# News this Week

Science  25 Aug 2000:
Vol. 289, Issue 5483, pp. 1266
1. BIOETHICS

# Financial Conflicts Get More Scrutiny in Clinical Trials

1. Bruce Agnew*
1. *Bruce Agnew lives in Bethesda, Maryland.

With concern growing that some research universities are getting too cozy with drug companies, it's perhaps fitting that the debate over reducing conflicts of interest in clinical research sounds a lot like an argument about premarital sex. While some insist that abstinence is the only solution, others believe that education is enough to keep the problem under control. Last week, at a national conference,* the “abstainers” gained an important ally—Greg Koski, the incoming head of the federal government's new Office for Human Research Protections. And his support for the idea that scientists should have no financial ties to companies whose products they are testing hints at an upcoming shift in government rules that govern the relationship between scientists and the pharmaceutical industry.

Koski, after noting that some critics contend that “there are certain financial conflicts of interest that can be avoided,” said, “I believe that's true.” He added, “I believe that they probably should be avoided in most instances.” His comments came at a meeting convened by Health and Human Services (HHS) Secretary Donna Shalala as part of a reevaluation of federal protections for clinical research patients following the death last year of 18-year-old Jesse Gelsinger in a University of Pennsylvania gene therapy trial.

To the roughly 700 attendees—including university officials, Institutional Review Board (IRB) members, and industry research sponsors—it signaled that the government may soon go beyond its current policy of counting on universities to “manage or reduce” conflicts. That 5-year-old policy, itself a reaction to suggestions that drug trials were affected by researchers' ties to companies, is generally seen as having had little effect. Indeed, Koski said that in recent years, industry-academia ties “have gotten entirely out of control.” And most participants said they felt some action was needed, even if they were uncertain what it should be.

“These are very significant issues, and they simply have to be addressed,” says Nils Hasselmo, president of the Association of American Universities (AAU). Wendy Baldwin, deputy director for extramural research at the National Institutes of Health (NIH), predicted that the exercise would take time. “This is actually the beginning of the process,” she said. But there was consensus that the problem, aggravated by the burgeoning biotechnology industry, won't correct itself. “Let's be realistic,” said Jane Henney, commissioner of the Food and Drug Administration. “Profits do drive this business. As a result, financial conflicts of interest are now an inherent part of the process, and we must deal with them.”

A decade ago, when NIH began considering a conflict-of-interest rule for all federally funded researchers, many individuals and some universities contended that such conflicts didn't exist or didn't matter. In 1995, after a long review, NIH's parent agency, the Public Health Service, issued a rule that requires federally funded researchers to disclose to university committees any “significant” interests—defined as $10,000 in income, a$10,000 equity stake, or 5% ownership in a company that might be affected by a scientist's research. The committees are supposed to “manage, reduce, or eliminate” the conflicts.

NIH officials say they believe that universities “in general” are complying, but they don't really know. They acknowledge that they began monitoring compliance only this year. Acting NIH Director Ruth Kirschstein told the conference that some universities have adopted a “culture of compliance”—while others have not.

Gene therapy leader Savio Woo of Mount Sinai School of Medicine in New York City suggested that the best solution may be a simple one. In an April policy statement, Woo noted, the American Society of Gene Therapy's board of directors declared that clinical researchers should have no “equity, stock options, or similar arrangements” with companies sponsoring trials. Not a single member has complained, he said. Koski challenged other professional societies to adopt the same policy: “Just say no.”

But most of the discussion at the conference revolved around questions of how to “manage” conflicts rather than do away with them. Breakout panels debated whether IRBs—which must approve consent forms and patient protections in all clinical trials at federally funded institutions—should try to resolve conflict-of-interest issues. The consensus answer seemed to be “no,” because IRBs are already overloaded and understaffed. Should IRBs take account of possible conflicts of interest? The answer to that one seemed to be “yes”—although NIH officials say only about 25% of IRBs look into the question now. Conference attendees also appeared to agree that clinical-trial patients deserve to be told, in an informed consent form, if researchers might have a financial stake in the outcome, as was done in the Penn trial (see graphic). But how much detail should be disclosed will be hard to decide.

The conference barely touched on a new issue introduced by Kirschstein and Baldwin: What should be done when a university owns a piece of a company whose value will be affected by the outcome of a clinical trial? Such situations appear to be growing more numerous, although Kirschstein says no one has much data about the topic, except for “a few anecdotes, I think.”

Gene therapist Woo says he knows enough to express his views: “I find it difficult to understand a nonprofit, public university holding equity in a for-profit company,” Woo says. Nonprofit universities should be “precluded” from such investments, he says.

That position is too radical for AAU's Hasselmo. “We shouldn't throw out some valuable babies with the bath water here, because some of these collaborations are very important,” he says, noting that an AAU task force is trying to develop principles for managing conflicts. Universities, he adds, see self-policing as preferable to “further rules and regulations” by the government.

Koski noted that the problems facing U.S. clinical research extend beyond federally funded academic medicine. A growing proportion of the work is being performed outside of academic health centers and beyond government oversight, he said. This situation calls for “uniform guidance” at the national level, he added, warning that “if guidance itself is not effective, then it seems to me that rules and regulations and legislation will follow.”

Koski, who takes up his new job next month, said that shoring up the protections for human subjects in research involves issues that “go well beyond conflict of interest.” Proposals by HHS's Office of Inspector General for redesigning the entire system of protecting clinical research subjects “are very, very much on my mind,” Koski said. “Individuals and institutions who fail to truly accept their responsibilities and work to achieve them,” Koski said, “simply should not be permitted to engage in” clinical research. “More on that after Labor Day,” he promised. But he clearly intends to take a tough line.

• *Conference on Human Subject Protection and Financial Conflict of Interest, held at NIH in Bethesda, Maryland, 15–16 August.

2. GENOMICS

# Building a Case for Sequencing the Chimp

1. Ann Gibbons

First came humans, then mice and, most recently, rats (see next story). And now, a motley queue of other vertebrates—including dogs, chickens, and pufferfish—has formed, each one vying to have its genome sequenced next on the limited budget of the National Human Genome Research Institute (NHGRI).

The most recent entrant is the chimpanzee. In a letter to Science on page 1295, an interdisciplinary group—which includes 26 geneticists, anthropologists, and molecular evolutionists—says top priority should be given to a primate. Their first choice is the chimp, whose genome is 98% identical to that of humans.

