and considering new clinical trials. Apparently, the reported death of Alzheimer's disease immunotherapy was an exaggeration.

4. NANOTECHNOLOGY

Yellow Light for Nanotech

1. Fiona Proffitt

LONDON, U.K.—Although “gray goo” made of self-replicating “nanorobots” is unlikely to doom the planet, some kinds of nanomaterials could be hazardous and require a closer look, according to a 12-month study* published last week by the U.K. Royal Society and the Royal Academy of Engineering. Overall, however, the report concludes that most nanotechnologies pose no new risk and no general moratorium is needed.

Many products that incorporate nanoparticles, such as computer chips and self-cleaning windows, are no cause for new concern, said Cambridge University mechanical engineer Ann Dowling, who led the study, at a press conference last week. But because some chemicals are more toxic in their nano form and can penetrate cells more readily, nanomaterials should be subjected to toxicity studies “without delay,” she said. Panel member Anthony Seaton, an expert in occupational and respiratory medicine at Aberdeen University in the U.K., added, “At the moment, it would be wrong to pretend we know much about the toxicology of nanoparticles.”

The panel concluded that nanoparticles and nanotubes—tiny tubes of carbon that have many potential uses, such as in friction-reducing oil additives and electronic displays—should be tested and regulated as new chemicals under existing U.K. and E.U. legislation. “We believe no new bodies are needed to regulate nanotechnologies,” Dowling said, but existing bodies should review their regulations, and manufacturers should publicly disclose test results. Only large quantities of new materials would need to be tested; small-scale producers such as laboratories would not be affected. Nanotechnologists seem pleased with the panel's conclusions. Physician Michael Horton of the London Centre for Nanotechnology says, “The report was entirely right in its optimistic caution.”

U.K. science minister David Sainsbury commissioned the study in July 2003 following alarmist reports in the media about inhaling toxic particles and the perils of self-replicating gray goo. The Royal Society and the Royal Academy will hold a public meeting to discuss the report on 29 September, and the government says it will respond by the end of the year.

5. ASTROPHYSICS

Dark-Matter Sighting Ends in Shock

1. Robert Irion

Rumors have been flying for months among astrophysicists that a new telescope in Africa had spotted particles of “dark matter” destroying one another at the heart of our galaxy. Now, the telescope's German-led team confirms that it has detected gamma rays blazing directly from the Milky Way's core. But the signal looks more like a shock wave from ordinary matter, the team reported last week at a meeting* in Heidelberg, Germany. Dark matter may be “the most interesting possible source of gamma rays,” says physicist Werner Hofmann of the Max Planck Institute for Nuclear Physics in Heidelberg. “But it is not the most natural explanation for what we see.”

Hofmann and a team of about 100 researchers used the High Energy Stereoscopic System (HESS), an array of four telescopes completed in December 2003 at a dark high-altitude site in central Namibia. Unlike conventional telescopes, which spy their targets directly, HESS watches for the traces of gamma rays and cosmic rays plowing into Earth's atmosphere. The impacts spark cascades of millions of secondary particles, which emit faint meteorlike trails of bluish light called Cerenkov radiation. HESS's multiple eyes, each covering more than 100 square meters, are designed to trace those trails back to their origins. “I'm really impressed and amazed by their sensitivity,” says astrophysicist Dan Hooper of the University of Oxford, U.K. Adds astrophysicist Paolo Gondolo of the University of Utah in Salt Lake City: “HESS is the best gamma ray telescope working now. It has the resolution necessary to test for the presence of dark matter.”

Theory maintains that the Milky Way is engulfed by a vast halo of dark matter, outweighing the ordinary matter in stars and planets by a factor of 10 or more. In one popular scenario, the dark matter consists primarily of “weakly interacting massive particles,” or WIMPs, that suffuse space but barely make their presence felt. When two WIMPs collide, they should spit out a flurry of other particles and gamma rays. Those immolations should happen most often at the Milky Way's core, where WIMPs are thought to swarm in a dense knot around the galaxy's supermassive black hole.

The steady gamma ray signal seen by HESS does indeed come from a tiny area at the galaxy's center. But there are problems with a dark-matter interpretation, Hofmann says. First, the pattern of energy looks like a classic shock wave, created by ordinary atomic nuclei slamming into ambient material in space. A likely source is the remnant of a violent supernova next to the galactic center, where strong magnetic fields have trapped and accelerated particles for thousands of years, Hofmann says.

Moreover, the gamma rays are so powerful that if they came from WIMPS, their masses—expressed in terms of energy—would be at least 12 trillion electron volts. That's 10 to 100 times higher than predicted by nearly all models of supersymmetry, a popular framework that extends physics to higher energies. “One clearly has to prefer a more normal explanation,” Hofmann says.

For now, Hooper agrees: “I won't completely write off an ultraexotic dark-matter particle, but it will take a lot more evidence to convince me.”

Researchers should keep an open mind, says physicist Joel Primack of the University of California, Santa Cruz. Thus far, the HESS team has analyzed data from mid-2003, when just two telescopes were operating. Now, with all four scopes running, HESS might see different types of gamma rays from the putative supernova remnant and the adjacent core of the galaxy. “It's likely HESS can disentangle the two,” Primack says.

Nor is Primack deterred by the surprisingly high WIMP mass implied by HESS. “The surprise is based on our prejudices of what supersymmetry might do,” he says. “But we're absolutely ignorant. We simply do not know.”

• * International Symposium on High Energy Gamma-Ray Astronomy, 26 to 30 July.

6. X-ray Scan Shows Oldest Known Bird Had a Bird Brain

Ever since its discovery in 1861, Archae- opteryx has been the classic example of a transitional fossil. With an impressive array of modern-looking feathers, the 147-million-year-old fossil is clearly dressed like a bird. But almost all of its skeleton, from its teeth to its long, bony tail, resembles that of a carnivorous dinosaur. Now, the first look inside the head of Archaeopteryx reveals a fundamentally birdlike brain, well suited for flying. The new anatomy will help explain the evolutionary transition from dinosaurs to birds and the evolution of flight, says Lawrence Witmer, a paleontologist at Ohio University College of Osteopathic Medicine in Athens: “It's a critical piece of the puzzle.”

Paleontologist Angela Milner of the Natural History Museum in London, U.K., and colleagues inspected the brain of the so-called London specimen of Archaeopteryx, one of seven known fossils of the magpie-sized creature. Although the brain itself isn't preserved, during life the brain pressed against the skull, leaving an impression of its lobes.

Working with paleontologist Tim Rowe and his imaging team at the University of Texas, Austin, the researchers scanned the 20-millimeter-long braincase with an industrial computerized tomography (CT) scanner, which has a higher resolution than medical CT scanners. They assembled the images by computer into a three-dimensional reconstruction of the brain (Science, 9 June 2000, p. 1728), touching up damage and filling in missing sections by reversing symmetrical portions that had survived intact.

