# News this Week

Science  03 Mar 2000:
Vol. 287, Issue 5458, pp. 1566
1. PALEOANTHROPOLOGY

# Chinese Stone Tools Reveal High-Tech Homo erectus

1. Ann Gibbons

About 800,000 years ago, a large meteorite struck Southeast Asia, exploding in an atmospheric fireball or perhaps slamming into the ground in a now-vanished crater. Either way, geologists say, the impact sent up a spray of molten debris and ignited fires throughout the landscape. In the Bose basin of the Guangxi Zhuang region of southern China, the fires cleared a thick cover of trees and brush and exposed red earth and underlying beds of large cobblestones. Now on page 1622, Chinese and American anthropologists suggest that after the initial cataclysm, early humans in this region found a heaven-sent opportunity in the newly exposed rock: For the first time, they had plentiful cobbles for flaking off stone tools. Using state-of-the-art dating techniques, the researchers show that thousands of stone tools found in the basin, including sophisticated two-sided cutters, were made at about the same time as the meteorite impact, 803,000 years ago.

That's a startlingly early date for such sophisticated tools in Asia, as other reliably dated large cutting tools in East Asia are no more than 500,000 years old. Yet some of the Bose basin artifacts rival the refinement of contemporaneous African stone tools, known as Acheulean technology. Thus the new study finally disproves a long-standing hypothesis that Homo erectus in Asia was less handy—and by implication, less intelligent and adaptive—than its African relative. “There is no essential difference in the biology and culture between the early human groups of the East and West,” says Huang Weiwen, a paleontologist at the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing, co-leader of the excavation.

Other researchers agree. “It shows that [Asian] H. erectus was culturally resourceful and was able to take advantage of these unusual environmental shifts,” says Russell Ciochon, a paleoanthropologist at the University of Iowa in Iowa City.

Most anthropologists have long agreed that the first early humans to make tools lived in Africa. Their creations have been classified in one of two traditions—the Oldowan, starting 2.5 million years ago, which includes simple stone cores and flakes; and the Acheulean, starting at least 1.5 million years ago, which includes large, teardrop-shaped, two-sided handaxes and cleavers. Although the Acheulean appears in Europe 500,000 years ago, it has been almost completely absent in Asia. That absence prompted Harvard University anthropologist Hallam Movius to write off Asia as a cultural backwater more than 50 years ago. He split the Early Stone Age world in two, drawing a technological barrier known as the Movius Line between H. erectus in Africa, the Middle East, and Europe and its cousins in northern India, China, and Southeast Asia (Science, 13 March 1998, p. 1636).

Some researchers pointed out that ancient Asians might have crafted tools in perishable wood or bone, and Chinese paleontologists have long argued that stone tools found at about a dozen sites in eastern Asia were separate but equal in sophistication to the Acheulean. But few of those sites have been reliably dated.

That's just what Huang and his colleagues, including excavation co-leader Richard Potts of the Smithsonian Institution in Washington, D.C., have now done. Geochronologist Alan Deino of the Berkeley Geochronology Center in California collected tektites—glassy remnants of molten rock thrown up by the impact—from exactly the same layer of soil as the stone artifacts. He then used the radiometric decay of argon isotopes to pinpoint the tektite age at 803,000 ± 3000 years.

These dates are now “the most precise paleoanthropological dates in East Asia,” says Potts—and they prove the early Asians' abilities. “What we have in the Bose basin is the most Acheulean-like assemblage of stone tools ever found in East Asia, requiring the same behavioral and technical competence.” He adds that not only the shape of the tools but also how they were made and strewn across the land is similar to Acheulean sites.

The dates are “outstanding,” filling in a crucial gap, says Clark Howell, a paleoanthropologist at the University of California, Berkeley. They give a shot of much-needed credibility to Chinese paleontologists' claims that tools at other Chinese sites may be as much as 2 million years old and as advanced as those of similar age in Africa. “It will help people cast off the control of the Movius Line,” says Huang, who hopes Western scientists will take a second look at Chinese sites.

Despite the excitement over the Bose basin tools' resemblance to African ones, however, the Acheulean signature piece—a teardrop-shaped handax—is missing. That suggests two separate toolmaking traditions that had not had recent contact, says Richard Klein, a paleoanthropologist at Stanford University in Palo Alto. “This site doesn't demonstrate that the Acheulean was there or that there was a cultural connection between Africa and Asia,” notes Klein. But, he adds, “it is an important site, because it demonstrates that people 800,000 years ago in China were flaking tools that are as sophisticated as anything made in Africa.”

2. AIDS RESEARCH

# Novel Protein Delivers HIV to Target Cells

1. Jon Cohen

HIV may well be the most studied virus of all time, yet the steps between its introduction into the body by sexual intercourse and an established infection still remain mysterious. Now, tumor immunologists have joined with AIDS researchers to uncover intriguing evidence that a little-understood protein may play a key role in HIV infection, enabling the virus to sneak behind the body's defenses. In addition to elucidating the mechanism of sexual transmission of AIDS, these findings may open new possibilities for AIDS vaccines.

The work, described in two papers in the 3 March issue of Cell, focuses on a protein dubbed DC-SIGN that juts from the surface of dendritic cells, sentries that alert immune system central when invaders breach the body's borders. The papers reveal that DC-SIGN behaves like fingers on the arms of dendritic cells, helping them carry HIV from the mucosal lining of the cervix or rectum to remote lymph nodes. There, DC-SIGN hands HIV over to CD4+ T lymphocytes, the immune system cells that the virus readily infects and destroys, eventually leading to AIDS.

The researchers also show that when HIV is bound to DC-SIGN, the virus remains viable for several days longer than it would on its own, thus increasing the odds that a tiny dose of the virus will reach its target. “It's very elegant work,” says Douglas Richman, an AIDS researcher at the University of California, San Diego, who has studied the interaction of HIV and dendritic cells. “It proposes another ingenious way in which HIV exploits the immune system to create mischief.”

The discovery that DC-SIGN appears to play a critical role in HIV infection began in the lab of Yvette van Kooyk, a tumor immunologist at the University Medical Center St. Radboud in Nijmegen, the Netherlands. Van Kooyk, Carl Figdor, Teunis Geijtenbeek, and their co-workers were not studying AIDS but were investigating how dendritic cells and T lymphocytes interact. Work by Ralph Steinman of The Rockefeller University in New York City and others had established that dendritic cells initiate an immune response by “presenting” foreign antigens such as viruses to the T lymphocytes. The T lymphocytes then send other immune troops into battle. But details about this antigen presentation have remained sketchy, including how dendritic cells and T cells attach to each other using so-called adhesion molecules on the cell surfaces.

The Dutch team became particularly interested in an adhesion molecule called ICAM-3 that is abundant on T cells. In one of the two Cell papers, the Dutch researchers describe how they isolated a new dendritic cell protein that binds ICAM-3 much more strongly than anything previously studied. (They called it DC-SIGN because it is a dendritic cell-specific, ICAM-3-grabbing nonintegrin.)

Only later did the connection to AIDS turn up, as described in the second Cell paper. To the Dutch researchers' surprise, a database search revealed that in 1992 scientists at Bristol-Myers had found an identical protein in placental cells. The Bristol-Myers team did not link the protein to dendritic cells but did describe how it strongly binds gp120, HIV's surface protein that allows it to grab onto the cells it infects.

The Dutch tumor specialists decided to join forces with Dan Littman's team, which studies HIV entry mechanisms at New York University's Skirball Institute of Biomolecular Medicine. In a series of test tube experiments, the researchers demonstrate that, contrary to their initial hunches, HIV does not use DC-SIGN to slip into dendritic cells. Rather, DC-SIGN enhances HIV's ability to infect CD4 cells, in part by binding tightly to the virus and stabilizing it during the journey from mucosa to lymph nodes. This stabilization makes a huge difference: Another experiment showed that HIV bound to DC-SIGN could still infect CD4 cells after 4 days, while HIV alone lost its infectivity in less than a day. “This certainly gives the dendritic cell a lot more capability of stealth,” says Steinman.

On a practical front, the findings may inform vaccine design. To date, many AIDS vaccine designers have aimed to elicit antibodies that interrupt the fusion of HIV to its CD4 cell targets. Now, they might seek to induce antibodies that block the binding of DC-SIGN to gp120, derailing the infection prior to HIV-CD4 fusion. Studies can also now ask whether such antibodies can protect monkeys given infectious doses of the AIDS virus.

The work on DC-SIGN also underscores the benefits that can accrue when “newcomers” from other disciplines turn fresh eyes on long-standing questions, in this case, about HIV infection. Says van Kooyk, “You never know how science will work out.”

3. STEM CELLS

# Protest Leads Europeans to Confess Patent Error

1. Michael Hagmann

Prodded by environmental activists, politicians, and the media, the European Patent Office (EPO) has said that it made a mistake last December in granting too broad a patent on a method to isolate genetically engineered stem cells. Last week EPO officials declared that the patent, awarded to the University of Edinburgh, U.K., should have been restricted to “nonhuman” animals to prevent the possible cloning of humans. The German government has announced its intention to file a formal complaint, and the company licensed to use the technology says it is eager to work with EPO officials “to rectify the problem.”

The patent covers a genetic selection method for purifying the highly treasured stem cells, a possible fountain of youth for all kinds of deteriorating organs. The last of its 48 claims refers to “a method of preparing a transgenic animal” using the stem cells. The patent uses the term “animal” in its scientific sense, to include humans. But that definition flies in the face of European patent guidelines that explicitly prohibit the patenting of processes that tinker with the genetic makeup of humans.

The apparent breaching of those guidelines sent activists into the streets in Munich, where they bricked up the main EPO entrance during a 22 February rally. “Issuing a patent that can be applied to create genetically engineered human embryos poses both ethical and legal problems,” says Christoph Then, a gene technology expert at Greenpeace, the organizer of the event. The day before, Greenpeace had published a report on the patent that coincided with an article in Financial Times Germany.

Later that day, EPO issued a statement that admitted its “error” and said the EPO “regrets that it has occurred.” But EPO can't erase that mistake by itself, says spokesperson Rainer Osterwalder. Critics have 9 months to respond to any patent issued, he explains, after which EPO will review the comments and take action. Any change in the patent could take several years, he notes. A day later, the German ministers of Health, of Education and Research, and of Justice decided to challenge EPO's decision.