By finding those few critical genetic differences between humans and chimpanzees, geneticists hope to solve the mystery of what makes humans unique. Specifically, they want to find the genes that underlie the striking differences between humans and chimpanzees in cognition, reproductive biology, and behavior. “Until we understand how we differ genetically from our nearest relatives—the apes—we won't understand the genetic basis for being human,” says Edwin McConkey, a molecular biologist at the University of Colorado, Boulder, and one of two co-authors of the letter. “The mouse genome will tell us why we are not mice, but it will never tell us why we are not apes.”

The advocates, who include Nobel Prize winners Francis Crick of the Salk Institute and George Palade of the University of California, San Diego, also argue that identifying the differences in the DNA of chimps and humans should explain why humans but not chimps get diseases such as malaria and Alzheimer's, and why chimpanzees rarely get cancer and get a much milder form of HIV. Finally, the group writes that a chimpanzee genome project might raise public awareness of this endangered species.

Those arguments are already well known at NHGRI, where deputy director Elke Jordan says that the chimpanzee is “definitely a strong candidate” to have at least part of its genome sequenced. Jordan even sees a way to reduce the estimated $100 million cost, by focusing not on the entire genome but on areas of suspected differences between humans and chimpanzees. Still, the chimpanzee lobby is up against a host of other organisms. Notes Jordan: “There are all kinds of animals of great interest to somebody.” 3. GENOMICS # Rat Genome Off to an Early Start 1. Elizabeth Pennisi Assuming that if two mammalian genomes are good, then three would be better, the National Human Genome Research Institute (NHGRI) has jump-started efforts to determine the order of the roughly 3 billion bases in the rat genome. The original plan had been to wait for funding, expected in fiscal year 2001 (Science, 26 May, p. 1317). Instead, two of the 10 centers involved in sequencing the mouse genome are now shifting to the rat. If the budget proposal passes, the National Heart, Lung, and Blood Institute (NHLBI) will kick in a total of$58 million, as planned, to be distributed in 2001 and 2002. During that time sequencers will produce a rough draft of the rat genome—in parallel with the rough draft of the mouse.

Having data from two rodent species should speed the discovery of genes and regulatory regions in the human genome and make it easier to determine their functions. Although the mouse is a favorite of geneticists, the rat has captivated physiologists for 150 years and is the animal most often used by pharmaceutical companies for preclinical testing of new drugs. Thus, with the rat genome in hand, “you can take the power of mouse genetics and the power of rat physiology and link them together,” says Howard Jacob, a physiological geneticist at the Medical College of Wisconsin in Milwaukee.

View this table:

NHLBI has supported rat genome work since 1995, although Jacob notes that “it's been a stealth project” that hasn't received wide notice. The project has generated sequencing tools, such as a physical map of the rat genome and a set of bacterial clones of rat DNA, but full-scale sequencing was on hold. In the past year, however, the big genome-sequencing centers have expanded their capacity so much that NHGRI director Francis Collins became convinced that they could tackle the rat genome as they were finishing the human genome and preparing the mouse draft. In May, the NHLBI advisory council agreed to put aside $32 million in 2001 and another$26 million in 2002 for the rat.

But NHGRI has advanced its troops even before the new year begins, shifting two groups, the Baylor College of Medicine in Houston and Genome Therapeutics Corp. (GTC) in Waltham, Massachusetts, into the rat effort. Baylor's Richard Gibbs will put the remaining $14 million from his mouse grant toward the rat, and GTC's Doug Smith will divert about$10 million from mouse and human sequencing for GTC's initial rat work. Together, they hope to sequence the entire rat genome once over within a year. The two centers are likely to be among those that receive the NHLBI contribution, which will be used to sequence the genome at least four times over to produce a rough draft.

If all goes well, the mouse and rat genomes will be available at the same time. Because the two rodents are separated by about 16 million years of evolution—while the human and mouse are separated by 80 million years—the rat and mouse genomes will share some DNA that is not obviously conserved between either rodent and the human genome. Thus, the rat genome should help to identify regulatory regions that might be missed in a mouse-human comparison.

NHGRI plans to push ahead on the mouse genome to produce a high-quality, complete version. So far, that's not in the cards for the rat. But that suits Jacob just fine, even though he works on the rat. He says: “I think it does not need to be finished at the current cost for finishing.”

4. STEM CELL RESEARCH

# U.K. Backs Use of Embryos, Sets Vote

1. Richard Stone

LONDON The U.K. government leaped into an ethical minefield last week, endorsing a report it had commissioned that calls for an expansion of research on human embryos. The report advocates tapping embryos for their stem cells, unspecialized cells that may ultimately serve as seed material for growing tissues to treat diseases. It also opens the door to cloning human embryos for research—an activity that has triggered sharp debate. Legislation implementing the recommendations will go to Parliament for a vote this fall.

If passed, the new U.K. regulations would likely be more permissive than guidelines expected out shortly from the U.S. National Institutes of Health. With Canada, Germany, and Japan also hammering out guidelines, says stem cell researcher John Gearhart of The Johns Hopkins University School of Medicine, “you'll soon see other players in the field.”

Current U.K. rules allow research on human embryos only for studies aimed at improving infertility treatment, devising better contraceptives, and screening for genetic abnormalities before implantation. Nearly all embryos used in such studies are leftovers from in vitro fertilization clinics, and research is limited to embryos less than 2 weeks old, before neural development occurs.

But recent advances in stem cell research prompted the U.K. Department of Health to ask its chief medical officer, Liam Donaldson, to appoint an independent panel to review the science and ethics of human embryo research. The panel delivered its report in May, and last week the Department of Health unveiled both the report and the government's response. The department is now discussing with the research councils, which dole out much of the government's science funding, how to fund more human embryo research.

View this table:

Topping the panel's list of recommendations is a call for allowing researchers to extract embryonic stem cells, which can be coaxed to form various cell types. Culled from 5- to 6-day-old embryos, such cells might be grown in the test tube into tissues suitable for transplantation. The hope is that embryonic stem cells would serve as a stopgap until scientists learn to reprogram adult cells to serve as stem cells. “Winding the clock back on adult cells is very much the Holy Grail of stem cell research,” says Donaldson. But scientists shouldn't count on adult cells, warns Peter Andrews of the University of Sheffield, who studies human embryonal tumor cells. “In the end,” he says, “the therapeutic approach will be the one that's easiest to follow.”