Archaeopteryx's brain turned out to be much like that of modern birds, the group reports this week in Nature. For starters, it's big relative to body mass. With a volume of about 1.6 milliliters, the brain was three times larger than those of living reptiles. But it wasn't full-fledged: Modern birds, for their body size, have brains that are 33% to 500% larger than Archaeopteryx's.

Birdlike features of the anatomy include enlarged cerebral lobes (relative to the width of the brain), compared with its reptile relatives. In living birds, these lobes process sensory information from the inner ear and muscles. “It's the command and control center for flight,” Milner explains. That center was likely kept busy: Feeding into it were the optic lobes, each enlarged almost to the size of the cerebellum and located on the sides of brain—just as they are in birds and pterosaurs. (In reptiles, they're on top of the brain.)

Also sending flight information were the semicircular canals of the inner ear, which help an animal sense its orientation in space. Animals with larger loops relative to body size, such as birds—including Archaeopteryx, the CT shows—tend to be more nimble (Science, 31 October 2003, p. 770). “Archaeopteryx was agile, quick, and jerky in its movements,” says Witmer, who likens the extent of its acrobatics more to those of a chicken than a falcon or swallow. Even though Archaeopteryx lacked some of the skeletal features to fly like an eagle, it appears to have evolved all the brains for it.

7. SCIENTIFIC PUBLISHING

Seeking Advice on 'Open Access,' NIH Gets an Earful

1. Jocelyn Kaiser

The National Institutes of Health is forging ahead with plans to require that papers from NIH-funded research be made freely available. Last week, in a hastily called meeting, NIH director Elias Zerhouni told journal publishers he is not happy with the “status quo” and is under pressure from the public to expand access to research results. He got an earful from scientific societies worried that any mandatory plan will drive their journals under.

The discussion was sparked by a July report from the House Appropriations Committee instructing NIH to consider requiring its grantees to deposit manuscripts in PubMed Central, its full-text Internet archive, when they are accepted by a journal. PubMed Central would post them 6 months after the journal published them, or immediately after publication if the author's NIH grant pays for any publication charges (Science, 23 July, p. 458).

In response, Zerhouni held an invitation-only meeting on 28 July with 44 participants, many from scientific societies, as well as commercial and open-access journals. “There really is a strong advocacy for this” from scientists and universities as well as patients, explains NIH Office of Science Policy Director Lana Skirboll. Zerhouni also thinks an archive of NIH-funded research would help the agency manage its grants portfolio.

Many journals already make content freely available within a year or 6 months, but imposing a time limit could doom some journals, participants warned. Martin Frank, executive director of the American Physiological Society, noted after the meeting that publishers are already tinkering with having the author pay publication costs in exchange for immediate open access, and he argues that a single policy mandated by NIH “doesn't take into account the broad diversity of publishing.” Says Frank: “Let me do the experiment.”

Another concern is that posting manuscripts could be confusing: Would the PubMed Central version or the published paper be the document of record? Some publishers suggested that instead, MEDLINE, the NIH abstracts database, could include links to full-text papers on journals' sites. Zerhouni, however, said he's concerned that some journal archives won't remain stable over the long term.

Critics also question whether NIH should divert funds from research to expand PubMed Central, which now costs $2.5 million a year and contains papers from about 150 journals. Frank estimates that it would cost$50 million to post full-text articles for all 4500 journals in MEDLINE.

Skirboll says NIH expects to hold at least one more meeting, this time with patient groups, then post a proposal for comment in the NIH grants guide, probably by December. Even when the plan is final, it can be modified if it causes harm, she adds. “Policies are not laws. … Anything NIH puts in place, we will evaluate.”

8. IN MEMORIAM

Philip Hauge Abelson, 1913-2004

1. Donald Kennedy, Editor-in-Chief

Philip H. Abelson, for 23 years the editor of Science, passed away on 1 August at 91. For us relative newcomers as well as those whom he brought here, his loss marks the end of an era. As an extraordinary role model here at Science, he cared about the full breadth of scientific work, having himself made major contributions in fields from nuclear physics to geology. As a colleague, he offered a thoughtfully dispensed supply of good counsel. And to the pages of this magazine, he brought an enhanced focus on the convergence of science and public policy—evident not only in the News pages but in his crisply opinionated editorials on research policy, regulation, and higher education.

Some disagreed with some of Phil's editorials, as he expected, and so the Letters column grew as a forum for discussion and debate over the important scientific issues of the day. After Dan Koshland succeeded him in 1985, the two adopted a friendly custom of dueling editorials—one week one, the next week the other. I suspect Dan and I are equally impressed, as his successors, with the size of the program Phil had ahead of himself as he took over. In his first editorial (Science, 19 October 1962), he modestly described himself as the “custodian of a uniquely valuable property.” What this custodian then announced was a plan to reduce publication time to 2 months—and to close News and Comment on Tuesday, print on Wednesday, and mail by midnight!

The Abelson scientific biography is an extraordinary saga, touching many of the important figures and scientific institutions that dominated American science during the 20th century. After graduating from Washington State University, he began his doctoral program in physics at the University of California, Berkeley, working with Ernest O. Lawrence on nuclear research and collaborating with Nobel Prize winner Luis Alvarez—and, as always, with the support and help of his wife Neva. During the year after he received his Ph.D., he worked with Edwin McMillan, bombarding uranium with neutrons in the Berkeley cyclotron to create neptunium. By that time, the Manhattan Project was getting under way, and a system for separating and concentrating uranium-235 was needed. Abelson worked on a thermal diffusion technique, and the method he developed in Philadelphia was later enlarged to make the huge facility in Oak Ridge, Tennessee, that produced the first bomb-grade material.

Phil spent much of his later career at the Carnegie Institution of Washington, where he was director of the Geophysics Laboratory from 1953 until his appointment as president of the institution in 1971, a position he held until 1978. I hope it will not escape the reader that for most of the time he was doing these things he was also the editor of Science. Maxine Singer, who watched much of Phil's Carnegie career as he moved from rank to rank, may have hit on an explanation for his polyvalence: “Until a few months ago when illness struck, Phil was a remarkable resource for learning what was going on across an amazing array of scientific fields; I have never known anyone who read and thought so broadly and deeply.”

Comments from Phil's colleagues at Science portray two different values. One, from Editorial, said: “He was an unabashed, passionate advocate for science and scientific progress.” He was an optimist who once edited a volume of essays—they were actually editorials—entitled Enough of Pessimism. As a member of our Senior Editorial Board during the past several years, he frequently reminded us of the importance of technology—the instrumental innovation that drives science forward. In a way, he was a hybrid scientist-engineer: a scientist who earned his engineering stripes on the battlefield in the course of a rich, technology-intensive career.