But the controversy may not drag on that long. Co-inventor Peter Mountford, chief scientific officer of Stem Cell Sciences (SCS) in Melbourne, Australia, which has an exclusive license on the technology, says the company's goal is to coax the isolated stem cells to turn into several different cell types, such as nerve cells or liver cells, and then use them in drug-screening assays. “That would allow us to save lots of laboratory animals,” says Mountford. SCS is “already talking to the EPO and exploring possibilities for clearing up the mistake,” says George Schlich, the company's patent attorney.

In the long run, SCS also plans to develop cell replacement therapies for certain human disorders, such as neurodegenerative diseases or diabetes. “But the company never intended to produce genetically engineered humans,” Mountford insists. Then says he never thought so, but he wonders if human stem cells “will be taken out of the patent entirely” given some of the company's therapeutic goals.

In the meantime, the patent remains in effect, and work, mainly with rodent stem cells, continues in Australia and in the United Kingdom, under co-inventor Austin Smith. Even so, a patent does not sanction work that violates national laws, notes Osterwalder, and neither country allows human cloning.

4. CHEMISTRY

# Novel Catalyst Runs Quick and Clean

1. Robert F. Service

Score at least a partial victory for green chemistry, the campaign to make industrial processes more environmentally benign. On page 1636 of this issue, three researchers at Delft University of Technology in the Netherlands report a way to clean up a commonplace family of chemical reactions—turning alcohols into aldehydes, ketones, and carboxylic acids, starting materials for everything from pharmaceuticals to fragrances. The Dutch work replaces reactions that rely on the toxic heavy metal chromium and dangerous organic solvents with alternatives that work with everyday oxygen and water. If adopted by industry, the new process has the potential to displace thousands of tons of hazardous waste every year.

“It's very interesting chemistry,” says Terry Collins, a chemist at Carnegie Mellon University in Pittsburgh, Pennsylvania. “Getting rid of chromium is a great thing to be doing.” Collins and others caution that the new method of converting alcohols to other compounds may not be quite ready for prime time. But in the lab, at least, it far outshines the standard approach.

Alcohols are short hydrocarbons that harbor an extra oxygen and hydrogen atom. To transform them, chemists must oxidize them in a controlled manner by stripping off two or three hydrogen atoms. The widely used oxidant chromium oxide is a master at such reactions, so thirsty for electrons that it readily swipes a pair of electrons from an alcohol's hydrogen atoms and pulls the protons along with them for good measure.

The problem is that once satiated, the chromium oxide is unable to give up the hydrogens again. To transform another alcohol molecule, more chromium is needed, so waste is generated as fast as the desired product is. To get rid of chromium, the Delft researchers—organic chemists Roger Sheldon and Isabel Arends and graduate student Gerd-Jan ten Brink—sought a catalyst that could perform the same reaction over and over again without being used up in the process. Other groups had shown that a palladium atom linked to an organic group called phenanthroline—a trio of hydrocarbon rings —was capable of just that sort of catalysis. The palladium atoms initially snatch hydrogens from the alcohols but later give them up to oxygen atoms in the solvent, generating water and returning the catalyst to its original state. Thus, even though palladium is expensive, far less of it is needed to run the reaction. The rare metal is also less toxic than chromium, another environmental benefit.

That took care of the chromium, but problems remained. The process still required dangerous organic solvents. What's more, recovering the reaction products from the mix of solvent and catalyst required turning up the heat to distill the solvent, a treatment that could destroy the catalyst, ten Brink says.

Sheldon and his colleagues set out to coax similar palladium catalysts to work in a friendlier solvent: water. By linking palladium to phenanthrolines modified with sulfur-containing groups, they made the catalyst water soluble. When the researchers added various alcohols, they found that the catalyst worked well, especially when helped by a common basic compound such as sodium hydroxide, which speeds the reaction by plucking hydrogens off the alcohol. And because the oily reaction products—the useful aldehydes, ketones, and most carboxylic acids—do not dissolve in water, they float atop the palladium solution, where chemists can easily siphon them off while keeping the catalyst intact.

So far the Delft team has shown that the catalyst neatly strips hydrogens from 10 different simple alcohols. If it works equally well on more complex molecules, such as those with delicate appendages that are used widely in organic chemistry, then it could be useful for a wide variety of lab reactions, Collins says. But making the jump to industrial scale could be challenging, says Joseph DeSimone, a chemist at the University of North Carolina, Chapel Hill. The difficulty, ironically, is in the water. “Water-based systems inevitably get contaminated in the process,” DeSimone says; even though oily products don't mix with water easily, it takes expensive distillation processes to get them all out. Sheldon counters, however, that reusing the catalyst solution over and over will keep water waste to a minimum.

Both agree that it will likely be up to industry researchers to work out such practical issues and see whether the new process is economical. “Finding chemistry that is safe, cheap, and environmentally friendly isn't always easy,” DeSimone says. But, he adds, “that's what makes it good science.”

5. ASTROPHYSICS

# WIMPs at Last? Or More Wimpy Sightings?

In the latest chapter in a decades-long whodunit, a group of physicists claims to have identified dark matter, the shadowy stuff thought to account for 90% of the universe's mass. Researchers from the Dark Matter experiment (DAMA) at Gran Sasso National Laboratory in Italy reported on 25 February that the number of particles entering their underground detector varies slightly with the seasons. The result, they say, proves that the Milky Way galaxy twirls in the midst of a gigantic cloud of weakly interacting massive particles, or WIMPs. But the case isn't quite closed: Physicists conducting the Cold Dark Matter Search (CDMS) at Stanford University in Palo Alto, California, reported at the same conference* that they see no evidence of the particles.

Physicists and astronomers have long known that there must be more mass in the universe than meets the eye. If not, the galaxies themselves should fly apart. Like riders on a fast-spinning carousel, the stars whirling around a galaxy are flung outward by their own inertia. Indeed, in the outer reaches of a spiral galaxy like the Milky Way, the stars travel so fast that the gravity from all the other matter that can be seen in the galaxy could not hold them. Some other type of matter, invisible and elusive, must therefore provide the missing mass and the extra gravity. The nature of this dark matter has remained a mystery. Although the DAMA discovery would solve it, other scientists are greeting the announcement with caution. “This would definitely be one of the biggest finds in science ever,” says Frank Avignone, a physicist at the University of South Carolina, Columbia. But, he adds, “what [the DAMA researchers] have is tantalizing evidence.”

To amass that evidence, the DAMAresearchers counted light flashes generated by an array of nine sodium iodide crystals, each a kilogram in mass, kept in a copper box more than a kilometer underground. Each flash signaled the passage of a particle, possibly a WIMP. The researchers tracked the count rate over the last 4 years. They looked for a slight annual increase peaking in June and a concomitant annual decrease bottoming out in December.

If the galaxy spins in the middle of a huge stationary WIMP cloud, then Earth rushes into a WIMP wind averaging 220 kilometers per hour. But the speed of that wind varies slightly with the seasons as Earth zips around the sun. In June, Earth swings into the wind, which then appears to blow roughly 15 kilometers per hour faster than average. In December, Earth swings to leeward, and the wind drops off by the same amount. Just as a bike rider gets wet faster when riding directly into a driving rain, the DAMA detector should count more events when Earth pushes directly into the WIMP wind. A year ago, the DAMA team announced tentative evidence of a seasonal variation (Science, 1 January 1999, p. 13); last week, they reported seeing a difference that they say has only one chance in 10,000 of being a statistical fluke.

The question is whether the changing signal is caused by WIMPs or by something originating closer to home, says Michael Turner, a cosmologist at the University of Chicago. A variety of less exotic particles such as neutrons will also produce flashes of light when passing through the detector, and the DAMA researchers must rule out all possible sources of contamination that might vary throughout the year. “Whether [the variation] has to do with the seasons of the Earth or the seasons of the galaxy remains to be seen,” Turner says.

Researchers from CDMS believe stray neutrons account for all 13 events they see in their much smaller detector. The CDMS device consists of three discs of germanium with a total mass of half a kilogram, cooled to within a tenth of a degree of absolute zero. When a particle crashes into the ultracold semiconductor, the researchers measure both the number of electric charges it knocks loose and the amount of heat it deposits. A low ratio of charge to heat indicates that a massive neutral particle—a WIMP or neutron—has bounced off a germanium nucleus. Of the few collisions bearing that telltale signature, the CDMS team says, all appear to be due to neutrons. If so, chances are that the DAMA team is seeing familiar particles, too. Stanford physicist Blas Cabrera says, “With respect to the DAMA results, we're ruling out the signal that they've seen.”

Whether or not the DAMA result holds up, Turner says, the search for dark matter may be speeding toward an end. In recent years, researchers have determined that other once-prime suspects, such as neutrinos and brown dwarfs, cannot account for all the missing mass. But WIMPs might, and new experiments scheduled for the next few years will be capable of spotting particles as massive and as weakly interacting as theory says they ought to be. “It's a 70-year detective story,” Turner says. “An arrest is imminent.”

• *Fourth International Symposium on Sources and Detection of Dark Matter in the Universe, 23-25 February, Marina del Rey, California.

6. GLOBAL HEALTH

# Group Urges Action on Third World Drugs

1. Martin Enserink

How can the pharmaceutical industry be enticed to make drugs and vaccines for infectious diseases that sicken or kill billions of people worldwide, yet offer little in the way of economic returns? That conundrum occupied a group of senior policy officials last week at the Global Health Forum, a closed-door meeting hosted by the Institute for Global Health in San Francisco. The 3-day affair, which boasted an “all-star cast” of global health experts, came up with few new ideas, but its message is being heard loud and clear: President Clinton has already signaled his interest in launching an initiative aimed at narrowing the seemingly intractable gap in health between rich and poor countries, and last week a bill was introduced into the U.S. Senate that would incorporate many of the forum's suggestions.

Pharmaceutical companies already have the scientific knowledge and tools they need to develop drugs and vaccines for scourges such as malaria, AIDS, and tuberculosis. What's more, such drugs could save millions of lives and spur economic development in poor countries, said the panel, which included representatives from the White House, the U.S. Congress, the World Health Organization, the World Bank, the World Trade Organization, and pharmaceutical giants Glaxo Wellcome and Merck. Yet these diseases attract minimal attention from the pharmaceutical industry because executives don't see a market. And even when effective drugs are available—such as the cocktail of AIDS drugs that has slashed mortality in wealthy countries—they may be too expensive for countries in Africa and Asia.