The report also advocates the limited use of nuclear transfer techniques as a source of stem cells. To ensure that tissue grown from stem cells is not rejected as foreign by a patient's immune system, a nucleus from one of the patient's own cells would be fused with an egg that had its nucleus removed, and the egg would then be prodded to divide. However, clinical research to test therapeutic cloning is a long way off and may require additional legal safeguards, says Donaldson: “We're talking about research at this stage, not treatment.” Making babies from cloned human embryos—the reproductive cloning that the sheep Dolly made famous—would remain a crime under British law.

A third line of research backed by the report would explore the feasibility of preventing the 50 or so diseases caused by mutations in the genes carried by mitochondria, the powerhouses of the cell. Mitochondria are handed down only by the mother, and one approach might be to transplant the nucleus from an egg of an affected woman into an egg from a normal donor stripped of its nucleus, and then fertilize the hybrid egg.

Donaldson says the recommendations do not break new ethical ground but simply expand research already allowed under current law. Still, rather than risk defections, the ruling Labor Party plans to allow Parliament members to vote their conscience on the sensitive issue.

The battle lines are already drawn: Opposition Member of Parliament (MP) Liam Fox, a physician who serves as the Conservative Party's “shadow” health secretary, has come out against therapeutic cloning. He has an influential ally in Cardinal Thomas Winning, head of the Roman Catholic Church in Scotland, who in the 20 August Sunday Telegraph equated therapeutic cloning with killing human beings and called on MPs to outlaw it.

Andrews, who has received heart-wrenching phone calls from people whose loved ones suffer from diseases that might be treated someday with stem cell-derived tissue, hopes the scientific argument will prevail: “If we don't start investigating, we aren't going to get the answers we need.”

5. NUCLEAR CHEMISTRY

# Element 107 Leaves the Table Unturned

1. Robert F. Service

Hard as it is to make new elements, it's a lot easier than figuring out how they behave chemically. Consider element 107, bohrium. It was first glimpsed in 1976 by high-energy physicists at the Joint Institute for Nuclear Research in Dubna, Russia. Not until this week, however, did an international team of chemists report on the first successful analysis of its chemical properties. “This is exceptional work,” says Walter Loveland, a nuclear chemist at Oregon State University in Corvallis, calling the Swiss-led effort “a unique event and a serious advance in chemistry.”

The results, announced at a meeting of the American Chemical Society,* show that bohrium behaves almost exactly as theorists predicted it would. “Bohrium is boring,” says team member Andreas Tuerler. But that straight-arrow comportment, he adds, is itself something of a surprise.

To predict the properties of unknown elements, chemists consult the periodic table, a chart that sorts elements into families according to the arrangement of electrons in their reactive outer shells. For the 115-odd known elements, the table works uncannily well. But sooner or later, physicists believe, it is bound to become a victim of Einstein's theory of relativity.

The more massive an element is, they point out, the faster its electrons swarm the nucleus. Eventually, the electrons should start to show relativistic effects—changes of mass that will distort the shape of the swarms. Those distortions should give ultraheavy elements properties that could not be predicted by looking at their lighter kin. Elements 105 and 106 showed hints of unruly behavior, and scientists were eager to see if bohrium would be the straw that broke the camel's back.

Testing the chemistry of such elemental heavyweights, however, is exceedingly difficult, largely because the unstable nuclei at their cores fragment into smaller, more stable “daughter nuclei” almost the instant they come into being. A bohrium nucleus created in 1981 lasted only 9 milliseconds—far too short to run through chemical experiments. Fortunately, single elements can come in various flavors, or isotopes, each of which harbors a different number of neutrons. And some isotopes live longer than others.

So nuclear chemists Tuerler, Heinz Gäggeler, and their colleagues at the Paul Scherrer Institute in Villigen, Switzerland—along with team members from Germany and the United States—smashed a beam of neon atoms into a berkelium target, creating two new bohrium isotopes. One of those, 267Bh, possessed a half-life of 17 seconds—long enough to make it an excellent candidate for testing its chemical reactivity.

From its electronic structure, nuclear chemists judged that 267Bh should behave similarly to other elements in group 7 of the periodic table, such as technetium and rhenium. To test that hypothesis, Tuerler's team swept the atoms directly from their production facility into a 1000ºC flow chamber, where they met up with hot oxygen and hydrochloric acid (HCl), gases that react readily with technetium and rhenium. What was left then passed through a chromatography column cooled to a comparatively chilly 70º to 180ºC. Bohrium by itself can't make this journey in the cold, as it will quickly fall out of the gas and settle on the sides of the apparatus. But if it were anything like technetium and rhenium, it would continue to float freely if it combined with oxygen and HCl to make BhO3Cl, barium oxychloride.

That's exactly what the researchers found. Running day and night for a month, the experiment produced only six atoms of the long-lived 267Bh. But each atom flew through the full chemical separator, where its fingerprint-like decay pattern was picked up by detectors. Bohrium's chemistry was nailed, and the element certified as an obedient member of group 7. The results preserve the periodical table—for now.

• * 220th ACS National Meeting, Washington, D.C., 20–24 August.

6. ENDANGERED SPECIES

# Migrating Otters Push Law to the Limit

1. Gretchen Vogel

Fourteen years ago, Congress declared the Southern California coast an otter-free zone—but the unwitting creatures aren't cooperating. That's no surprise to federal biologists, who this summer issued a report* concluding that the otter-free zone harms the already-endangered population. Federal officials are now trying to come up with a better plan, but it's likely to draw from politics as well as science.

Hearings last week in Santa Barbara and Monterey showcased a decades-long tussle over the range of the southern sea otter, which was hunted nearly to extinction during the 19th century. The few dozen animals that remained in 1911 expanded along California's central coast, but by the late 1970s the colony still numbered fewer than 2000, earning it a place on the endangered species list. Worried that an oil spill or other catastrophe could wipe out the entire population, officials from the U.S. Fish and Wildlife Service (FWS) proposed an ambitious relocation plan in the early 1980s to transport more than 100 otters to San Nicolas Island, 100 km west of Los Angeles.

The fishers in the region were furious about this plan to establish a second colony. Although sea otters are undeniably cute, their voracious appetites are far from endearing. Lacking blubber, the animals keep warm with a racing metabolism that drives them to eat a quarter of their 30-kilogram body weight each day—mostly invertebrates such as clams, sea urchins, and abalone. “We have size limits, but otters don't,” says commercial sea urchin diver Bruce Steele, who is based in Santa Barbara. “They do an awful lot of damage really quickly.”