The other characterization, from a longtime member of the News department, described Phil as having reached the “generativity” stage: mature and confident enough of his own place to invest his energy in helping others succeed. All three of his successors have benefited from Phil's presence and his support. Although he was a willing and helpful critic, he did not mind divergence of views. On the contrary, he often encouraged pieces with which he fundamentally disagreed. The only thing he insisted on was that we get the facts right and honor the data.

His own editorials were clear, rich with content, and sometimes angry. He didn't like government regulation much, particularly when it involved regulation of science, and when I was at the Food and Drug Administration doing some of that, his editorials occasionally made me wince. But his arguments were honest, asking only to be judged on their merits. The last paragraph of one of his editorials, written in 1976 when society was concerned about the unanticipated risks associated with new technologies, is revealing. After surveying the cost-benefit pendulum of innovation, he comes down against the pessimists: “One would not advocate that we become a nation of Panglosses. However, enough of pessimism. It leads nowhere but to paralysis and decay.”

Paralysis and decay? Not on your life—not for a man who walked 4 miles every day before breakfast.

9. EVOLUTIONARY BIOLOGY

The Birth of the Nucleus

1. Elizabeth Pennisi

When and how did the command and control center of the eukaryotic cell arise?

LES TREILLES, FRANCE—What stands between us and Escherichia coli is the nucleus. Eukaryotic cells—the building blocks of people, plants, and amoebae—have these specialized, DNA-filled command centers. Bacteria and archaea, the prokaryotes, don't. The nucleus's arrival on the scene may have paved the way to the great diversity of multicellular life seen today, so the membrane-bound organelle fascinates scientists probing the evolution of modern organisms. “The question of the origin of the cell nucleus is intimately linked to the question of our own origin,” says Patrick Forterre, a molecular biologist at the University of Paris-Sud in Orsay, France.

Last month, Forterre and two dozen microbiologists, evolutionary biologists, cell biologists, and others met* here to hash out leading theories about the origin of the nucleus. One camp holds that the organelle is the result of a microbial merger. Another contends that residual nuclei hidden away in some bacteria indicate that the crucial innovation is far older than commonly thought. Perhaps the most radical theory of all puts viruses at the center of this cellular development.

At the meeting's end, the discussions of the origin of the nucleus had left biologists with a key insight: They had underestimated the complexity of the eukaryotic cell's 1.5-billion-year-old precursor. The data presented indicated that this ancestral cell had more genes, more structures, and more diverse biochemical processes than previously imagined.

But when it came to accounting for how the nucleus was born, no single hypothesis bubbled to the top. “It's like a puzzle,” says Forterre. “People try to put all the pieces together, but we don't know who is right or if there is still some crucial piece of information missing.”

Biologists have long considered the nucleus the driving force behind the complexity of eukaryotic cells. The Scottish botanist Robert Brown discovered it 180 years ago while studying orchids under a microscope. In his original paper, Brown called the novel cellular structure both an areola and a nucleus, but the latter name stuck. Now, as then, the organelle's complexity inspires awe. The nucleus is a “huge evolutionary novelty,” says Eugene Koonin of the National Center for Biotechnology Information in Bethesda, Maryland.

Each nucleus in a eukaryotic cell consists of a double lipid-based membrane punctuated by thousands of sophisticated protein complexes called nuclear pores, which control molecular traffic in and out of the organelle. Inside, polymerases and other specialized enzymes transfer DNA's protein-coding message to RNA. Other proteins modify the strands of RNA to ensure that they bring an accurate message to the ribosomes outside the nucleus. The nucleus also contains a nucleolus, a tightly packed jumble of RNA and proteins that are modified and shipped out of the nucleus to build ribosomes.

The picture is far different in bacteria, in which DNA, RNA, ribosomes, and proteins operate together within the main cell compartment. It's a free-for-all in that as soon as the DNA code is transcribed into RNA, nearby proteins begin to translate that RNA into a new protein. In eukaryotes, “the double membrane [of the nucleus] uncoupled transcription and translation” and resulted in better quality control, says John Fuerst, a microbiologist at the University of Queensland, Australia. As a result, RNA is modified as needed before it comes into contact with a ribosome outside the nucleus.

The nuclear distinction between prokaryotes and eukaryotes shaped early speculation about the development of complex life. Until the 1970s, two competing theories dominated the debate over early eukaryotic evolution. According to one, a subset of bacteria slowly developed eukaryotic features, such as the nucleus. In the other, eukaryotes came first, but over time, some of them lost the nucleus and evolved a cell wall, spawning modern-looking bacteria.

Then the Woesean revolution struck. By looking at DNA sequence differences in the same gene across hundreds of microorganisms, Carl Woese, a microbiologist at the University of Illinois, Urbana-Champaign, showed that “bacteria” were actually two kingdoms, the bacteria proper and the archaea, which apparently arose some 2 billion years ago, millions of years before eukaryotes. The initial genetic analyses indicated that archaea were more closely related to eukaryotes than were bacteria. This kinship hinted that eukaryotes came from the seemingly simple archaeal stock.

Recent comparisons of fully sequenced microbial genomes have, however, added a twist to this story: Eukaryotes contain both archaeal and bacterial genes. Archaeal genes tend to run processes involving DNA and RNA, so-called information functions; the bacterial genes are responsible for metabolic and housekeeping chores. From the jumble of genes, some evolutionary biologists have concluded that this division of labor arose from the ancient symbiotic partnership between bacteria and archaea, a partnership that gave rise to eukaryotes.

Friendly mergers

Such a partnership may have been enough to create the nucleus, according to Purificación López-García and David Moreira of the University of Paris-Sud. The two evolutionary biologists speculate that the original union between bacteria and archaea grew from metabolic requirements. The nucleus, they further argue, arose as a way for these endosymbionts to keep their metabolic chemistries from interfering with one another. “You needed the [nuclear] membrane because you have two competing pathways,” López-García explains.

In 1998, she and Moreira proposed that in life's earliest days, methane-making archaea sometimes lived within bacteria that depended on fermentation for sustenance: the so-called syntrophic model. The relationship worked for the archaea because fermentation yielded a resource they needed, namely hydrogen. The bacterium may have benefited because fermentation requires that hydrogen concentrations remain low.

López-García and Moreira hypothesize that Earth's changing environmental conditions ultimately prompted a shift in the symbiosis. The archaeum gradually lost its appetite for hydrogen, ceased making methane, and instead relied more on the bacterial host for other nutrients. The archaeum's membrane, which had been critical for methanogenesis, became superfluous. At the same time, the outer bacterial membrane invaginated the cellular compartment, eventually surrounding the archaeal DNA but excluding the ribosomes. The change was advantageous to the bacteria, because in separating ribosomes from the microbial chromosomes, it helped ensure more accurate conveyance of the DNA's message. This set-up persisted and ultimately evolved into the eukaryotic nucleus, says López-García. And what remained of the archaeal cytoplasm became the nucleolus.