The solution, according to the panel, lies in a package of incentives that would make it worthwhile for the pharma and biotech industries to step in. One approach is for governments and multilateral organizations to push research and development by subsidizing part of the huge costs, either directly or through tax breaks. Another is to assure companies of a future market—for instance, by establishing “purchase funds” and agreeing to buy certain quantities of a product once it becomes available. The panel also lauded partnerships in which publicly funded scientists work together with industry, such as the recently created Global Alliance for Vaccines and Immunization (GAVI), to speed drug discovery and development.

The Global Health Forum's approach has already found a receptive ear in Washington. In his State of the Union address, President Clinton announced a $50 million U.S. contribution to GAVI, as well as a tax credit of up to$1 billion for companies investing in new vaccines for malaria, AIDS, and TB. A delegation from the Global Health Forum was scheduled to meet with Clinton this week to present their findings and discuss Clinton's proposals, which are “absolutely on the right track,” says Richard Feachem, who directs the Institute for Global Health.

Meanwhile, Senator John Kerry (D-MA) introduced an ambitious bill, dubbed the Vaccines for the New Millennium Act, on 24 February. Kerry proposed to “change the death spiral” by making childhood immunization “a major goal of U.S. foreign policy.” His bill calls for donations of $150 million to GAVI and$30 million to the International AIDS Vaccine Initiative. It also proposes several tax credits for industry and a purchase fund to buy and distribute vaccines as soon as they are approved. To cover the cost, Kerry is asking Congress to set aside $100 million a year for the next 10 years. The political fate of these plans is uncertain. Even so, Feachem is encouraged by these and other initiatives in the European Union and Japan. Says Feachem, “The global awareness of this challenge is running at a level which we haven't previously seen.” 7. RESEARCH FACILITIES # Glittering Future for Yale Medical School 1. Constance Holden The late Bartlett Giamatti, former president of Yale, was fond of saying that “if Yale intends to be the best, it has to be able to afford the best.” Its current leaders seem to be taking that aphorism to heart: A month after announcing a planned$500 million upgrade of its science and engineering programs (Science, 28 January, p. 579), Yale said last week that it will pour another $500 million into renovations and new construction on its medical school campus over the next 10 years. “The university is in a strong financial position,” Yale president Richard C. Levin acknowledges. A 9-year bull market has beefed up Yale's endowment, now$7.2 billion, he says, and “fund-raising efforts have been very well received.” He predicts that “invest[ing] simultaneously in science activities on both ends of our campus will be enormously synergistic.”

The heart of the expansion is a new six-floor lab building that will increase the medical school's lab space by 25%. Some accompanying growth is also expected in research faculty. Yale is already the fifth-largest recipient of funds from the National Institutes of Health. The medical school will continue to turn out about 100 graduates a year.

“I'm a happy man today hearing this announcement,” says Leon Rosenberg, a professor of molecular biology at Princeton University who was Yale medical school dean for 7 years. “I think it reaffirms the university's goal of maintaining Yale medical school as among the very most research-intensive national institutions.”

The investment comes at a time when many university medical centers are suffering from rising costs and reduced clinical income, says the Association of American Medical Colleges. But Rosenberg says that because Yale has been so successful in winning research grants, it hasn't needed to rely heavily on clinical income.

8. MICROBIAL GENOMICS

# Culling Genes Early Yields Rich Harvest

1. Elizabeth Pennisi

CHANTILLY, VIRGINIAA team of human sequencers using high-powered computers has just finished assembling the entire genetic sequence of the common bacterium Caulobacter crescentus. The feat, announced at a meeting* on microbial genomes held here last month, marked another important milestone in the burgeoning business of gene sequencing. But the real news was that even before the sequence was completed, another team had scoured the emerging data and found several hundred new genes involved in the bacterium's cell cycle.

That accomplishment underscored an important take-home message from the meeting: Sequence data don't have to be perfect, or even finished, to be extremely useful. Indeed, another team reported that it has used early sequence data to identify targets for a vaccine against a pathogen that causes meningitis. And researchers studying the microbe that causes anthrax said they will soon start analyzing gene expression even though these genes are still buried in tiny pieces of unconnected sequence data. “It's amazing how fast [the genome data have] been put to use,” raves microbial genomicist Siv Andersson of the University of Uppsala, Sweden. “People should be looking at genomes long before they are done,” adds Janine Maddock, a microbiologist at the University of Michigan, Ann Arbor.

Take the case of C. crescentus, a bacterium that thrives in aquatic environments that lack sufficient nutrients for most other life-forms. This makes the bug a potential candidate for cleaning up pollution. But microbiologists are fond of it for another reason as well: Because it goes through distinct morphological stages, it is useful for understanding differentiation in prokaryotic organisms (those without a cell nucleus).

Typically, C. crescentus has a whiplike appendage called a flagellum that it uses for swimming. But when it's time to reproduce, C. crescentus jettisons its flagellum, replacing it with a short stalk that anchors the tiny cell to a nearby surface. The DNA then replicates and the stalked cell divides asymmetrically, pinching off a new, mobile “swarmer” cell. These characteristic “stalked” and “swarmer” stages enable microbiologists to associate genetic changes with distinct stages of the cell cycle.

The Institute for Genomic Research (TIGR) in Rockville, Maryland, has been sequencing the organism's 4-million-base genome, which is about the same size as that of Escherichia coli. At the meeting, William Nierman reported that TIGR had just finished putting the pieces of the sequenced genome together. But a team at Stanford University headed by Lucy Shapiro, in cooperation with TIGR, began working with these data about 9 months ago, long before they were assembled—in fact, they were still in 700 separate pieces.

The group scanned the early sequence with gene-finding programs, culling about 3000 tentative genes, team member Michael Laub reported at the meeting. They spotted DNA from each gene onto a glass slide and used this microarray to monitor the RNA transcribed from each gene at 15-minute intervals over C. crescentus's life cycle.

Their initial results indicate that the organism alters the activity of 462 genes—some 400 of which are newly recognized to change—over the course of the cell cycle, says Laub. “They found genes they never would have thought of looking for,” notes Andersson. Laub and his colleagues expected to see changes in the expression of the genes that make the flagellum, for instance. But they can't explain why 107 genes related to energy use and metabolism are altered as well. Laub speculates that metabolic requirements change depending on where the organism is in its life cycle. “The array data are leading us in new directions,” he notes.

Other microbiologists at the meeting were impressed not just with the Stanford team's data but that they were able to garner them at all with a microarray. Microarrays are still tricky to use, and bacterial RNA is much harder to work with than, say, yeast or human. “This is the first successful microbial cell cycle experiment that's ever been done,” says Maddock. Moreover, it demonstrates that microbial RNA can readily be put to use in these global expression studies, adds Frank Rosensweig, an evolutionary biologist at the University of Florida, Gainesville. “I regard this as a real breakthrough paper.”

Microarrays aren't the only way to make use of preliminary sequence. For the past 2 years, TIGR researchers have been working with E. Richard Moxon, a microbiologist at the University of Oxford, to sequence a strain of Neisseria meningitidis. Early in the sequencing process, Moxon and TIGR's partner, Chiron Corp. of Siena, Italy, began analyzing those DNA fragments to look for proteins that might be new vaccine candidates. Rino Rappuoli and his team at Chiron used computer programs to identify DNA sequences likely to code for proteins found on the surface of the bacterium. The researchers then inserted these genes into bacteria, isolated the proteins produced, and injected the proteins into mice that were later exposed to the pathogen. Rappuoli reported at the meeting that, of some 600 proteins the computer identified, 350 were successfully produced in bacteria, and 25 of those induced a protective immune response in the mice—some strong enough to warrant further investigation.

Other global expression studies will start soon on the anthrax genome. Even though the entire sequence may not be complete until June 2001, TIGR's Timothy Read plans to start microarray studies in July to identify target proteins. Les Baillee, a microbiologist with the Defense Evaluation and Research Agency in Porton Down, Salisbury, United Kingdom, is eagerly awaiting the results, which he says will enable anthrax researchers to avoid laborious screening and focus directly on likely vaccine candidates. These data should be valuable, too, for researchers studying Bacillus anthracis's close cousins, one of which causes food poisoning and the other of which is used to control insect infestations of crops. Says Read with obvious delight: “The sheer number of ways you can use genome data is amazing.”

• *The Fourth Annual Conference on Microbial Genomes, 12 to 15 February.

9. CONFLICT OF INTEREST

# NEJM Admits Breaking Its Own Tough Rules

1. Constance Holden

The New England Journal of Medicine (NEJM), which prides itself on having the toughest conflict-of-interest guidelines for authors in scientific publishing, has been forced to admit that it has been regularly breaching those standards. Whereas some researchers say that the missteps show that such strict standards are impractical, the journal's editors see them as a spur to do better.

The problem came to light last fall when the Los Angeles Times published two articles documenting instances in which NEJM review authors had financial links to drug companies that sold products they were writing about. The NEJM did its own review and came up with 19 rule-breaking articles covering treatments for diseases such as multiple sclerosis, breast cancer, and diabetes. In a terse apology in the 24 February issue, the editors list these as cases “in which one or more authors … received major research support … from relevant companies or served as consultants at the time they were invited to prepare their articles.”

NEJM Editor Marcia Angell says that the mistakes were due to “poor communication and poor coordination” among editors. That's no surprise, she says, given that NEJM is charting new territory: “We are attempting to maintain a conflict-of-interest policy that no one else even bothers to try.”

The journal makes public any information on the corporate ties of authors of research papers, and it essentially forbids writers of reviews and editorials from having any industry connections. The problem, says Angell, is that for reviews there was “a discrepancy between policy and practice. … We permitted major [industry] research support to researchers if that support was given to the institution” rather than to the individual. That exemption was proposed by the editor of the drug therapy reviews, Alastair J. J. Wood of Vanderbilt University in Nashville, Tennessee, and the editors at the journal's Boston headquarters accepted it.

Through this generous loophole were admitted almost half of some 40 drug-therapy review articles published since 1997. Vera Price, a dermatologist at the University of California, San Francisco (UCSF), who published an article on hair-loss treatments, told editors, for example, that she had received research funds and consulting fees from a company that sells such treatments. But because the research money had gone to UCSF first, she was asked to sign a statement saying she had “no current, recent past, or planned future financial associations … with a company that stands to gain” from products discussed in the article. Angell says the NEJM basic policy will remain unchanged, and no exceptions will be made for institutional funding. Authors will also be asked to submit a detailed accounting of all funding sources.