In 1986, Congress struck a compromise that declared the waters south of Point Conception to be a no-otter zone—except for the experimental colony on San Nicolas Island. FWS was required to round up any otters that strayed into the divers' zone and cart them back to San Nicolas or north of Point Conception—a task that proved exceedingly difficult.

For some reason, few otters were content to stay at San Nicolas. Although FWS relocated 140 animals, fewer than 25 live on the island today. FWS spent several years rounding up stray otters, but in 1993 the agency quietly stopped transporting animals to San Nicolas and also stopped enforcing the no-otter zone.

The implicit decision to abandon the policy might have remained in place had not an adventurous troop of some 100 animals decided to migrate south in early 1998. “They knocked down our harvest resources by 80% or 90% in 2 years,” says Steele, explaining why he and other commercial divers filed suit in May to force FWS to maintain the no-otter zone.

FWS has defended its biological ground in a report issued last month. The agency says that the animals are still imperiled—their numbers fell from a 1995 high of 2377 to 2090 in 1999 before an increase this spring. And the exclusion zone is not helping. Not only do some animals die during capture or in transit, but introducing stray animals into existing colonies in the north can disrupt the current inhabitants and threaten their health. FWS biologists conclude that “continuing the containment program would jeopardize the existence of the species,” says Greg Sanders of FWS. The move south “likely represents a natural range expansion” vital to the population's health, he says.

FWS is now considering several options. One is to declare the original relocation plan a failure because the colony at San Nicolas is too small for its original purpose: to rescue the species if the mainland population were wiped out. That admission would mean moving the remaining San Nicolas otters to the mainland and abolishing the no-otter zone.

Sea otter advocates prefer a second option, which would leave the San Nicolas colony in place and abandon the no-otter zone. The animals at San Nicolas are reproducing, they note, and otters born there might be more likely to stay. To that end, FWS is devising a supplemental environmental impact statement that will compare the effect on otters and on fisheries of continuing, modifying, or abandoning the otter-free zone.

Diver Steele hopes for a compromise that would leave the San Nicolas otters in place and create a smaller otter exclusion zone around key fishing areas. That approach, he says, might enable otters and commercial divers to coexist—at least for a time. “[The otters] are coming, and when they get there it's pretty much over for us,” he says. “I know I'm going to lose, but I'm trying to lose as slowly as possible.”

7. PALEONTOLOGY

# Team Rejects Claim of Early Indian Fossils

1. Pallava Bagla

NEW DELHI A team of Indian paleontologists has failed to find evidence to support a 1998 paper that cast doubt on the earliest claimed dates for the origin of animals.

Two years ago an Indo-German team of paleontologists pushed back the origins of multicellular life by 400 million years to an astounding 1.1 billion years with the discovery of trace fossils in central India (Science, 2 October 1998, pp. 19, 80). The findings were immediately challenged by Rafat Jamal Azmi, an Indian paleontologist working at the Wadia Institute of Himalayan Geology in Dehra Dun. Writing in the Journal of the Geological Society of India (GSI), Azmi described finding small, shelly fossils (SSFs)—widely agreed upon as being 540 million years old—in a rocky layer in the Vindhyan Mountains that he claimed was laid soon after the sediments from which the trace fossils were discovered, casting doubt on the antiquity of the earliest animals. The discovery, if true, would have made the mountains much younger than previously thought.

The society asked a team of more than a dozen distinguished Indian scientists to investigate Azmi's claim. The team reports in the June issue of the GSI journal (vol. 55, p. 675) “that the identification of fossils by R. J. Azmi is far from convincing, and that more detailed work [would be] necessary before the authenticity of the find is accepted.” The report says that the presence of small, shelly fossils could not be confirmed either by its own team or by a panel assembled by the Geological Survey of India, whose members visited the site and collected samples that were “devoid of SSFs.”

Shashi Bhushan Bhatia, a micropaleontologist and former professor at Panjab University in Chandigarh, led the GSI panel that investigated Azmi's findings and physically examined Azmi's fossils. He says that Azmi turned aside specific questions from the panel and “came up with new data” each time he was quizzed.

However, Azmi says that the two investigations “confirm the reproducibility of morphologically similar forms” and that he stands by his original finding. The controversy, he adds, is a “nonissue and an unfortunate fallout” resulting from “nonexperts [who] have poked their noses into a highly specialized field.” He says the debate has fallen into the “realm of subjectivity” but that “there is no question of any contamination or misrepresentation” of the samples.

The geological society has no plans to publish anything more on the matter nor take any action against Azmi. “It will not serve any useful purpose to prolong this debate,” says the journal's editor, M. Ramakrishnan, adding that “no further correspondence will be entertained.” Azmi has protested the policy, however, and asked for an international panel of experts on small, shelly fossils to take another peek at his original sample.

8. NEUROSCIENCE

# Synapses Shout to Overcome Distance

1. Laura Helmuth

How do you make yourself heard if you are standing far from the fray? If you are a synapse, like a human, you shout. So says new research published in the September issue of Nature Neuroscience, answering a question that has perplexed neuroscientists for decades: namely, how a message delivered at a synapse far from the cell body—which must fade as it travels through the cell—can make itself heard above the din of messages picked up by close-in synapses.

Neurons receive signals sent by other neurons via long tendrils called dendrites that branch out from the neuronal cell body. The neuron fires, passing along its own message, only after the cell body receives and sums up some threshold level of dendrite-transmitted messages. Recent evidence has suggested that hinterland synapses do pick up useful signals, but no one knew quite how.

Suspecting that distant synapses might speak with louder voices, neuroscientists Jeffrey Magee of Louisiana State University Medical Center in New Orleans and Erik Cook of Baylor College of Medicine in Houston, Texas, stimulated synapses locally and listened in as they fired. When this happens, the resulting signal is transmitted to the cell body by an electric current generated as ions surge in and out of the cell across its outer membrane. When the researchers measured this current, they found that the more distant the synapses, the stronger the signal. By the time the signals reached the cell body, those that traveled long distances sounded about as loud as those that originated nearby.

The finding “will open up a whole new field,” says Daniel Johnston of Baylor College of Medicine, who adds that neuroscientists will want to know “How does the cell know [to build more powerful synapses at a distance]? And how does [the current gradient] develop?”