The researchers suggest that modern methanogenic archaea bearing a resemblance to eukaryotes are possible descendants of the ancient methanogens that entered into the nucleus-generating symbiosis with bacteria. These archaea and eukaryotes have similar genes encoding proteins involved with DNA and RNA. For example, they share genes for histones, proteins that help stabilize chromosomes. In contrast, bacteria don't have histones.

Another modern microbe, the myxobacterium, may resemble the ancient bacterial host in which the nucleus evolved. Like eukaryotic cells, myxobacteria communicate with other cells, move, and can form multicellular complexes. Myxobacteria “have complex structures that are very striking” and reminiscent of eukaryotic cells, López-García notes. These bacteria also have cell-signaling molecules, such as kinases and G proteins, in common with eukaryotes.

Self-starters

López-García and Moreira's proposal assumes that bacteria and archaea appear earlier on the tree of life than eukaryotes, but Fuerst holds that the reverse is true. He is convinced that eukaryote-like cells were around before bacteria and archaea or emerged right at the time when these prokaryotes split off to form separate kingdoms of their own. Fuerst points to an unusual group of bacteria that he's studied for the past decade. These remarkable microbes have nuclei, or something akin to them, and may resemble the early cells that evolved into modern eukaryotes, according to Fuerst.

Found in soil and fresh water, these microbes, called planctomycetes, have cell walls that are not quite as rigid as those of other bacteria. As early as 1984, researchers had suggested that some planctomycetes also have internal membranes. In 2001, Fuerst and his colleagues, using sophisticated electron microscopy techniques, confirmed the existence of these membranes, even revealing double ones like those of a nucleus. Those observations “turn the dogma that ‘prokaryotes have no internal membranes’ upside down,” says Philip Bell, a yeast biologist at Macquarie University in Sydney, Australia.

Using sophisticated electron microscopy techniques, Fuerst and his colleagues have now verified that there are discrete membrane-bound compartments within two planctomycetes, Gemmata obscuriglobus and Pirellula marina. One compartment, pushed up along the periphery, seems to have very little in it. A second sits in the center of the microbe and holds a dense collection of genetic material—RNA and DNA mixed with DNA- and RNA-processing proteins. The stuff in between—the cytoplasm—is full of proteins, ribosomes, and RNA.

At least one planctomycete has a double internal membrane around its DNA instead of the more typical single membrane. The membrane is not continuous but consists of pieces of folded membranes linked together. The gaps between the folds could indicate how nuclear pores got their start, says Fuerst.

Explaining these structures has always posed a sticking point for nuclear evolution. Without pores, the nucleus can't function. But nothing similar to these complex channels had been seen in bacteria before. At the meeting, however, Fuerst showed dramatic electron micrographs of craterlike spots in the internal membranes of planctomycetes. These depressions closely resemble nuclear pores, he says. Although nuclear pore genes are hard to compare, Fuerst is encouraged that a preliminary look at a planctomycete genome hints that the bacteria have primitive versions of eukaryotic genes for some key nuclear pore proteins.

“If you combine all the evidence, it makes a consistent picture,” he asserts. “Gemmata is a valid model for a nonsymbiotic origin of the eukaryotic nucleus.”

It may not be alone. There's a recently discovered phylum of sponge-dwelling bacteria that also seem to have nuclei, says Fuerst, and there are likely more, yet-to-be-discovered microbes with similar features. Bacteria with nuclear pores and internal membranes, features typically considered eukaryote-specific, suggest that the nucleus was born much earlier than traditionally thought. If Fuerst's scenario is correct, “then the nucleus actually precedes eukaryotes,” says Koonin.

In fact, this compartment could date back to the last universal common ancestor (LUCA), a putative organism from which eukaryotes, bacteria, and archaea eventually emerged, says Fuerst. If that's the case, certain LUCA features, such as the nucleus, were retained in eukaryotes but lost to some degree in most archaea and bacteria. Indeed, that seems to be the case, as eukaryotic cells possess features now seen in each of these groups.

Hostile takeover

A third option for the origin of the nucleus revolves around viruses. “Viruses predated the divergence between the three domains of life,” says David Prangishvili, a virologist at the University of Regensberg, Germany. He argues that viruses were already quite common in the primordial soup and only later became dependent on cells to survive. When these early cells came along, “viruses played a critical role in the evolution of the complex [eukaryotic] system,” adds Forterre.

Viruses do have the ability to set up permanent residency in a cell, infecting but not killing the host. Thus they and their genes can stay around and influence a cell's evolution. Bell, Forterre, Prangishvili, and Luis Villarreal, a virologist at the University of California, Irvine, each have a different proposal for how viruses were important to the evolution of the nucleus. Their supporting data are provocative, but circumstantial and controversial. “I do not believe [it],” says Jacomine Krijnse-Locker of the European Molecular Biology Laboratory in Heidelberg, Germany. “The idea of the viruses ‘inventing’ [eukaryotic cells] from scratch is hard for me to conceive.”

When viruses persist in cells instead of killing them, cells “can acquire a whole new set of genes in one event,” counters Villarreal. While in residence over millions of years, the new viral genes could have supplanted bacterial or archaeal genes, replacing, for instance, proteins that process DNA. These extra genes could also evolve to play new roles in the cell.

Villarreal points out that there are intriguing similarities between nuclei and viruses, which are basically packets of DNA surrounded by a protein coat—and often by a membrane. In red algae, for example, a nucleus can move from cell to cell, much like an infectious virus. And in general, cell nuclei and viruses lack protein- and lipid- producing pathways within their borders. Both contain linear chromosomes, whereas most bacterial chromosomes are circular. Both disassemble their “membrane” during replication. Both transcribe DNA but don't translate mRNA within their boundaries. As they replicate within a cell, some poxviruses even make a membrane around their DNA using the endoplasmic reticulum of the infected cell. The eukaryotic cell uses this same material to build its nucleus.

Large, complex DNA viruses, which include poxviruses and the African swine fever virus, likely bear the closest resemblance to the putative viral ancestor of the nucleus, Bell suggests. DNA strands in these viruses have primitive telomeres, protective DNA sequences found at the ends of eukaryotic chromosomes.

Bell speculates that a virus living in an archaeum set the stage for the nucleus. Ultimately, viral DNA and archaeal DNA merged inside the virus, and the new genome later shed genetic material from both. In the end, “the unique genetic architecture of the eukaryote is a result of superimposing a viral genetic architecture on an archaeal genetic architecture,” Bell argues.

“If this is true, then we are all basically descended from viruses,” remarks Forterre.

Did a virus provide the first nucleus? Or was it something an early bacterial cell evolved, either on its own or in partnership with an archaeum? To resolve the origin of the nucleus, evolutionary biologists are exploring new techniques that enable them to determine relationships of microorganisms that go much further back in time. And as new genome sequences become available, such as those of several planctomycetes, Fuerst and others plan to search for more genetic similarities between these bacteria and eukaryotes. Meanwhile, García-López anxiously awaits sequenced genomes of myxobacteria and plans to compare them with the genes of eukaryotes.