Some observers believe that NEJM's policy is unrealistic. “It's almost impossible to find a very informed commentator on a medical topic who hasn't had money from the pharmaceutical industry,” says Tony Delamothe, deputy editor of the British Medical Journal. The BMJ doesn't ban anyone on the basis of their funding sources, he says, but requires that all such information be divulged to readers.

But Wood and Angell think that their 10-year-old policy is the best. “To say ‘caveat emptor’ is not helpful to readers,” says Angell. Other journals are not as conscientious on that issue, adds Wood: “We frequently see articles that we've previously rejected for conflict of interest popping up in other prestigious journals.”

# Budget Pressures Force Closing of Kitt Peak Dish

1. Mark Muro*
1. Mark Muro writes from Tucson, Arizona.

TUCSON, ARIZONALike a homeowner with limited storage space, the National Radio Astronomy Observatory (NRAO) is discarding a cherished possession to make room for a big new acquisition. But some scientists say the observatory is acting in haste, before it has worked out the financing for its new purchase and years before delivery.

Last week NRAO officials announced that they would shutter a pioneering millimeter-wavelength telescope on Kitt Peak in southern Arizona on 1 July, laying off half the 25-member staff. The observatory is building one of two prototypes for a proposed array of 64 dish antennas in the Chilean desert, a joint project with the European Southern Observatory that could cost each partner an estimated $200 million. But that project, called the Atacama Large Millimeter Array (ALMA), hasn't received any construction funds and won't come online for several years, creating a gap that many U.S. radio astronomers say will put a serious crimp in the field. “Young researchers are going to get tired of waiting for research time and go off and get grants to do something else,” warns Tom Bania, a professor of astronomy at Boston University. “It doesn't make much sense [to close Kitt Peak] when you're making a big commitment to the field with ALMA.” A flat budget is forcing NRAO's hand, says director Paul Vanden Bout. The observatory would receive$32.5 million in the 2001 budget request from the National Science Foundation (NSF), unchanged from the current year (Science, 11 February, p. 952). “We had once hoped to keep the 12-meter [dish] going until ALMA began interim operations, probably in 2005, but that hope began to fade last year,” Vanden Bout says. A final decision to shut the telescope was made “in the last few weeks,” he adds, and that suddenness “may have shorted discussion a little.”

Indeed, the abrupt closure has disturbed many researchers. The Arizona dish, which opened in 1967, pioneered exploration of the molecular composition of the interstellar medium at millimeter wavelengths. Later, it proved ideal for studying molecular clouds, star formation, and distant galaxies, as well as the atmosphere of Mars and Venus. Used by 150 investigators a year, it is also the only U.S. millimeter-wavelength telescope run full-time as a national facility and open to all astronomers.

For that reason, Lucy Ziurys, an astrochemist at the University of Arizona in Tucson, frets that closing the telescope will doom many research projects, noting that no other facility offers the same combination of highly sensitive and stable receivers to detect faint signals, extremely efficient data collection, and wide frequency coverage in the millimeter range. “I myself won't be able to finish five or six projects,” she says.

Others worry that the closure could drive young researchers out of the field. These critics doubt that ALMA will begin even interim operations by 2005, given that NSF has requested $6 million to extend a 3-year,$26 million design and development effort for another year and won't make a bid for construction funds until 2002 at the earliest.

To be sure, the directors of at least two university facilities—the California Institute of Technology's Owens Valley Radio Observatory and the Five College Radio Observatory in Massachusetts—say they would welcome proposals from Kitt Peak researchers. The university community “may well be able to pick up much of the slack,” says Anneila Sargent, president-elect of the American Astronomical Society, director of Owens Valley, and a member of the board of Associated Universities Inc., which operates NRAO for NSF. “Compromises and adaptations will be possible.” But some astronomers are skeptical that university-run dishes and arrays will be able to accommodate researchers displaced from Kitt Peak. “Yes, the university facilities make time available to outside scientists, but they're not really oriented to the general user like a national observatory,” says astronomer Jean Turner of the University of California, Los Angeles.

Whatever the outcome, all parties agree that the decision to close the 12-meter telescope is a sad one. “You'd like to focus on the future without letting go of the present and the past,” says Vanden Bout. “Unfortunately, that couldn't happen here.”

11. MAGNETIC RESONANCE IMAGING

# Detecting Enzyme Activity in Live Animals

1. Evelyn Straus

Thomas Meade and his colleagues at the California Institute of Technology in Pasadena have adapted a technique perhaps best known for peering inside athletes' injured knees to watch genes being turned on in living tadpoles. The researchers report in the March issue of Nature Biotechnology that they've used magnetic resonance imaging (MRI) to track the expression pattern of an enzyme called β-galactosidase in living Xenopus laevis tadpoles. They were able to see the enzyme being produced deep within the animal's head, where conventional imaging techniques can't reach without slicing through the animal.

“They can see a measurable result in a living animal,” says Claude Meares, a chemist at the University of California (UC), Davis. “That's really quite exciting.” What's more, the resolution—the highest so far in these types of studies—was good enough to discriminate structures as small as individual cells. Richard Harland, a developmental biologist at UC Berkeley, describes that achievement as “impressive.”

Meade's team is one of several groups using MRI to probe cellular processes deep inside living organisms (Science, 17 December 1999, p. 2261). The payoff could be considerable. By allowing researchers to follow the activity of specific genes in living embryos, for example, the technique should generate new insights into embryonic development. And ultimately, experts hope, it will provide more sensitive methods for diagnosing diseases such as cancer and also help physicians measure how well therapies for cancer and other diseases are working.

Typically, MRI detects perturbations induced in hydrogen atoms—particularly those in water—by an intense magnetic field. To measure the activity of β-galactosidase, Meade and his colleagues needed to find a way to amplify the signal only in those cells where the enzyme is active. They turned to gadolinium, a metal that enhances the contrast in MR images because its unpaired electrons interact with the protons in water, boosting the signal. The researchers enclosed the gadolinium in a chemical cage that normally keeps it from interacting with water, but they provided the cage with a gate, in the form of a sugar molecule, that springs open when clipped off by β-galactosidase. This exposes the gadolinium to water, thus upping the MRI signal wherever the enzyme is active.

To test the technique, Angelique Louie, a postdoc in Meade's lab, injected both of the first two cells of Xenopus embryos with the caged gadolinium. Then she injected DNA or messenger RNA that encodes β-galactosidase into just one of the two cells and allowed the embryos to grow into tadpoles.

The researchers generated MR images of the living animals. Then they compared these images with the patterns obtained when they killed the animals and stained them with a reagent that reveals β-galactosidase activity. Bright regions in the MR images correlated strongly with the locations of enzyme production revealed by the staining. “You can see things to a cellular level in deep tissues,” says Louie.

The method holds promise for a wide variety of applications. In principle, Meade notes, the chemical properties of the gate that shields the gadolinium can be modified so that it opens in response to any of many different enzymes. In addition to creating agents that could be used to study embryonic development, researchers could, for example, devise compounds that are activated specifically in cancer cells. This might provide a technique for early detection of new tumors or those regrowing after treatment, notes Daniel Sullivan, a radiologist at the National Cancer Institute in Bethesda, Maryland. Similarly, it might someday be possible to monitor the effectiveness of gene therapy by designing the gadolinium cage so that it's opened by a therapeutic gene's product.

Researchers have a long way to go before such applications become reality, however. In order to be medically useful, the caged gadolinium would have to penetrate into the tissues of the body after it is injected into the bloodstream. The next step, Meade says, is to look at how well the compound distributes through small animals such as mice. If it doesn't, he says, he hopes to devise ways to deliver the compound efficiently, say by attaching proteins that can snake their way into cells. “The door's been cracked,” Meade say. “Now it's just left to our imagination to see what we can develop.”

12. EVOLUTION

# In Search of Vertebrate Origins: Beyond Brain and Bone

1. Carl Zimmer*
1. Carl Zimmer is the author of At the Water's Edge.

Melding genes, neurons, and fossils, a new synthesis overturns long-held ideas about the rise of our favorite lineage and shows how a good theory can propel science—even if it's partly wrong

Walk through the halls of the American Museum of Natural History in New York City, and you will see our lopsided bias toward vertebrates on spectacular display. The history of the vertebrates unfolds in hall after hall of magnificent fossils, from dinosaurs to cave bears. Meanwhile, equally magnificent specimens of invertebrates such as Nautilus and giant clams are tucked away in a few smaller, less popular rooms scattered throughout the building. Most museums have a similar split, yet invertebrates make up the vast majority of Earth's animal biomass and include many millions of species, compared to only 42,000 known species of vertebrates. But museums are run by humans, who are most interested in animals like ourselves. And some of the signs of our kinship with reptiles, birds, and fish are obvious to even the most casual visitor: We all have skeletons, complete with backbone and skull, and big, complex brains.

For all the attention lavished on vertebrate evolution, however, just when and how vertebrates arose has long been a mystery. For most of the 20th century, primitive vertebrate fossils seemed a confusing mess, and paleontologists had little luck finding fossils that preserve the earliest hints of brains and bones. The basic anatomy of vertebrates' closest living relatives—which might provide clues to what our earliest ancestors looked like—was worked out over 70 years ago, and anatomical studies since then have yielded few fresh insights. “It made the field pretty stagnant,” says Nicholas Holland of the Scripps Institution of Oceanography in La Jolla, California.

But in the past few years, work in several different disciplines has converged to provide a surprising new picture of the transition from invertebrate to vertebrate, a picture that upsets some previous ideas. Developmental geneticists have begun to uncover the genes that create the body plan in vertebrates and their closest living invertebrate relatives, just as neurobiologists are exploring the detailed neural connections of these seemingly simple animals. And late last year Chinese paleontologists announced the earliest fossils yet found of vertebrates and their close relatives, both dating back to 530 million years ago (Science, 5 November 1999, p. 1064, and 3 December 1999, p. 1829).

These studies suggest that the evolution of the vertebrate brain may have had a surprisingly early start in invertebrate ancestors, long before the evolution of the mineralized skeleton that makes most vertebrates so distinctive. What's more, the skeleton may have arisen in an unexpected form: as teeth. The true innovation that launched the lineage of fish, dinosaurs, and people seems to have been new kinds of embryonic tissue, which could form new sensory organs. That allowed protovertebrates, such as those represented by the new Chinese fossils, to embark on a new way to make a living—as predators. Vertebrate evolution is turning out to be more complex—yet more comprehensible—than scientists ever expected.