Magee says that many potential mechanisms could contribute to stronger signals from distant synapses. One possibility is that neighboring cells send more units of their chemical neurotransmitters when they communicate with farther-out synapses, although it's unclear how the neurons might be trained to do this. Alternatively, within the receiving dendrite, distant synapses may be literally bigger, studded with more of the receptors that detect incoming messages. Magee hopes to tease these possibilities apart, starting by using an electron micrograph to see whether far-flung synapses stretch out over a larger area than those close to the cell body.

9. ECONOMICS

# Does Science Drive the Productivity Train?

1. David Malakoff

From the president on down, many are hailing science as the fuel for today's booming economy, and bigger research budgets are seen as essential to continued prosperity. But how strong is the evidence?

When President Bill Clinton unveiled a plan early this year to take the first step toward doubling the National Science Foundation's (NSF's) budget, his pitch rested on the promise of prosperity. Spending more on everything from biology to nanotechnology, he argued in a January speech, would help extend an unprecedented U.S. economic boom—a boom that was fueled by discoveries made decades ago in government-funded labs. In particular, Clinton spotlighted the economic contributions of taxpayer-funded information technologies (IT), such as supercomputers and the Internet, which he said are now “responsible for about 30% of our economic growth.”

The statistic thrilled science supporters in the friendly crowd at the California Institute of Technology in Pasadena. For years, everyone from university presidents to science society lobbyists has been arguing that more government spending on a broad range of research could produce economic miracles. But the hard numbers needed to convince lawmakers proved scarce.

Now science advocates are awash in attention-grabbing statistics. This month, for instance, the Labor Department reported that productivity—worker output per hour —grew at 5.3% in the year prior to June, a 17-year high. And several recent studies conclude that up to 80% of the productivity jump is due to the “IT revolution.” Even Alan Greenspan, the powerful head of the U.S. banking system, says past science investments that led to computers are paying off. “The U.S. is confronting what can best be described as another industrial revolution,” he has told audiences.

Prominent science advocates—including NSF chief Rita Colwell and Democratic vice presidential nominee Joe Lieberman—have seized upon such statements to advance their agendas. And science lobbyists are holding up the computing-inspired economic boom as an example of how government investments in other areas, such as biology, could yield similar gold (see sidebar). But some economists are challenging the credibility of the statistics. One prominent skeptic, economist Robert Gordon of Northwestern University in Evanston, Illinois, says the IT revolution is overrated—a minor uprising compared to the truly society-shaking innovations of the past, such as electricity. Other economists are leery of efforts to isolate the exact percentage of economic growth that can be credited to new technologies, saying the data and models are weak.

Even some science lobbyists worry that hitching basic research's star too closely to economic arguments could backfire, prompting legislators to take a firmer hand in guiding cash toward less risky projects that they believe will pay off big. “For years, we've been saying that science is important to the economy, but everybody took it with a grain of salt,” says Al Teich, head of the public policy program at the American Association for the Advancement of Science (AAAS, publisher of Science) in Washington, D.C. “Now people are starting to believe us, and it's a little scary.”

## Pins and productivity

The current debate over the economic impact of science and technology isn't new. In the late 1700s, economics pioneer Adam Smith observed in his seminal treatise, The Wealth of Nations, that new inventions had helped English pin factory workers produce nearly 5000 pins per day, many times what could be done by hand. Today, according to economists, that total has risen to 800,000 pins per day. But economists disagree over how much of such productivity gains should be credited to new technologies and how much to other factors, such as better trained workers.

The most influential answer came in 1957, when economist Robert Solow of the Massachusetts Institute of Technology published a formula for breaking down the causes of productivity gains into several categories. They included various forms of capital investment and a so-called “residual,” which he dubbed “technical change.” The paper, which helped Solow win a Nobel Prize in 1987, “was a shot heard ‘round the world. It transformed the study of technical change into something more than an obscure sideshow,” says economist Frederic M. Scherer of Harvard University. It also began an arms race of predictions. A new generation of growth accountants, for instance, used Solow's equations to estimate that up to half of all past economic growth could be attributed to the introduction of new technologies, from electricity and the internal combustion engine in the late 19th century to radio and modern chemistry in the early 20th.

In the 1980s, however, growth accountants grew perplexed when they tried to measure the impact that computers were having on productivity: It wasn't there. In a famous 1987 quip, Solow characterized the puzzle—which came to be known as Solow's Paradox—this way: “The computer age is everywhere, except in the productivity statistics.”

That changed in 1996, however, when U.S. productivity in nonfarm businesses shot up by a percentage point, to more than 2.5% per year, a huge increase (see chart). Among those who tried to explain the boom were Stephen Oliner and Daniel Sichel of the Federal Reserve Board in Washington, D.C., which steers U.S. monetary policy. In a 1994 study, the pair had used government labor data to argue that Solow's paradox was no paradox at all. “There was no puzzle, just unrealistic explanations,” they recall in a recent paper (federalreserve.gov/pubs/feds). Computers did not contribute much to growth in the early 1990s, they say, because they were still a relatively small part of the machinery purchased by U.S. businesses. By 1995, however, computers and related communications equipment had reached critical mass, “boosting their contribution to growth.” Overall, Oliner and Sichel attribute about two-thirds of the one-point increase in annual productivity growth over the past 5 years to the manufacture and use of new IT equipment. “Information technology largely is the story,” they conclude.

Their interpretation has attracted both supporters and detractors. “It's a very serious effort,” says Solow. And Roger Ferguson, vice chair of the Federal Reserve Board, has cited this study as “evidence that fundamental changes are under way in our economy.”

But even those economists who agree that computers are boosting productivity quibble over how much. Karl Whelan, another Fed economist, attributes nearly 80% of recent productivity gains to computerization. But Dale Jorgenson of Harvard and Kevin Stiroh of the Brookings Institution, a think tank in Washington, D.C., are stingier. In a forthcoming article in Brookings Papers on Economic Growth, they give computers credit for just about half of the productivity increase since 1995.

## Not-so-new economy

Others, however, doubt that computers are having such major impacts and attribute the productivity rise to other factors, from the ordinary dip and fall of the business cycle to changes in the way the government collects labor statistics. In a discussion paper published last July, for instance, the Federal Reserve Board's Richard Kiley concluded that companies are still having trouble integrating new computers into their businesses. These “adjustment costs” have pulled productivity down by about a quarter-point a year since 1995, he figures, and the trend won't reverse until firms fully digest the new technology.