Overall, says Forterre, it's “a really exciting time to tackle questions which were previously only considered seriously by a few theoritists.”

• * “The Origin of the Nucleus” was held in Les Treilles, France, from 7 to 13 July.

10. EDWARD HAMMOND PROFILE

Activist Throws a Bright Light on Institutes' Biosafety Panels

1. Martin Enserink

Edward Hammond's aggressive sleuthing has triggered a debate on the oversight of the growing field of biodefense research

AUSTIN, TEXAS—In late January, Edward Hammond sent out a blizzard of faxes to almost 400 research institutes from Honolulu to New York. His request was straightforward enough: He asked for the minutes of the last two meetings of each organization's Institutional Biosafety Committee (IBC).

Hammond, who directs the Sunshine Project, a small nonprofit organization based in Austin, wondered whether the IBCs fulfill their oversight role for certain types of biology experiments as prescribed by guidelines from the National Institutes of Health (NIH). In particular, he questioned whether they would publicly share their deliberations. Such openness, he says, is vital to prevent biodefense research from going astray.

Today, Hammond is fighting testy e-mail battles with his targets over their tardy responses. How to answer his query has become a hot topic among biosafety officers and university lawyers. Some universities have sent him minutes, but with almost every detail blanked out, arguing that the redacted information is private, proprietary, or security-sensitive. More important, Hammond has concluded that the IBC system, designed in the 1970s to review recombinant DNA research, is in disarray. He claims that dozens of IBCs, many of them at the nation's research powerhouses, aren't staffed properly, don't seriously review proposals, or never meet at all. Outraged, he has filed complaints with NIH, asking it to cut off funding retroactively to 19 institutions. Dozens more complaints are on the way.

NIH officials are investigating the charges, but there's no reason to assume that the entire system is broken, says Allan Shipp of NIH's Office of Biotechnology Activities (OBA), which oversees IBCs. Most IBCs are “very earnest in their attempts and desire to fulfill their responsibilities,” he says.

Some researchers who have followed Hammond's quest—he posts alleged violations frequently on his Web site—disagree. “Frankly, I've been surprised by the number and magnitude of the deviations from the guidelines that he has identified,” says molecular biologist Richard Ebright of Rutgers University in Piscataway, New Jersey. To him, the results are an indictment of OBA as well. “If many institutions do not have IBCs in place for a long period of time, or their IBCs don't schedule meetings, then that office is not functioning,” he says.

Hammond's critics say he doesn't distinguish between correct paperwork and biosafety itself. The latter is a topic he doesn't know much about, argues Stefan Wagener, president of the American Biological Safety Association. Many also dislike the confrontational tone of his prolific correspondence. “He's an irritant sometimes,” says virologist C. J. Peters of the University of Texas Medical Branch in Galveston. “He's fond of trouble, but the kind of information that he's after doesn't make us much safer.”

In a café near his tiny office, the San Antonio native, who graduated in Latin American studies and community and regional planning, explains the motivation behind his crusade. Safety isn't Hammond's main concern. He sympathizes with biodefense activists who, fearful of escaping germs, rail against planned high-level biosafety labs in their neighborhoods, but he's more interested in another issue: transparency. “The public has a right to know,” he says, “that's what it's really all about.” He is unapologetic about being aggressive. “You have to be tough to be heard,” he says. “If you are working with Ebola, the public has a right to ask questions.”

Without appropriate public oversight, Hammond argues, biodefense spending could easily cross over into offensive research. Some recent studies—such as the creation of the poliovirus from scratch and the partial resurrection of the 1918 pandemic flu virus—trigger a vicious cycle, he asserts: Under the guise of defending against potential threats, researchers generate new ones, requiring new countermeasures.

German biologist Jan van Aken founded the Sunshine Project— exposure to sunlight can inactivate many biological weapons—in 1999 to investigate activities that could undermine the 1972 Biological and Toxin Weapons Convention. In 2000, he joined with Hammond and his wife Susana Pimiento, a lawyer from Colombia, to set up a U.S. branch. The group's \$100,000 annual budget is funded by liberal-leaning charities such as the Ben & Jerry's Foundation and individual donors.

One of Hammond's first targets was the U.S. program—still ongoing—to use pathogenic fungi to eradicate opium poppy, cannabis, and coca crops in South America and Asia. Using the Freedom of Information Act, he has unearthed “a tremendous amount of information” about that effort, says Mark Wheelis, an arms control researcher at the University of California, Davis, who serves on Sunshine's advisory committee. Hammond has also dug into the Pentagon's secretive research into so-called nonlethal weapons, which include psychoactive and anesthetic drugs. These weapons may violate the 1993 Chemical Weapons Convention. “He has done an immense service to the arms control community,” says Wheelis. “Most of us simply don't have the time to chase those documents.”

Minutes Man

Now Hammond has become a watchdog of the biodefense business, and he's using the IBCs to get a foot in the door. Set up in the 1970s in response to worries about genetic engineering, IBCs review studies involving recombinant DNA at every institute that receives NIH funding. NIH rules require them to have members from outside the institute and make meeting minutes accessible. Although recombinant DNA work is their official mandate, many institutes have also charged IBCs with looking at other potentially hazardous work.

Hammond concedes that most of the vast stacks of the documents he has received don't contain anything very exciting. It's what he hasn't received, however, that upsets him.

Take Mount Sinai Medical Center in New York City, which has dozens of projects that entail recombinant DNA work, including studies with Ebola and Lassa fever viruses. Yet its IBC has met only once and reviewed three proposals since 2001. The committee's minutes—which Mount Sinai provided to Hammond and subsequently to Science—consist simply of the research proposals and signed letters of approval from the IBC. A Mount Sinai spokesperson provided Science with a list of reasons why experiments that Hammond says should have been reviewed are, in fact, exempt from the guidelines.

IBC meetings are an equally rare event at Rockefeller University in New York City, where the panel last met in September 2003, after a 5-year hiatus. The Rockefeller IBC reviews all proposals—some 161 since 2000—electronically, explains Amy Wilkerson, associate vice president for research support. She, however, has declined to share any electronic records with Hammond, who says this is at odds with the spirit of the IBC system.

At Tulane University in New Orleans, Louisiana, Hammond's January fax was simply ignored, as was a follow-up by certified mail. When he faxed a final, more threatening request on 7 July, the university responded with a four-line letter saying it “has no documents responsive to your request.”

OBA will investigate each of Hammond's complaints, says Shipp. In May, it put out a memo instructing IBCs that minutes should contain, at a minimum, “the major points of discussion and the committee's rationale for particular decisions.” Mount Sinai told Science it will change its practices accordingly and will also honor a recent NIH suggestion that its IBC meet at least once a year.