## Brain and bone together

One way to track vertebrates' evolutionary history is to analyze their closest living relative. Molecular and anatomical research both give this honor to the lancelet Amphioxus, a 5-centimeter-long sliver of a beast that as an adult burrows in sand and filters food from the water. It has little in the way of a skeleton, and its central nervous system consists of a nerve cord with a barely swollen tip. But it does possess vertebrate traits such as gill slits, rows of muscle blocks along its flanks, and a notochord, a stiff rod of tissue that supports the nerve cord along its back. Because of these shared characteristics, biologists classify lancelets and vertebrates together in a phylum called chordates.

Paleontologists have long suspected that vertebrates diverged from a lancelet-like relative sometime in the Cambrian period, which began 545 million years ago. Meanwhile, molecular studies of gene similarities between lancelets and today's vertebrates suggest that the vertebrate lineage goes all the way back to 750 million years ago. But the fossil record provides few clues to help resolve this contradiction, because there are no animal fossils that old and no examples of an intermediate species. Until very recently, the earliest undisputed vertebrates were a mere 475 million years old.

These small, jawless fish with bodies completely covered in bony plates of armor are thought to have dined on sea-floor invertebrates and to have used their armor to defend against predators. Fossils retaining the imprint of the brain reveal that these fish had already evolved many of the major features of modern vertebrate brains, such as divisions into forebrain, midbrain, and hindbrain. “There's no question by that date a vertebrate brain had evolved,” says Linda Holland, Nicholas Holland's wife and a fellow Scripps biologist.

If these armored fishes represent the earliest vertebrates, they suggest that brains and bone evolved together. Yet lampreys and hagfish, the only jawless fish alive today, are squishy creatures without a speck of armor and scant amounts of cartilage—and are far more primitive than the fossil forms.

With no obvious intermediates among either ancient or living creatures, biologists were hard put to explain the origins of the vertebrate skeleton and nervous system. Then in 1983 two researchers proposed a new theory that provided an intriguing answer to these puzzles. Their insight rested in part on evidence from another discipline: embryology. Glenn Northcutt, now of the University of California, San Diego, and Carl Gans, now at the University of Texas, Austin, argued that the key to vertebrate evolution was the invention of a head, which in turn was made possible by the evolution of a new kind of embryonic cell.

Studies of living vertebrates reveal that as an embryo forms, a sheet of cells on its surface curls up into a tube that sinks into its body. This structure, called the neural tube, eventually becomes the central nervous system, including the brain and spinal cord. Along the edges of the sheet, a special collection of cells called neural crest cells breaks away and wanders around the embryo, helping to shape many structures such as eyes, nose, nerves, head muscles, and skull bones.

It was the neural crest, Gans and Northcutt proposed, that gave vertebrates the flexibility to build a new kind of body, one that included the complex sense organs, big brains, and powerful pumping throats seen for the first time in lampreys and fossil jawless fish. Along with the new body plan came an ecological shift, as vertebrates evolved from small, passive filter feeders to large, active predators that darted about hunting their prey. “If you're a filter feeder, there are real restraints on how big you can get,” says Northcutt. “Developmental changes produced new structures and presented the opportunity to the animal to start doing something else.”

This developmental revolution, Gans and Northcutt argued, also sparked the origin of bone. Neural crest cells build the electroreceptors that line the bodies of fish; once these receptors evolved, the researchers theorized, neural crest started building mineralized bone around them to insulate them from the rest of the body. Later, the bone spread out to form a protective coat of armor, as seen in the early bony fish.

This comprehensive model “was one of the most important contributions ever made to the question of the origin of the vertebrates,” says Nicholas Holland, because it united disparate lines of evidence and challenged scientists to find ways to test it. It would take over a decade, however, before they had the tools to do so. Their findings partly confirm the model—but suggest some surprising revisions to it.

## Raising lancelets

Researchers had long been stymied in their efforts to see whether the biology of lancelets supports the Gans-Northcutt model, because no one knew how to rear lancelets in the lab. A partial breakthrough came in the early 1990s, when Nicholas and Linda Holland figured out how to gather sexually mature wild lancelets from off the coast of Florida on summer nights. In the lab, the Hollands apply an electric current to make the lancelets shed eggs and sperm, then the researchers raise the embryos. “The progress that we make is comparatively slow, because if we're really lucky we'll have embryos on a dozen nights,” says Linda Holland.

With their meager supply of developing lancelets, the Hollands and others began studying the expression of genes that build the creatures' bodies, using special tags to stain cells expressing the products of known developmental genes. After examining dozens of genes, the picture that emerges is that of a protovertebrate brain. The lancelet doesn't have a true neural crest, but it does have cells in the same position as neural crest cells, and they express some of the same genes that neural crest cells express before they begin to migrate. These cells also migrate, but only as a sheet moving on the surface of an embryo, not as small clusters traveling inside it. “They haven't managed to break loose and wander,” says Linda Holland. Their work thus both confirms and refines Gans and Northcutt's notion of the importance of the neural crest. “One innovation of vertebrates is certainly the invention of the wandering neural crest,” says Linda Holland. “It opened up the potential to get awfully fancy in the vertebrate head.”

What's more, the Hollands and other researchers found evidence that even without a true neural crest, the swollen bud on the front end of the lancelet nerve cord bears a striking similarity to the vertebrate brain. The same genes that organize major regions of the forebrain, midbrain, and hindbrain of vertebrates express themselves in a corresponding pattern in this small cluster of cells in the lancelet's nerve cord. It would be tempting to conclude that these patterns are an atlas of the primordial vertebrate brain, but the lancelet genes may actually be performing quite different tasks from the vertebrate genes, even though they're expressed in the same place, cautions Holland.

## Slicing the lancelet brain

While the Hollands probe the genetics of lancelet development, University of Saskatchewan biologist Thurston Lacalli is working on a parallel research program to uncover the animal's detailed neuroanatomy. Starting in 1991, Lacalli's technician Jenifer West photographed 2000 cross sections of the front end of the nerve cord in a lancelet larva. Lacalli began painstakingly tracing out the shapes and connections of each of the approximately 300 neurons, combining them into three-dimensional computer reconstructions. The work is slow: So far Lacalli has identified and traced only two-thirds of the neurons and published data on only half of these. For other lancelet researchers, the wait is agonizing. “It's like taking a 747 and chopping it up a millimeter at a time,” says Nicholas Holland.

But already Lacalli's work supports the Hollands' claims that the lancelet nerve cord is divided like a vertebrate brain. In the regions of the lancelet nerve cord where the Hollands found forebrain and midbrain genes at work, the neuronal structure matches that of the vertebrate forebrain and midbrain. “When the two lines of evidence point to the same thing, then we have a lot of confidence,” says Linda Holland.

Lacalli goes even further, claiming that clusters of neurons in the lancelet brain seem to perform the same functions as their vertebrate counterparts—even though in the lancelet these clusters may be made up of only a handful of neurons. “It's a surprise that it fits into a vertebrate model so neatly,” says Lacalli. For example, noting a retinalike pattern of connections near a cluster of pigment cells near the tip of the lancelet, Lacalli claims that the cluster is a single eye, homologous to the paired vertebrate eyes. The lancelet eye is too crude to form images, but Lacalli suspects it can detect moving shadows of predators. And the hairlike projections that ring the lancelet's mouth—used to accept or reject food—are connected to nerves in much the same way as cells in vertebrate taste buds, Lacalli says.

In a paper in press in Acta Zoologica, Lacalli presents an even more dramatic correspondence: He claims that lancelets have a rudimentary limbic system. The vertebrate limbic system, which includes the hypothalamus, monitors the body's internal state, such as its temperature and hormone levels. It then uses this information to control basic behaviors such as when to sleep, when to eat, when to flee, and when to fight. Lacalli has found lancelet neurons whose structure and organization resemble those of vertebrate limbic neurons and that are located in the corresponding parts of the midbrain and forebrain. He suggests that the common ancestor of vertebrates and lancelets used its protolimbic system to switch between its handful of behaviors, such as swimming and feeding. “They fed and they escaped; maybe they even decided to migrate at night. They had [essential] decisions to make. And the way they made these decisions is part of the limbic system,” he says.

Other researchers say Lacalli makes a strong case. “Excellent work,” says Rudolf Niewenhuys, an expert on the limbic system at the University of Nymegen in the Netherlands. “The very beginning of [the limbic system] is to be found here in [Lacalli's] work, because he shows that there is the precursor of the hypothalamus,” a crucial part of the limbic system.

The work of Lacalli, the Hollands, and others suggests that in some basic ways, the vertebrate head is not new. Wandering neural crest may have been a key development in the evolution of the vertebrate nervous system, as Gans and Northcutt argued, but by the time the head arose, some of the fundamental structure of the vertebrate brain was already in place. “The regions of the brain that you and I think with are not there,” says Lacalli. “But the regions that motivate us, to determine whether we're going to eat or run away or lie down and rest, those things we see some evidence of.”

## Predators on the prowl

Northcutt agrees that “there are far more similarities between lancelets and vertebrates than any of us would have believed.” But to him the head of vertebrates, with its ability to integrate a host of different signals from the senses, still represents a huge evolutionary and developmental step. “One of the major areas of research that will go on for some time is how the [vertebrate and lancelet] are different. Because it's the difference that becomes critical for understanding vertebrate evolution.”

Lancelets, for example, apparently have no sense of smell. One of the parts of the vertebrate brain that's missing from the lancelet nerve cord is the most forward portion of the forebrain, known as the telencephalon, which among other tasks handles signals from the nose.

Such differences add further weight to Gans and Northcutt's idea that early vertebrates shifted from filter-feeding to predation. But instead of a divided brain, one of the key inventions of early vertebrates might well have been a nose. “A lancelet doesn't need to sniff out its prey, but as the early vertebrates became predators, smell became an asset,” says Nicholas Holland. They would also benefit from eyes to see prey and sophisticated control of their bodies to chase prey down.