Perhaps the strongest attack comes from Northwestern's Gordon. In a widely cited critique (faculty-web.at.northwestern.edu/economics/gordon) soon to appear in the Journal of Economic Perspectives, Gordon assails the claims that computers and the Internet represent an industrial revolution equal to that which produced the “golden age” of 1913 to 1972, when U.S. productivity rose at more than 3% per year. In particular, Gordon argues that computer-driven productivity gains—while significant—are confined to a handful of industries, such as computer manufacture and telecommunications, that constitute just 12% of the nonfarm economy. “There is no revival of productivity growth in the 88% of the private economy lying outside” those industries, he writes. Economists have mistaken a short-term uptick in the business cycle for a longer term rise in productivity, he asserts.

Solow, for one, says that Gordon's idea that the business cycle is inflating computing's contribution to productivity is “worth thinking about. Making corrections for [the cycle] is very difficult.”

The debate is unlikely to be settled anytime soon. “The game of growth accounting is very much like trying to explain how much of a cake's good taste is due to the sugar and how much to the cream,” says Richard Nelson, an economist at Columbia University in New York City. “There are enormous measurement problems” that muddle growth analyses, adds Steven Payson, an economist with the NSF and author of Economics, Science and Technology (Elgar Publishing, 2000). Government statistics, for instance, often misclassify spending or obscure a company's real operations. And mathematical models typically lag behind what's happening in the real world.

To aid policy debates, “economists can, and should, do much better,” Payson says. For one, he'd like to see them use measures that more accurately reflect a new technology's capabilities. Computers, for instance, could be measured in terms of calculations per second. In the meantime, Payson says, “people need to be very cautious about how they use” the productivity statistics in making the case for greater R&D investments.

## Political economics

But science advocates aren't waiting for any fine-tuning. Lobbyists from virtually every discipline—from physics to biomedicine—argue that, given the potential rewards of boosting public investment in fundamental research, their field is vastly underfunded. “We even cite the statistics to support our call for greater investment in science education,” says David Schutt, a lead lobbyist for the American Chemical Society in Washington, D.C. “Are they our whole story? Certainly not. But it doesn't hurt” in making the pitch for improving education.

Greenspan's vocal recognition of technology's role in the boom has also lent credibility to the science community's economic case, says Kathleen Kingscott, a science policy specialist in IBM's Washington office. “What he is saying has changed the debate,” she says. “It's no longer: ‘Should government invest in science?,’ but ‘How much can we do?’” The changing mood has also pushed leading politicians from both parties—not just Lieberman but also Senate Majority Leader Trent Lott (R-MS) —to highlight science's economic impact in their policy statements. Under Lieberman's leadership, for instance, the centrist New Democrats last month released a legislative blueprint that calls for major spending increases for basic research. “Science and technology form the core of a new economic policy paradigm,” says Rob Atkinson of the Progressive Policy Institute in Washington, D.C., which organized the exercise. Still, Atkinson thinks it may be a while before lawmakers from other camps sign on. “We have a long, uphill fight to make it clear that science policy is economic policy,” he says.

Pick a number.

Economists differ over information technology's impact on overall productivity.

View this table:

Although most economists might not go that far, there is a broad consensus among them that more R&D investment wouldn't hurt—even if the numbers are debatable. But that general agreement doesn't necessary help lawmakers, who still face tough decisions, says AAAS's Teich. “Policy-makers are presented with the same dilemmas as before,” he says. “Productivity statistics don't tell you the right amount to put into different areas of research.” The result, he worries, is that science funding “could become even more political,” as lawmakers vie to steer dollars into their districts. Solow sums up the problem another way: “There is no way that anybody can tell you what an extra billion dollars added to NSF's budget will get you in terms of productivity.”

Still, science lobbyists are hoping that economic arguments will pay off in hard cash, starting next month when Congress returns to finish work on the 2001 budget. And they are counting on the economic boom—which is expected to produce record budget surpluses —to tilt the negotiating table in their favor.

But it's not clear if they'll be able to use the boom to their advantage in the future. Solow, for instance, “is not prepared to bet any part of the farm” that the economic surge will continue. And some science lobbyists don't relish the prospect of trying to argue that science is good for the economy during a downturn. That, says Schutt, “is an experiment I don't want to run.”

10. ECONOMICS

# 'To Your Health' Is More Than a Toast to Economists

1. David Malakoff

The debate over the role of innovation in the country's current economic boom has focused mainly on information technology (IT), a fast-growing and seemingly ubiquitous part of today's society. But there's another pervasive activity that's become a battleground for economists and policy analysts: biomedical research. Here, even the terms of measurement are debated. Whereas growth accountants use standard monetary measures of return on investment to estimate IT's impact on productivity, those who study the country's $45 billion annual investment in biomedicine tend to talk instead about “the social rate of return.” In health, they argue, the coin of the realm is having a longer, more comfortable life. Two reports released last May conclude that this return is huge—in some cases, more than$20 for every dollar invested. One even claims that “medical research surpasses every other source of rising living standards in our time.” But some economists question the usefulness of such studies. The dozens of rate-of-return studies completed over the last 40 years have “questionable validity,” says economist Steven Payson, an academic currently working at the National Science Foundation. Not only have the results varied wildly, he says, but none provides data on what policy-makers really want to know: Will extra spending produce substantially greater results? “The question is whether the second billion buys you as much as the first one did,” says Payson.

One of the new studies—Exceptional Returns, from Funding First, an initiative of the Mary Woodard Lasker Charitable Trust in New York City (laskerfoundation.org)—concedes that translating biomedical research benefits into dollars and cents is “difficult.” But in a series of papers, the nine authors, all economists, make the case that the healthier, longer lives made possible by modern medical treatments are worth trillions of dollars to the economy. Kevin Murphy and Robert Topel of the University of Chicago, for instance, estimate that the few extra years of life the average American gained between 1970 and 1990 added $57 trillion to U.S. coffers. By their reckoning, extending life during prime working years (ages 35 to 44) was worth up to$171,000 per year for a man and $120,000 for a woman. There's a problem with these raw numbers, however: They may also reflect benefits from such low-tech factors as better nutrition, more exercise, or safer workplaces. In an attempt to isolate the contribution of biomedical research, David Cutler of Harvard University and Srikanth Kadiyala of the National Bureau of Economic Research in Washington, D.C., looked at one major area—efforts to reduce premature deaths from heart disease. They concluded that about one-third of the fall in mortality rates over 40 years, from 400 to 200 per 100,000, could be credited to new technologies and drugs. The new technologies, such as ventilators that help victims survive the critical first few hours after a heart attack or stroke, accounted for at least 20% of the reduction, they argue. Another 13% of the drop was linked to new drugs that reduce the risk of problems by lowering blood pressure or cholesterol. Using Murphy and Topel's numbers, the report concludes that better treatments were worth about$500 billion per year between 1970 and 1990—a figure that is about 20 times greater than the country's annual spending on medical research during that period. “By any benchmark,” the report concludes, it was “an astonishing return for the investment.”