Hammond's efforts come at a key time for IBCs. In March, the U.S. government announced plans to have them review any experiments that could play into the hands of bioterrorists (Science, 12 March, p. 1595). From the responses Hammond has received, Ebright says, “it's clear that they're not prepared for this extra burden.”

11. PLANETARY SCIENCE

Rainbow of Martian Minerals Paints Picture of Degradation

1. Richard A. Kerr

Better spectroscopic observations from Europe's Mars Express and analyses by NASA's rovers are revealing a diversity of minerals that tells of water shaping the planet

To a geologist, there's nothing like getting your hands on a rock to see what it is made of. But spectroscopists can get some sense of the makeup of a distant planet's rocks by splitting the light that comes off the planet's surface into the squiggly lines of a spectrum. The peaks and valleys of those spectra, properly interpreted, can reveal the planet's mineralogical composition. Spectra of Earth can splash a riot of color across the wavelengths from the blue of the visible to the far infrared, revealing “a mineralogical museum,” notes planetary scientist John Mustard of Brown University in Providence, Rhode Island. Mars, on the other hand, had presented spectroscopists with not much more than “little bumps” to mull over. “Perhaps Mars is mineralogically impoverished,” Mustard mused a couple of years ago.

Fortunately for Mustard and his colleagues, they are finally seeing a spectral diversity on Mars that, although it doesn't rival Earth's, tells a far more complete story of how water came to chemically alter much of the martian surface. Mars, it turns out, is not so much mineralogically impoverished as incompletely studied. With a new spectrometer now in orbit aboard Mars Express, instruments on the Opportunity and Spirit rovers getting up close to rocks (see special section, p. 793, for the first published results from Spirit), and yet more capable spectrometers on the way, “we have a real opportunity to put the whole of Mars together,” says planetary spectroscopist Jessica Sunshine of SAIC Inc. in Chantilly, Virginia.

The emerging picture is of a salt-laden, often corroded planet that had standing water early in its history. Volcanic emanations made that water acidic enough to leach salt from the rock and lay it down in thick beds, and water beneath the surface seems to have altered rock as well. Most of the planet is now covered by weathering products of yellow-brown dust or rock rinds. But the nature of the weathering and to what extent it has continued to the present are still being debated; even the new and improved spectral squiggles are leaving room for interpretation.

Salty Mars

It was a unique bit of spectral color that brought the Opportunity rover to the shallow sea deposits of Meridiani Planum in the first place. As the Thermal Emission Spectrometer (TES) on Mars Global Surveyor scanned the planet strip by narrow strip beginning in 1999, the planet looked pretty simple. The better part of it is bright, dust-covered regions. In TES spectra of the infrared radiation emitted by the surface—the so-called midinfrared of 5- to 50-micrometer wavelengths—the dark areas are volcanic rock that has low or medium amounts of silica, the basic ingredient of rock. But one area on the equator about the size of Oklahoma had a booming spectral signal of the iron-oxide mineral hematite. Hoping to land on a once-buried lakebed or hydrothermal deposit—common places to find hematite on Earth—mission controllers set the Opportunity rover down on Meridiani Planum last January.

Opportunity found the hematite expected from remote sensing, but not in any of the expected geologic settings. The hematite had formed in marblelike concretions while buried in dirty, salt-laden deposits laid down as a shallow sea or a series of puddles evaporated (Science, 5 March, p. 1450). When the rover applied its analytical instruments directly to the centimeters-thick deposit of little Eagle crater, the outcrop turned out to be almost half sulfate salts. Small amounts of sulfate had been inferred from martian soil sulfur analyses since the Viking landers of the late 1970s, but remote sensing had seen nary a wisp of sulfates from orbit. Opportunity is now inching down the steep interior of the large crater Endurance and finding meter after meter of the same sulfate-rich evaporite as at Eagle crater. Presumably it goes down the entire 300 meters of the light-toned, layered stratum seen from orbit underlying Meridiani Planum.

Now sulfates—as well as other weathering products—are turning up all across Mars. In late December, the European Space Agency's Mars Express went into orbit carrying the Visible and Infrared Mineralogical Mapping Spectrometer (OMEGA) among its seven instruments. It is the first-ever spectrometer spanning the near-infrared wavelengths of 0.35 to 5.2 micrometers to make it safely into Mars orbit and operate for more than a few weeks. Its 10-times- finer spatial resolution and near-infrared wavelengths sensitive to altered, fine-grained material revealed far more “color” on Mars than spectroscopists could see before.

In March at the Lunar and Planetary Science Conference (LPSC) in Houston, Yves Langevin of the University of Paris South (UPS) in Orsay and the OMEGA team reported the detection of a magnesium sulfate mineral called kieserite. This sulfate “seems to be ubiquitous in low-lying regions” where water might have collected and evaporated, he said, such as at the bottom of a canyon of the Valles Marineris. OMEGA also detected clays, produced by the water weathering of silicate rock, and serpentine, the weathering product of olivine.

At last month's biennial scientific assembly of the Committee on Space Research in Paris, OMEGA principal investigator Jean-Pierre Bibring of UPS mapped out the distribution of both magnesium and calcium sulfates in the tiny fraction of Mars covered by OMEGA so far. They appear not only where ancient waters may have collected but also in some, although not all, of the layered deposits beyond Meridiani Planum. Layered deposits have of late become the leading geological mystery on Mars (Science, 8 December 2000, p. 1879). Some geologic force—water, wind, volcano, or impact—laid down light-toned material inside impact craters and in other low-lying regions. The Opportunity and OMEGA discoveries seem to show that at least some of the mysterious layered deposits were formed beneath standing water: ponds, lakes, or oceans.

Ancient age of corrosive ponds

To geochemists, a sulfate-salty Mars tells a story of a young planet corroded by acid. In a 1987 paper, the late Roger Burns detailed the geochemical consequences of a young, volcanically active Mars. Sulfuric acid derived from volcanic emissions would have mixed with any water that was about and chemically eroded rock to produce a variety of sulfates, in particular a potassium iron hydroxy sulfate called jarosite.

The Opportunity rover's Mössbauer instrument did in fact identify jarosite in the evaporite at Eagle crater. Because the Meridiani Planum rocks are some of the oldest seen on the planet, that's “a compelling case for acidic water on [early] Mars and lots of it,” says geologist Jeffrey Kargel of the U.S. Geological Survey in Flagstaff, Arizona. In recognition of Burns's foresight, Opportunity team members named the largest evaporite outcrop of Endurance crater Burns Cliff.

Water on early Mars as acidic as gastric juices could not only have helped corrode Mars and contribute to sedimentary deposits, but it could have played a pivotal role in martian climate. Signs that running water cut valleys during the first billion years or so of martian history—when life was beginning on Earth—have convinced most researchers that early Mars was “warm and wet,” or at least not so cold that all water was continually locked up as ice. But the young sun was not stoked to its full heat and brilliance in the first billion years of its life, so climate modelers have had to invoke some sort of extra heating early on, such as a strong greenhouse, to explain the warmth.