In the past 6 months paleontologists may have captured that crucial step from filter-feeding to active predation. Last November, Chinese researchers reported a trove of 300 specimens of a creature called Haikouella. In some ways these sliver-shaped impressions on ancient rocks look like lancelets, but they also have a few key vertebrate traits unnecessary for filter feeders, such as eyes and muscle blocks. These clues suggest that Haikouella is poised at the transition from invertebrate to vertebrate, closer to vertebrates than even the lancelet.

Some researchers have questioned this close kinship, noting that Haikouella has a few anatomical peculiarities, such as in the organization of its muscle blocks. But overall, these fossils “look like little vertebrates,” says Linda Holland. That makes another feature of their anatomy significant: The fossil nerve cord has an even larger swelling than does that of the lancelet. “It has more stuff up front,” says Linda Holland. “I'd say they do have a brain.” If so, that pushes the origin of a vertebrate-like brain back to more than 530 million years ago. And Haikouella is just the sort of brain-powered, sensory-enhanced predator that Gans and Northcutt predicted 18 years ago.

## How bone was born

If Northcutt and Gans's theories about the origin of the vertebrate brain have been borne out, their ideas about bone are taking a real body blow. In an upcoming paper in Biological Reviews of the Cambridge Philosophical Society, paleontologists Philip Donoghue of the University of Birmingham, U.K., Peter Forey of the Natural History Museum in London, and Richard Aldridge of the University of Leicester, U.K., create a new evolutionary tree for vertebrates that for the first time incorporates a mysterious group of animals called conodonts. These creatures left behind vast numbers of enigmatic little fossils in the shapes of cones and thorns, ranging in age from 510 million to 220 million years old. Over the years “conodonts have been attributed to almost every major phylum you can think of,” says Donoghue. Finally in the 1980s new fossils began to emerge with the conodont elements lodged in soft tissue.

Now researchers envision conodonts as eel-shaped predators with a pair of giant eyes and a gaping mouth filled with the toothlike, bony conodont elements, which are made of dentine and other ingredients of the vertebrate skeleton. This new information seemed to elevate conodonts to the status of chordate predators, but paleontologists have fought over exactly what sort of chordate they might be. Donoghue and his co-workers tried to resolve the debate with a massive study of both fossil and living creatures, analyzing 103 different traits in 17 different groups of chordates, ranging from lancelets to jawed vertebrates. “With the fossils we're dealing with, it's as good as we're going to get for a long time,” says Donoghue.

Their results show that after the vertebrate lineage split from lancelets, the first group to branch away were the hagfish; lampreys are only slightly less primitive. Conodonts, surprisingly, turn out to be full-fledged vertebrates, even closer to living jawed fish than to lampreys or hagfish. Only after the rise of conodonts did the armored jawless fish, the ostracoderms, appear, and from one of their ranks, the jawed fish eventually evolved.

According to the new tree, hagfish and lampreys offer a good representation of what the most ancient vertebrates were like: unarmored and without mineralized skeletons. And conodonts represent the first appearance of a mineralized skeleton. “The conodont skeleton is the primitive vertebrate skeleton,” says Donoghue. And it's not the sort of skeleton Gans and Northcutt predicted, notes conodont expert Mark Purnell of the University of Leicester, who calls the results “significant.” Mineralization began not in the skin of fish but in the mouths of conodonts, and it presumably made them fiercer predators.

“I think they have good evidence that that is the case, and if it is the case there are some very, very important things there,” says Northcutt. “Much of the story Carl [Gans] and I put together has to be wrong,” at least when it comes to the evolution of bone.

The conclusion that bone was born after the rise of vertebrates is not yet certain, as more primitive chordates may turn out to have possessed the precursors of conodont mouth parts. Hagfish have “toothlets” made of keratin plus a little phosphate, which might have originated as genuine dentine-based teeth and shifted to other materials later. And Jun-Yuan Chen of the Nanjing Institute of Palaeontology and Geology in Nanjing, China, and his colleagues claim that Haikouella had mineralized “pharyngeal teeth” in its throat. Whether these so-called teeth have anything to do with the rise of the vertebrates will have to wait for microscopic analyses of the fossils and for an end to the debate over whether they are chordates at all.

Although these open questions remain, scientists are no longer resigned to the idea that they will never be answered. Now that the stream of data about the origin of vertebrates has started flowing, it shows no sign of slowing down. Museums may never mount a major exhibit about the neural crest, but fitting the developmental data with genetics and paleontology, as Gans and Northcutt first did years ago, is beginning to create a much more satisfying picture of how our favorite group of animals came to be. “I think we're going to see exciting new data in all three fields,” says Northcutt.

P. C. J. Donoghue et al., “Conodont affinity and chordate phylogeny,” Biological Reviews, in press.

L. Z. Holland and N. D. Holland, “Chordate origins of the vertebrate central nervous system,” Current Opinion in Neurology 9, 596 (1999).

T. C. Lacalli and S. J. Kelly, “The infundibular balance organ in Amphioxus larvae and related aspects of cerebral vesicle organization,” Acta Zoologica 81, 37 (2000).

R. Glenn Northcutt, “The agnathan ark: The origin of craniate brains,” Brain, Behavior, and Evolution 48, 237 (1996).

13. AAAS MEETING

# Going Deep for an Unearthly Microbe

1. Elizabeth Pennisi

WASHINGTON, D.C.—More than 6000 scientists, policy-makers, and journalists gathered here 17 to 22 February for the American Association for the Advancement of Science's annual meeting. A crowded agenda included everything from discussions of ethical issues to announcements of new results from a wide range of disciplines.*

Even though the late Carl Sagan had his eyes on deep space, his soon-to-be namesake comes from a different deep place: beneath the sea floor. Microbiologist John Baross and his team at the University of Washington, Seattle, have recovered a cunning new microbe from the scalding fluid ejected during a submarine eruption. The bug, which Baross hopes to name Saganella, appears to be as multitalented as the famous astronomer, author, and TV star.

Typical microbes live within a relatively narrow temperature range. Not the versatile Saganella, which thrives in extreme heat (50° to 90°C) and can survive relatively frigid room temperature as well, Baross reported. “The fact that proteins can operate across that range of temperatures is amazing,” says Peter Fields of Stanford University in Palo Alto, California, who studies protein function in Antarctic fish. He believes that Saganella or another one of the rare subsurface organisms Baross has found “might be a record breaker.”

The hunt for these “extremophiles”—microbes that often live in extreme environments without the light, oxygen, or other ingredients supposedly essential for life—is difficult. For the past several years, Baross and his team have chased down new sea-floor eruptions, trying to reach the caldrons in time to collect samples from the spewing fluids. Saganella, recovered from a site off the Pacific Northwest coast, was identified when graduate student Melanie Summit grew organisms from this sample under various temperature regimes in the lab. Genetic analyses indicate that Saganella is not a bacterium but an unusual member of an ancient microbial group called the archaea. It has a metabolism unlike any Baross has seen before; he is not sure what its energy source is in the wild.

Saganella's existence has heartened those pursuing Sagan's goal of finding life in outer space. The microbe is “absolutely remarkable” and is a potential model for extraterrestrial life, says Kenneth Nealson, an astrobiologist at NASA's Jet Propulsion Laboratory in Pasadena, California. “If an organism can do this on Earth,” he adds, “there's no telling what it could be doing someplace else.”

• *See Science, 25 February, p. 1374, for coverage of an early session at which the nearly complete genetic sequence of the fruit fly was announced.

14. AAAS MEETING

# Rings Reveal a Supernova's Story

1. Charles Seife

WASHINGTON, D.C.—More than 6000 scientists, policy-makers, and journalists gathered here 17 to 22 February for the American Association for the Advancement of Science's annual meeting. A crowded agenda included everything from discussions of ethical issues to announcements of new results from a wide range of disciplines. *

A rainbow of rings, invisible to the human eye, has revealed the inner workings of a nearby supernova. New spectra taken by the Chandra x-ray telescope tell a surprisingly clear story of the remnants of a stellar cataclysm, researchers at the meeting said.

Astronomers were ecstatic when the Chandra X-ray Observatory lifted off last July, providing them with the most sensitive x-ray eye ever launched (Science, 30 July 1999, p. 652). Not only does Chandra provide scientists with pictures of hot objects, but its spectroscope also yields spectra that reveal the energies of x-rays spewing from all kinds of targets. The satellite is able to place one of two diffraction gratings—one for lower energies and another for higher—in the path of incoming radiation. This turns an image into an x-ray rainbow, similar to how a prism splits visible light.

Normally, astronomers point the instrument at distant (and thus small) sources, so they can create a spectrum for an entire object, says astrophysicist Kathryn Flanagan of the Massachusetts Institute of Technology (MIT) in Cambridge. But such readings often provide little detail, because the spectroscope blends the incoming x-rays from the entire source together, producing a homogenized image. To get around this problem, Flanagan and her team last year decided to look at a large supernova remnant located a mere 200,000 light-years away in the Small Magellanic Cloud. The glowing ring, named E0102-72, takes up more than 40 arc seconds in the sky, an enormous size compared to usual targets.

Still, the astronomers weren't sure they would be able to interpret the spectra produced by such a giant. Whereas distant point sources produce tiny spectral dots, larger objects are seen as a series of rings, potentially creating a horribly fuzzy picture. But “as soon as we saw what the image looked like, we knew we were in luck,” says Flanagan. “It was sharp.”

The images were so clear that Flanagan was able to analyze the supernova remnant's structure and even detect ripples left behind by shock waves spreading through surrounding gas clouds. When such powerful shock waves hit, they rearrange atomic structures, stripping electrons from gas atoms. In this case, the spectra indicated a small gas ring near the supernova's center that was rich in the neon and oxygen ions typical of recently shocked regions. It was nestled within a larger ring flush with related, more highly charged ions that form in the wake of the wave—pointing to an inward-moving shock wave. “Your eye is able to follow the progress of the shock,” says Flanagan. As an added bonus, the Doppler effect changes the wavelengths of light emanating from moving gas clouds, which made it possible for Flanagan's team to figure out how fast different regions of the ring are traveling.

The findings are “quite intriguing,” says Wallace Tucker, an x-ray astrophysicist at the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts. “I've always felt that the spectrograph is the dark horse of Chandra to produce some important results, and this is proving to be true.”

The MIT group plans to look at a more complicated supernova remnant in the Large Magellanic Cloud, and sometime next year they will point the x-ray spectrograph at a large remnant in our own galaxy: Cassiopeia A. Says Flanagan: “I wake up in a cold sweat thinking of what that's going to look like.”