The other report, issued by the Senate's Joint Economic Committee (www.senate.gov/∼jec), cites similar gains in arguing for a bigger National Institutes of Health budget. In general, it notes, taxpayer-funded research “generates high rates of return to the economy, averaging 25% to 40% a year.”

These high average numbers mask the fact that individual estimates vary wildly from one area of science to another, Payson notes in his recent book, Economics, Science and Technology. “When one study comes up with a 0% return, and the other with a 100% return, it is surely unscientific to conclude that the return is somewhere around 50%,” he says. That variability also poses a problem for legislators trying to decide which areas should receive scarce federal dollars. Given those limitations, as Payson writes, claims of a 20-fold payoff for research investments deserve “greater scrutiny.”

11. PRIMATOLOGY

# Human Diseases Threaten Great Apes

1. Dan Ferber*
1. Dan Ferber is a writer in Urbana, Illinois.

Researchers are uncovering disturbing evidence that scientists and tourists are infecting wild primates with human pathogens

High in the misty mountains of Rwanda, hundreds of international tourists flock each year to view the endangered mountain gorilla. The visitors come not only to admire these animals but also to support their protection. But the tourists' presence, as well as that of the scientists who study the gorillas, puts the animals at risk.

In 1988, the animals were sneezing, coughing—and dropping like flies. At first, nobody knew the cause, but then blood and tissue samples from one gorilla showed telltale signs of measles infection. No one ever identified the source of that outbreak, which killed six animals and sickened 27 more. Nor did anyone isolate human measles virus from any gorilla. But “from all outward signs, it appeared to be measles, and it was most probably of human origin,” says Annette Lanjouw, director of the International Gorilla Conservation Program in Nairobi, Kenya. Because the loss of a single population could have been catastrophic to the species, the veterinarians who monitored the animals suspended their usual hands-off policy and gave the remaining 65 healthy gorillas in that social group a measles vaccine to ward off the disease. The epidemic stopped as suddenly as it had started.

That outbreak seemed like an isolated occurrence, but looking back, experts see it as an early sign of an emerging threat. Just as deadly viruses like Ebola and HIV have jumped from primates to people, increasing evidence suggests that human diseases have infected wild primates, perhaps with fatal consequences. As primate populations dwindle and people press ever closer to the animals' forest homes, experts say that the threat of human disease is rising—particularly to populations, such as the Rwandan mountain gorillas, that have become accustomed to people.

“We're just starting to appreciate … how devastating pathogen transmission could really be,” says primatologist Randy Kyes of the University of Washington, Seattle. In response, ape specialists, including the American Society of Primatologists, are now calling for stricter health standards for researchers and tourists. They are also urging researchers to learn how to diagnose disease in their study animals.

These efforts may provide a crucial safeguard as wildlife veterinarians and epidemiologists work to determine the extent of the problem. Although anecdotal accounts abound about recent outbreaks, so far, hard data are lacking to finger human exposure as the true culprit. Even so, “there's emerging evidence that there is an impact,” says veterinarian and epidemiologist Jonathan Sleeman, former director of the Mountain Gorilla Veterinary Center in Rwanda. Studies have documented that infections do occur, as antibodies to human diseases such as influenza, measles, and tuberculosis have been detected in some wild macaques and orangutans. Also, gorillas and chimps that live close to humans have more parasites than animals in remote areas.

For example, last year in the International Journal of Primatology, Janette Wallis of Oklahoma University Health Sciences Center in Oklahoma City and D. Rick Lee of the M. D. Anderson Cancer Center in Houston described more than a dozen outbreaks of what may have been human diseases in gorillas, chimpanzees, baboons, and monkeys from five different field sites. Several of the outbreaks had never before been reported. The animals had come down with a diverse range of diseases, including measles, polio, and scabies, Wallis says.

During one outbreak in 1996, 11 chimpanzees, including a mother and her twin infants, succumbed to respiratory infections at Gombe National Park in Tanzania. The chimps were all members of a group that were handed food every day by a field worker in an effort to habituate them. When the rains came that spring, many of the workers contracted colds or flu, which can kill a chimpanzee. Wallis, who coordinated chimpanzee field research at Gombe from 1989 to 1994, speculates that sick workers may have infected the chimps.

Studies at other sites show a similar trend. Parasitologist Thaddeus Graczyk of Johns Hopkins School of Public Health, John Bosco Nizeyi of Makerere University in Kampala, Uganda, and their colleagues have found that the number of mountain gorillas in the Bwindi Impenetrable National Park carrying the common human gut bacteria Salmonella or Campylobacter has doubled in the past decade. This team already reported last year in the Journal of Parasitology that the protozoan Cryptosporidium and the roundworm liver parasite Capillaria hepatica, which infects humans and is spread via contaminated water, were widespread in the feces of mountain gorillas that have frequent contact with tourists. And in unpublished work from Gombe National Park, Felicia Nutter and Chris Whittier of North Carolina State University in Raleigh have shown that fecal samples from a chimpanzee group at Gombe that kept their distance from humans had just six species of parasites, whereas samples from a habituated group had 13 species.

Researchers don't really know, however, whether animals typically carry these parasites. “We're missing what's normal,” says wildlife veterinarian Billy Karesh of the Wildlife Conservation Society in the Bronx, New York. A growing number of researchers are trying to collect those baseline data. Primatologists Alecia Lilly and Patrick Mehlman of the State University of New York, Stony Brook, for example, are comparing parasite levels in fecal samples from wild western lowland gorillas in remote areas of central African forest with those near human settlements. On the other side of the world in Saba, Malaysia, a team led by Annelisa Kilbourn of the Shedd Aquarium in Chicago has assessed pathogen and parasite levels in orangutans from pristine forests.