A dense carbon dioxide atmosphere could have boosted the early martian greenhouse, but the gas is not geochemically inert; it too forms an acid with water and corrodes rock to form carbonate salts. Locked up in carbonates, carbon dioxide couldn't warm the planet. With enough volcanoes erupting, however, sulfuric acid could have frustrated carbonate formation, kept the carbon dioxide as a gas, and propped up the martian greenhouse, notes planetary geologist Jeffrey Moore of NASA's Ames Research Center in Mountain View, California. The huge Tharsis volcanic complex and a host of other Hawaiian-style volcanoes on Mars suggest that there was lots of eruptive activity into martian middle age.

Questions of color

Although OMEGA is bringing a broader spectral view to martian remote sensing and the two rovers are providing some much-needed ground truth for orbiting instruments, they certainly haven't settled many debates on the nature of the martian surface. A central question is what, if anything, water was doing after the early “warm and wet” era. For example, exactly what TES data reveal about the darker, dust-free regions covering much of Mars remains unsettled. Do their spectral signatures divide them into areas of rock of either low or moderate silica content? Or are they fresh rock and alteration-coated rock? Although the answers remain unclear, the case for alteration—perhaps in the middle history of Mars—does seem to be gaining ground.

Other chemical rock alteration cannot yet be tied to early Mars. Early on, Spirit found two kinds of “crud,” as one team member describes weathering products, coating many rocks in Gusev crater that neither its remote-sensing Mini-TES instrument nor its two contact analyzers could make heads or tails of (Science, 9 April, p. 196). And now Spirit has identified hematite in rocks of the Columbia Hills that are utterly unlike those of Meridiani Planum. Severe, wet alteration of some sort of rock in the Columbia Hills seems to have occurred, says rover team member Raymond Arvidson of Washington University in St. Louis, but details remain murky.

The soil of Gusev crater is generating another debate over how much weathering occurred when. The rover science team concludes that the soil is mostly local volcanic rock pulverized by impacts or sandblasted off exposed rock by the wind, with a bit of windblown dust added in. Exposure to the martian elements that weathered large Gusev rocks apparently has failed to weather away even the vulnerable olivine exposed in the soil.

Three nonteam spectroscopists—Melissa Lane of the Planetary Science Institute in Tucson, Arizona; Darby Dyar of Mount Holyoke College in South Hadley, Massachusetts; and Janice Bishop of NASA Ames—argued at the LPSC that the soil's rock has in fact completely rotted away to crud. Lane, who was a student of Philip Christensen of Arizona State University in Tempe, the TES, THEMIS, and Mini-TES PI, argued that Mini-TES analyses did not compare Gusev soil spectra with enough spectra of known compounds. She found that hydrous iron sulfate—another acid weathering product predicted by Burns—is as good a match to absorptions that Christensen and his colleagues attribute to trace carbonate and loosely bound water. And Mössbauer specialist Dyar—who along with Bishop was a student of Burns—argued that Mössbauer soil spectra match hydrous iron sulfate just as well as they do olivine. So, what the rover team takes to be unaltered rock, Lane and her colleagues see as alteration products formed well after warm and wet Mars.

Resolving such differences could require many sorts of observations by both remote sensing and rover-manipulated analyzers, says planetary spectroscopist Carlé Pieters of Brown University. “It's clear you need multiple pieces of information,” she says. In the past, instruments have been flown one at a time, she notes, but that is changing with the current rovers, Mars Express, and the upcoming NASA 2010 Mars Science Laboratory rover and the 2006 Mars Reconnaissance Orbiter. Even so, she says, understanding martian dust, soil, and weathering—and thus water's role in martian history—will probably require the return of samples.

12. BASIC AND CLINICAL IMMUNOLOGY MEETING

An Old Favorite Is Resurrected: Regulatory T Cells Take the Stage

1. Jennifer Couzin

MONTREAL, CANADA—More than 7000 researchers gathered here from 18 to 23 July for the International Congress of Immunology and the Annual Conference of the Federation of Clinical Immunology Societies.

When roughly 1000 people packed a convention center hall here for talks on a mysterious class of T cells, it was clear that 20 years after falling out of favor, regulatory T cells have made a stunning comeback. The cells, which make up roughly 5% to 10% of T cells in people, suppress the function of other T cells and may help physicians control a range of infections, autoimmune diseases, and organ transplant rejection. That no one understands exactly how these cells rein in the immune system or how to harness their powers doesn't appear to have dampened enthusiasm one bit. “It's over the top at the moment,” says immunologist Anne O'Garra of the National Institute for Medical Research in London.

Regulatory T cells, formerly called suppressor T cells, first attained popularity in the early 1970s. But by the mid-1980s, they'd lost their appeal, in part because they were so difficult to isolate and grow. Aided by improved technology in the last 5 years, immunologists led by Shimon Sakaguchi of Kyoto University in Japan found new markers with which to identify the cells, such as the surface proteins CD4 and CD25, and the field was reborn. What scientists learned was remarkable: In test tubes and mouse studies, regulatory T cells seemed to ease inflammation and regulate other immune cells implicated in autoimmune diseases such as type I diabetes. In some experiments, they also prevented transplanted organs in mice from being rejected.

At the meeting, David Hafler of Harvard University suggested that patients with multiple sclerosis, an autoimmune disease, have normal numbers of regulatory T cells positive for CD4 and CD25, but the cells are sluggish, unable to rein in other T cells as they normally would. Fiona Powrie of the University of Oxford, U.K., meanwhile, reported that CD25 cells given to mice with a version of inflammatory bowel disease infiltrate the animals' guts and reverse inflammation.

Although CD25 is the most popular marker for regulatory T cells, there's a major catch: All activated T cells express it, so it's only useful when studying inactive or “naïve” cells that haven't been challenged by, say, a pathogen. Another popular marker, FoxP3, a transcription factor, is present only inside the cell, not on its surface. Because it's tough to spot and manipulate, FoxP3 can have limited usefulness in identifying and sorting regulatory T cells.

Two groups, one led by O'Garra and the other led by Maria Grazia Roncarolo, who directs the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, now propose that the secreted cytokine interleukin-10 (IL-10) provides a good marker with which to identify regulatory T cells. O'Garra reported that IL-10- making T cells that displayed regulatory abilities didn't always express much Fox P3, raising questions about its appropriateness as a marker. Roncarolo, meanwhile, reported that IL-10 regulatory T cells blocked the development of diabetes in mice that are susceptible to it.

It remains unclear how regulatory T cells suppress the immune system and whether they falter in people with autoimmune diseases. Ethan Shevach of the National Institute of Allergy and Infectious Diseases, who has helped lead the comeback of regulatory T cells, revealed new data suggesting that the cells destroy B cells in test tubes; if this occurs in live animals, it could represent another route by which regulatory T cells suppress immune activity. “It's extremely exciting,” says O'Garra, who believes the work has “major implications” in explaining the suppressive nature of regulatory T cells.