• *See Science, 25 February, p. 1374, for coverage of an early session at which the nearly complete genetic sequence of the fruit fly was announced.

15. AAAS MEETING

# Power From Pond Scum

1. Jocelyn Kaiser

WASHINGTON, D.C.—More than 6000 scientists, policy-makers, and journalists gathered here 17 to 22 February for the American Association for the Advancement of Science's annual meeting. A crowded agenda included everything from discussions of ethical issues to announcements of new results from a wide range of disciplines. *

Suppose you could fuel your car by dipping a hose into your garden pond. That's roughly the idea behind a 25-year-old dream of using solar-powered microbes to convert water into oxygen and hydrogen, the cleanest fuel there is. At the meeting, scientists described two new methods for coaxing algae into churning out hydrogen.

As the only product of burning hydrogen is water, hydrogen-fueled vehicles would produce no pollution, making the gas—which can be produced renewably—an attractive alternative to nonrenewable oil. But although energy researchers have tinkered with microbes that produce hydrogen since the 1973 oil embargo, they've never achieved very high yields. Green algae, for instance, could potentially produce plenty of hydrogen, because they can directly split water into hydrogen and oxygen, in a process that's the biological equivalent of electrolysis. But there's a major catch: As these one-celled plants make hydrogen, they also produce oxygen through photosynthesis; this oxygen shuts off the hydrogen-producing enzyme, hydrogenase. As a result, the algae produce only trace amounts of hydrogen.

At the meeting, researchers described two tricks for getting around this problem. Tasios Melis of the University of California, Berkeley, and co-workers at the National Renewable Energy Laboratory (NREL) in Golden, Colorado, worked with algae called Chlamydomonas reinhardtii that are common in fish ponds and aquaria. The team showed that if they starved the algae of sulfate salts, the microbes could no longer maintain a protein complex needed for producing oxygen photosynthetically and went straight down the hydrogen-producing metabolic pathway. As they reported in the January issue of Plant Physiology, the team was able to get an average of 3 milliliters of hydrogen per hour to bubble up from a 1-liter bottle of algae. After 4 days of production, they had to let the algae switch back to normal photosynthesis to rebuild burned-up proteins. “For the first time, we've been able to produce bulk gas using a green algae, which should be the most efficient organism,” says NREL biologist Michael Seibert.

The second approach, described by biophysicist Elias Greenbaum of Oak Ridge National Laboratory in Tennessee, is to leave a lot of nitrogen gas above the bottled algae so that the oxygen wafts out of the water and doesn't stop the reaction. Oxygen does eventually build up, but then Greenbaum flushes it out with nitrogen. Greenbaum was able to equal the Melis group's output for 58 days, “by far the world's record for sustainable production” from microbes, he says. He thinks he can ramp up even further by using oxygen-tolerant algae mutants being bred by the NREL scientists.

The researchers still have a long way to go. Right now, they're only producing a small fraction of the hydrogen that theoretical models suggest they can, and they want to study the biochemical pathway of hydrogenase to figure out how to get more. Even at 10-fold higher yields, however, you'd likely need a large (45-square-meter), shallow pond to produce enough hydrogen to power one car. And the pond would have to be located in a place with lots of sun, like the U.S. Southwest. Still, experts say the technology is worth pursuing as an alternative to using photovoltaics or wind power to split water. “We don't know which technology will come out ahead,” says NREL process analyst Margaret Mann.

• *See Science, 25 February, p. 1374, for coverage of an early session at which the nearly complete genetic sequence of the fruit fly was announced.

16. AAAS MEETING

# How to Steer a Hurricane

1. Robert Irion

WASHINGTON, D.C.—More than 6000 scientists, policy-makers, and journalists gathered here 17 to 22 February for the American Association for the Advancement of Science's annual meeting. A crowded agenda included everything from discussions of ethical issues to announcements of new results from a wide range of disciplines. *

When the weather turns hot and sticky, hurricanes force thousands of American coastal dwellers to batten down their hatches. Some storms ravage states along the Gulf of Mexico, while others menace the Eastern Seaboard. Now, researchers have proposed that a long-term climate pattern over the Atlantic Ocean steers most hurricanes toward one region or the other, but not both, for decades to millennia at a time.

Climatologists already knew about a connection between the famed El Niño- Southern Oscillation (ENSO) in the tropical Pacific Ocean and hurricanes in the Atlantic. Warm El Niño patterns seem to suppress major Atlantic storms, while hurricanes flourish during cooler La Niña seasons. Although that global link helps explain the number of storms, it doesn't predict where they'll strike. So climatologist James Elsner of Florida State University in Tallahassee and his colleagues looked for ties between hurricane tracks and the North Atlantic Oscillation (NAO), a seesaw shift in atmospheric pressures over the ocean (Science, 12 February 1999, p. 948). When the NAO is intense, a fair-weather ridge of high pressure dominates the north-central Atlantic. During a weak NAO, this “Bermuda High” sags southwest toward Florida.

To see whether NAO fluctuations influenced hurricane tracks, Elsner's team compared weather records with hurricane landfall reports from the last 150 years. They found a suggestive statistical link: In years of strong NAOs, most major hurricanes curved along the southern margin of the high-pressure ridge and then turned north to plow into the East Coast. But when the Bermuda High drifted farther south, it deflected big storms through the Caribbean Sea and into the Gulf of Mexico. Elsner will describe the results in an upcoming issue of the Journal of Climate.

Although the NAO pattern waxes and wanes, Elsner notes that it often lingers for decades at a time. This may explain why the biggest storms tend to strike either the Gulf Coast or the Atlantic Coast in batches that persist for 20 to 30 years, he says. Furthermore, team member Kam-biu Liu, a climatologist at Louisiana State University, Baton Rouge, found signs that the NAO may steer hurricanes over even longer periods. Ancient layers of sand washed inland by the most powerful hurricanes suggest that clumps of storms bombarded the Gulf Coast for 2500 years, followed by a millennium of relative calm. Other preliminary work examining thousands of years of hurricane deposits in Virginia and Cape Cod appears to show that a quiet Gulf Coast means a stormy East Coast, and vice versa, Liu says.

“The evidence seems strong for a link” between the NAO and hurricane tracks, says climatologist Kerry Emanuel of the Massachusetts Institute of Technology in Cambridge. But “until more rigorous statistical tests are done, I think the jury is still out.” If Elsner's team can prove its case, however, forecasters could eventually use the Atlantic climate to predict which stretches of coastline may bear the brunt of storms during a given season.

• *See Science, 25 February, p. 1374, for coverage of an early session at which the nearly complete genetic sequence of the fruit fly was announced.

17. AAAS MEETING

# The Brains Behind the Face

1. Gretchen Vogel

WASHINGTON, D.C.—More than 6000 scientists, policy-makers, and journalists gathered here 17 to 22 February for the American Association for the Advancement of Science's annual meeting. A crowded agenda included everything from discussions of ethical issues to announcements of new results from a wide range of disciplines. *

Beauty ads claim that retinoic acid, better known as vitamin A, removes wrinkles from aging faces. But new findings suggest that it is even more important for very young faces. Retinoic acid helps direct the proper development of both the face and the forebrain, which governs higher thought and reasoning, scientists reported at the meeting. The study is the first to implicate a single genetic pathway in the development of both the forebrain and the face, researchers say, and it may provide insights into some birth defects.

Although doctors have long observed that brain and facial defects usually occur together, researchers were not aware that the two structures had developmental genes in common. Because the brain provides a sort of scaffolding for facial features, scientists assumed that if something went wrong in brain development, the face would simply lack structural support and become deformed. But the new research suggests that problems with one gene pathway may cause both kinds of defects, says developmental biologist Harold Slavkin of the National Institute of Dental and Craniofacial Research in Bethesda, Maryland.

That pathway involves sonic hedgehog, a versatile developmental gene that was first discovered through its role in limb growth and patterning. Previous work by several groups had shown that it is also important for early head development. But what controls the gene? In the limbs, retinoic acid will turn sonic hedgehog on and off. To find out if that happens in the face, a team led by developmental biologist Jill Helms of the University of California, San Francisco, applied a molecule that blocks the retinoic acid receptor to the head region of developing chicks. They found that the populations of cells destined to become face and forebrain no longer expressed the correct genes and as a result stopped dividing and began to undergo programmed cell death. The chicks never developed a forebrain, forehead, nose, or eyes. However, if the researchers later applied extra retinoic acid, or extra doses of Sonic hedgehog and another growth factor, the chicks developed nearly normal features.

Scientists who had looked for signs of retinoic acid in the early face and forebrain had failed to find any sign of the molecule, Helms says. But she says that may be because its presence is fleeting and vitally important only within a narrow developmental window. When her team treated slightly older embryos with the blocking molecule, it had no effect.

Although the patterning of the midbrain and the hindbrain are well studied, Helms is “at the forefront” in the effort to sort out the earliest patterning of face and forebrain, Slavkin says. The work may also have practical implications: Helms notes that proper amounts of vitamin A during key stages of pregnancy might help prevent some birth defects.

• *See Science, 25 February, p. 1374, for coverage of an early session at which the nearly complete genetic sequence of the fruit fly was announced.

18. AAAS MEETING

# Science Gains at State Department

1. David Malakoff

WASHINGTON, D.C.—More than 6000 scientists, policy-makers, and journalists gathered here 17 to 22 February for the American Association for the Advancement of Science's annual meeting. A crowded agenda included everything from discussions of ethical issues to announcements of new results from a wide range of disciplines.s*

Secretary of State Madeleine Albright says she is just weeks away from announcing a new long-term plan to incorporate scientific expertise into U.S. foreign policy. That promise, announced in a 21 February speech at the meeting, was applauded by researchers who have been pressing the State Department to infuse more science savvy into its diplomatic corps, although some said they wanted details before passing judgment.

Albright's speech is the department's most prominent response so far to a National Academy of Sciences (NAS) report issued last October that laid out a 12-step plan for improving its technical expertise (Science, 15 October 1999, p. 391). Albright requested the report in 1998, after researchers expressed alarm about the dwindling number of scientifically trained diplomats serving in embassies and headquarters. To reverse that trend, Albright said she hoped to have a new science adviser on board by April and to release a plan that will look beyond the end of the Clinton Administration. “It will lay out my long-term vision for [upgrading science at the department],” she said. “This will be a multiyear, multi-Administration, bipartisan mission.”