These findings have some immunologists itching to test regulatory T cells in clinical trials, although others caution that such efforts would be premature, given the confusion still swirling around the cells. “Hopefully,” says Harvard immunologist Harald von Boehmer, “they'll allow clinicians to do what they haven't been able to do for 30 years: manipulate immunity.”

13. BASIC AND CLINICAL IMMUNOLOGY MEETING

And Action! Dendritic Cells Go Live

1. Jennifer Couzin

MONTREAL, CANADA—More than 7000 researchers gathered here from 18 to 23 July for the International Congress of Immunology and the Annual Conference of the Federation of Clinical Immunology Societies.

While regulatory T cells were fodder for gossip at evening cocktail parties, some of the most provocative news concerned another type of immune cell, the dendritic cell. By educating T cells as to appropriate targets, dendritic cells help the immune system maintain a tenuous but crucial balance between attacking pathogens and sparing the body's own tissue.

Because how cells behave in a petri dish may not reflect their typical actions in a live animal, a handful of immunology teams are now setting up reality shows starring dendritic cells. Using expensive high-tech imaging systems, they've developed intricate methods to visualize the cells in living mice. For example, 7 months ago, Ulrich von Andrian of Harvard University and his colleagues delineated how dendritic cells move as they perform one of their major functions: alerting T cells to a pathogen invasion. He found that the cells move briskly through certain parts of the lymph nodes and often interact only briefly with T cells.

Now a second group, led by Michael Dustin of New York University and Michel Nussenzweig of Rockefeller University in New York City, has offered a glimpse into how dendritic cells accomplish their second major function: ensuring that the body tolerates its own tissue. The team genetically altered mice to express a fluorescent protein in their dendritic cells, which made these immune sentinels easier to spot under a microscope. Then the investigators anesthetized the animals and carefully separated a flap of skin containing a lymph node—where many dendritic cells are found—from each rodent's thigh.

In live images of this system, they watched immature dendritic cells, which hadn't yet been primed by an antigen, form dense networks of almost motionless cells. T cells entering the lymph node reached this network and then quite literally stood still for over an hour, apparently communing with the dendritic cells.

Nussenzweig speculates that the network is an efficient way for immature dendritic cells, which closely monitor the lymph node environment, to pick up certain “self” antigens that enter lymph tissue—and in turn shut down potentially self-reactive T cells. In that way, they may protect the body from autoimmunity.

Why cells clump together in such nearly still networks isn't clear. “There's a world to be discovered” about dendritic cell behavior, says von Andrian.

On the clinical side, Jacques Banchereau, director of the Baylor Institute for Immunology Research in Dallas, Texas, presented new data implicating dendritic cells in a crippling form of arthritis, systemic onset juvenile idiopathic arthritis (SOJIA). Working with blood samples from children with this condition, he's found an upregulation of genes affecting an immune protein called interleukin-1. IL-1 is known to activate dendritic cells.

An IL-1-suppressing drug called Anakinra is on the market for use in rheumatoid arthritis, but it hasn't met with much success, notes Banchereau. When he and his institute colleague Virginia Pascual tested it on nine children with SOJIA, however, eight showed complete regression of disease, and the ninth was also helped. This suggests that unlike rheumatoid arthritis, SOJIA appears dependent on IL-1 and dendritic cell malfunction, concludes Banchereau.

14. BASIC AND CLINICAL IMMUNOLOGY MEETING

Genes Crisscross Disease Lines

1. Jennifer Couzin

MONTREAL, CANADA—More than 7000 researchers gathered here from 18 to 23 July for the International Congress of Immunology and the Annual Conference of the Federation of Clinical Immunology Societies.

Scientists have spent decades hunting for genes behind immune disorders, with relatively little success. But a new genetic tool and some recent studies suggest they're making progress at nailing down some elusive genes, including those that affect more than one disease.

The tool is the increasingly popular technique of RNA interference (RNAi), a relatively quick and simple method to dampen or shut off the expression of individual genes using small RNAs. Immunologist Luk Van Parijs of the Massachusetts Institute of Technology (MIT) recently completed one of the first RNAi gene screens focused on immunity. His lab selected 168 genes whose expression in immune cells is regulated by growth factors but whose roles in overall immune function—and dysfunction—remain unclear.

Using RNAi to quash one or more genes in mouse embryos and adult animals, the investigators examined hundreds of mice, including ones from strains already predisposed to cancer or type I diabetes. Van Parijs was excited to find that knocking out some of the immune genes slowed or sped the onset of those conditions. For example, in a strain of cancer-prone mice, RNAi was used to blunt the effects of a gene in the NF-κB family, which encode proteins that control gene expression. Van Parijs reported that tumor growth was accelerated in the animals, although he hasn't discovered why. The screen also indicated that genes controlling regulatory T cells influence the progression of type I diabetes.

Other researchers have begun to find that genes with a role in one autoimmune disease may contribute to other, related conditions. For example, John Rioux, director of inflammatory disease research at MIT's Whitehead Institute, is finding hints that lupus is tied to variations in IBD5, a gene previously implicated in inflammatory bowel disease.

Rioux is also working with Whitehead postdoc Emily Walsh on a dense genetic map that they hope will point to other lupus genes. Walsh focuses on haplotypes, stretches of DNA that can vary slightly between sets of individuals and encompass multiple genes. She has homed in on a suspect already, for example—a haplotype previously linked to an increased risk of lupus. It includes an immune-related HLA gene that has a known role in the condition, but there may be other connections, she says: “It smells like there are independent [genetic] effects” on this haplotype.

Another immune gene that apparently crosses disease boundaries is PTPN22, says Linda Wicker of the University of Cambridge, U.K. Like other labs, her group jumped on the gene earlier this year when it was linked with type I diabetes. In June, geneticist Peter Gregersen of the North Shore-Long Island Jewish Research Institute in New York reported tying the gene to rheumatoid arthritis. A month later, rheumatologist Timothy Behrens and his colleagues at the University of Minnesota, Twin Cities, implicated it in lupus.

Wicker is studying three other genes that seem to protect mice from diabetes with a combined power larger than their individual effects would suggest. Like many of her colleagues, she contends that immunologists and geneticists need to recognize that small variations in a gene, which may shift gene expression patterns or tweak a protein's amino acids, can spur autoimmune disease as readily as the complete loss of a gene's function. “Subtle changes … can really make a big difference through years of inflammation,” she says.

Wicker's team had studied the gene encoding interleukin-2 for years, painstakingly searching for different expression patterns in type I diabetes and finding none. Now she's discovering subtle variations in gene expression just in CD8 T cells that she thinks could explain the gene's potential effect on type I diabetes.

With the drought in gene-hunting for immune diseases over, says Wicker, “we can try to move on and figure out the biology.”