After the speech, authors of the NAS report—including Robert Frosch of Harvard University in Cambridge, Massachusetts—were pleased by the high-profile commitments. But they also agreed with a State Department official, who predicted that change is “going to be a long-term process.”

• *See Science, 25 February, p. 1374, for coverage of an early session at which the nearly complete genetic sequence of the fruit fly was announced.

19. SCIENTIFIC COMMUNITY

# Asilomar Revisited: Lessons for Today?

1. Marcia Barinaga

A conference last month asked whether the “Asilomar process” could help to resolve today's biotech controversies

PACIFIC GROVE, CALIFORNIAThe Asilomar conference on recombinant DNA was the Woodstock of molecular biology: a defining moment for a generation, an unforgettable experience, a milestone in the history of science and society. But was it something that could—or even should—be repeated?

Those were some of the questions on the minds of 55 scientists, lawyers, historians, and ethicists who gathered here last month at the Asilomar Conference Center near Monterey to mark the 25th anniversary of that historic meeting. In February 1975, 140 participants—mostly biologists, with a handful of lawyers and physicians and 16 members of the press—gathered at the rustic conference center overlooking the Pacific to tussle with an issue that had just burst onto the biology scene: the safety of recombinant DNA research. Known officially as the International Congress on Recombinant DNA Molecules but remembered ever since simply as “Asilomar,” that meeting was widely hailed as a landmark of social responsibility and self-governance by scientists. The participants in last month's conference*—who included 11 of the 1975 conferees—were not just here to reminisce. Legal scholar Alex Capron, a participant in the 1975 meeting and now co-director of the Pacific Center for Health Policy and Ethics at the University of Southern California in Los Angeles, assembled the group to discuss what lessons could be learned from the “Asilomar process” and, specifically, whether there are situations today in which it might be appropriately applied.

Asilomar occurred at a unique moment in biology. Researchers had just discovered how to cut and splice together the DNA of disparate species and were beginning to contemplate the cornucopia of experiments this opened up. “Recombinant DNA was the most monumental power ever handed to us,” said California Institute of Technology president David Baltimore, one of the organizers of the 1975 meeting. “The moment you heard you could do this, the imagination went wild.” But a number of scientists at the time raised concerns about whether such experiments might create dangerous new organisms, microscopic Frankensteins that could sneak out of the lab undetected on the sole of a Hush Puppy and threaten public health.

Those concerns triggered a “hectic experience” of scientific soul-searching that culminated in the 1975 Asilomar conference, recalled Stanford molecular biologist Paul Berg, another organizer of that meeting. Participants at a June 1973 Gordon Conference on Nucleic Acids had published a letter expressing concern about recombinant DNA research. In response, Berg led a committee of the National Academy of Sciences that in July 1974 took the unusual move of calling for a voluntary moratorium on certain types of recombinant DNA experiments until the hazards could be evaluated.

Berg and several colleagues organized the Asilomar meeting 7 months later to bring together “people who were engaged in the research or were likely or eager to use it.” The organizers also brought in researchers with expertise in bacteria and viruses to help assess the potential hazards. A sense of urgency pervaded the meeting, in part because researchers were impatient to put the new technology to work. Although most of the participants suspected that there was no real hazard, Baltimore said, the stakes were clearly “too important to be wrong.” The meeting's organizers decided not to address the ethical issues surrounding genetic alteration but to stick to safety issues they felt they could address as scientists. After much haggling, the group settled on a set of safety guidelines that involved working with disabled bacteria that could not survive outside the lab. The guidelines not only allowed the research to resume but also helped persuade Congress that legislative restrictions were not needed—that scientists could govern themselves.

The group that convened last month faced a very different set of circumstances. The technology that seemed like science fiction in 1975 is now commonplace and has yielded what Baltimore called “a remarkable harvest” of products and applications, such as genetically enhanced crops, tests for genetic diseases, and human gene therapy. Last month's meeting also had less of a sense of urgency because, for the most part, scientists consider these technologies safe.

But the public remains hugely concerned about the applications of genetic manipulation: Witness the recent protests in Europe over genetically modified crops. And society today is much more insistent on participating in the debate. “There are no important risks that scientists alone can assess,” said Princeton University president Harold Shapiro, chair of the National Bioethics Advisory Commission. “Scientists can make a great contribution, but they can't decide alone.”

What's more, the scientists themselves have changed. Those who gathered at Asilomar in 1975 represented a research community that was purely academic in its interests. Today, “there are few pure academics left” in molecular biology, Baltimore noted. As genetic engineering has gone commercial, academics have followed, and today most senior academic researchers have ties to biotechnology companies that would complicate any attempts at self-scrutiny.

During the course of last month's 2-day meeting, participants concluded that, for these and other reasons, it would not be appropriate now for scientists alone to take on the task of analyzing the risks of their work while setting aside the ethical issues, as they did a quarter-century ago at Asilomar. Nevertheless, as they debated the genetic modification of crops, gene therapy, and the use of genomic information, the participants identified instances in which society might have benefited if scientists had actively contributed to a public debate about the safety of their work.

One of those was gene therapy, the subject of the most intense soul-searching at the meeting. Gene therapy has been in the hot seat since the death last September of Jesse Gelsinger, an 18-year-old subject in a gene-therapy trial at the University of Pennsylvania. Others in the field knew that the adenovirus vectors being used in the Pennsylvania trial could cause potentially dangerous immune reactions, like the one that apparently killed Gelsinger, said gene therapy researcher Inder Verma of the Salk Institute in La Jolla, California. “Why didn't we stand up” at meetings and raise those concerns? Verma asked.

Picking up on Verma's remark, Baltimore urged that “it is absolutely necessary” for gene therapists to slow down and reexamine the standards for when to begin trials on human subjects. “There are times when some things shouldn't happen,” he said. Gene therapy vectors “that weren't working in animals are going into humans. A lot of us are saying what the hell are [doctors] doing putting these into people?” The Gelsinger death and the publicity it has generated are sure to raise public suspicion, said Maxine Singer, president of the Carnegie Institution of Washington: “It will be difficult to repair the damage that has already been done to biomedical research and gene therapy research.”

Some participants also suggested that the huge public backlash against genetically engineered crops might have been averted if scientists, both commercial and academic, had taken a more active role in analyzing risks—not only as they perceived them but also as society was likely to—and perhaps exercised restraint until those uncertainties could be resolved. What made Asilomar unique was that the scientists “gave other people's perspectives some standing,” said Shapiro. “Here is a case where commercial interests are suffering a great deal from not having confronted these problems in this way.”

But with substantial U.S. acreage—for example, one-third of the corn and half of the cotton and soybeans—planted with genetically modified crops, it is too late to go back to a scientist-controlled process of self-regulation, said Rebecca Goldberg of New York City-based Environmental Defense. Indeed, it is naïve to think that any controversial issue can, or should, be resolved by scientists alone, said sociologist Dorothy Nelkin of New York University. She pointed out that public fears about the safety of new genetic technologies often mask deeper societal concerns. In the case of genetically modified crops, for example, “when the French talk about risk, they are talking about McDonald-ization of France and the plight of the small farmer. When the British talk about risk, they are worrying about the alteration of nature. Even if it could be demonstrated that the risks were acceptable, the controversy would continue.”

Although it may be too late to influence the debate on genetically modified foods, at least some of the conferees thought an updated Asilomar-like analysis of scientific risks could still make an important contribution in two areas: germ line engineering and xenotransplantation. Gene therapy that alters germ line cells is an ethical minefield, as such alterations would be transmitted to future generations. “At Asilomar [in 1975], people said they would draw the line at germ line gene therapy,” said science historian Charles Weiner of the Massachusetts Institute of Technology (MIT). Now, although germ line therapy in humans is not actually being done, “it's on the table” as an option, said Weiner. Weiner and others worry that techniques developed to correct genetic diseases may eventually be used to engineer desired traits into children.

In addition to those ethical concerns, the group debated scientific risks. Geneticist Arno Motulsky of the University of Washington, Seattle, argued that germ line therapy could “lead to reduction of genetic disease” and so should not be dismissed out of hand. But physician and geneticist Paul Billings, co-founder of GeneSage, a San Francisco Internet-based genetic information and health company, countered that germ line therapy is not necessary, given other options such as prenatal or preimplantation diagnosis of genetic defects. What's more, he said, the altered genes, especially if they insert randomly into the germ line genome, may have unpredictable and potentially very subtle negative effects on health or intelligence. Although difficult to detect, such effects could be “quite significant” to individuals and their descendents, said Billings. To MIT molecular biologist Phillip Sharp, debate such as this emphasizes the need for an Asilomar-like “attempt at evaluation and consensus in the scientific community” concerning germ line therapy.

As for xenotransplantation, the transfer of organs from nonhuman species into humans, there are concerns that the procedure could endanger public health by transferring animal viruses to humans. Other countries are considering or have instituted moratoria on the procedure, said Lana Skirboll, director of the Office of Science Policy at the U.S. National Institutes of Health, but the United States has done nothing. “We need a scientific assessment,” she said.

At the end of last month's meeting, Berg reflected on the differences between 1975 and 2000 and what they might mean for the resolution of scientific controversies. One factor that made the first meeting work, he said, was the “suddenness of the issue.” Because molecular biologists weren't yet heavily invested in recombinant DNA technology and the public knew little about it, “it was much easier to get people to agree on a course of action,” Berg told Science. Most of the issues discussed at last month's conference are “chronic,” he noted. And “once an issue becomes chronic, positions become hardened, and consensus is much more difficult to achieve.” What's more, Berg and others noted that consensus might never have been reached if the scientists at Asilomar had not agreed to put aside the ethical issues and stick to biological hazards. In 1975, that process worked, and the research not only went on safely but won the public trust. Today “we are in a very different world,” said philosopher Stephen Stich of Rutgers University in New Brunswick, New Jersey, where that public trust is not so easily won.

But that in no way diminishes the need for scientists to reflect on the impact of their work on society, said Susan Wolf, a professor of law and medicine at the University of Minnesota, Minneapolis. What was unique about Asilomar was that “a group of scientists was convened to reflect upon how their work affected other people's lives,” said Princeton's Shapiro. And that, he and others agreed, is something that scientists owe society as they move toward whatever the next scientific revolutions might be.

• *Symposium on Science, Ethics, and Society: The 25th Anniversary of the Asilomar Conference, 15-17 February.