At the same time, primatologists are urging field workers and ecotourists to adopt the strict precautions already in place in primate centers. Workers at U.S. zoos and primate facilities don masks and gloves to handle the animals and must also undergo vaccinations, parasite screens, and annual tuberculosis tests. But some field sites have been slow to adopt similar measures. “It's easier for me to go up within 5 meters of one of the rarest animals in the world [mountain gorillas] with no health restrictions than it is for me to travel to Cincinnati or UC [the University of California] Davis and go behind the scenes in their primate house,” says Michael Cranfield, director of the Mountain Gorilla Veterinary Project.

In an effort to change that, Wallis led a working group at an international conference of ape researchers and zookeepers last May to discuss improved monitoring of primate diseases and better health care for people living near primate reserves. In July, the American Society of Primatologists asked its members to tighten safety standards, further underscoring the urgency of these issues. And that same month, a team of field researchers and wildlife veterinarians held a workshop in Africa to teach field workers how to recognize signs of illness in chimps, take samples, and conduct a necropsy—all of which will help them diagnose sick animals and catch outbreaks early. For Wallis, who has witnessed several outbreaks at Gombe, these efforts can't come a moment too soon. Says Wallis, “I just want to know we've done what we can.”

12. AIDS RESEARCH

# The Odd Intersection of HIV and Scrub Typhus

1. Jon Cohen

Can contracting another disease help suppress HIV? Researchers report intriguing new findings

Sometimes the most intriguing ideas come out of left field. Take the peculiar discovery in a new study from Thailand suggesting that a disease called scrub typhus may offer novel leads to developing anti-HIV treatments and vaccines.

Typically, when HIV-infected people become infected with other pathogens, the level of the AIDS virus in their blood skyrockets. But in the 5 August issue of The Lancet, researchers report that AIDS patients infected with the bacillus that causes scrub typhus—a mite-borne disease that produces fever but usually isn't fatal—have precisely the opposite reaction: Their HIV levels plummet. “It's very intriguing,” says Peggy Johnston, head of the AIDS vaccine branch at the U.S. National Institute of Allergy and Infectious Diseases (NIAID). “It's clear that there's something interesting going on here, and it does appear to be some kind of suppressive factor.”

The idea for the study began 2 years ago, when George Watt, a tropical disease specialist at the United States Armed Forces Research Institute of Medical Sciences in Bangkok, became intrigued by one HIV-infected patient who developed scrub typhus. Caused by Orientia tsutsugamushi (formerly Rickettsia), scrub typhus is transmitted by chiggers that fall off rodents and then live in the scrub bush. Surprised that this one patient's HIV level—or “viral load”—dropped coincident with an acute case of scrub typhus, Watt, Pacharee Kantipong of Chiangrai Regional Hospital, and their colleagues began systematically hunting for HIV-infected people who also had acute cases of scrub typhus.

As the researchers report in The Lancet, their massive, yearlong screening program in Thailand uncovered 10 people who clearly had both infections and no others. First, the Thai team compared viral loads in these patients to a control group of five HIV-infected people who did not have scrub typhus but did have either malaria or leptospirosis. Over the 28-day study, the investigators found that the patients with scrub typhus had significantly lower HIV viral loads than those with the other diseases. In two of these people, in fact, the levels fell so low that the most sensitive tests could not detect HIV. In another curious twist, the scrub typhus patients happened to have more damaged immune systems, with an average of only 117 CD4 white blood cells, as opposed to an average of 255 CD4s in the control group. (By definition, an HIV-infected person has AIDS when CD4 counts drop below 200.) The new findings are “an absolutely fascinating example of how one infection ameliorates the effect of another,” says Sanjeev Krishna, a malaria specialist at St. George's Hospital Medical School in London and an author of the paper.

More evidence that scrub typhus somehow suppresses HIV came from a second experiment, a comparison of viral variants in the same 10 scrub typhus patients and another control group whose CD4 counts were more closely matched. As HIV disease progresses, several researchers have shown that the virus typically evolves to a form more adept at destroying immune system cells. Specifically, once these nastier HIV variants infect cells, they can readily fuse with other cells to form clumps called “syncytia,” an efficient means of transmitting the virus and speeding the course of disease. None of the 10 patients with scrub typhus had a syncytia-inducing HIV variant, whereas five of the seven controls did.

Watt and his co-workers attempted to tease out how O. tsutsugamushi might thwart HIV. Preliminary data in both mouse and test tube experiments with human sera point to antibodies against scrub, which for some unknown reason seem also to bind HIV. “This is an opportunity to examine very seriously what scrub typhus is telling us about HIV,” says Krishna, who suspects that these new insights might provide clues for developing both AIDS treatments and vaccines.

NIAID's Johnston particularly enjoys the oddity of the finding. “I like surprises,” she says. “It keeps us thinking.”

13. AGROBIOTECHNOLOGY

# Asia Gets a Taste of Genetic Food Fights

1. Dennis Normile
1. With reporting by Pallava Bagla in New Delhi and Los Baños and Li Hui in Beijing.

Despite the need to feed growing populations in Asia, controversy over GM foods is putting a damper on efforts to develop and test new crops

LOS BAÑOS, THE PHILIPPINES The debate over genetically modified (GM) crops has come to Asia. It hasn't yet reached the intensity of the clash in Europe. But opposition in the Philippines has delayed field trials, Indian farmers have ripped up fields of genetically altered cotton, and Japanese consumers are not buying GM foods, damping the country's interest in the technology. Suddenly, a region that had been banking on GM crops to feed growing populations is facing an uphill battle to implement the technology.

The signs of opposition are scattered and vary from country to country. But they are enough to be worrisome to the region's leaders. “It is very disturbing that here we have a technology and its deployment is being delayed by green groups,” says Gurdev Khush, chief plant breeder for the International Rice Research Institute (IRRI) in Los Baños. “The delay will eventually hurt Asia.”

If Asia does back away from GM crops, it would be an ironic reversal of the region's history of embracing agricultural advances. Beginning 3 decades ago, Asian farmers rapidly adopted new rice varieties improved through classical breeding techniques, even though this involved altering their traditional farming methods. The result was a near doubling of Asian rice production in the 1970s and 1980s that headed off catastrophic food shortages.

But production gains have leveled off even as populations in developing Asia continue to grow. In the Philippines and Pakistan, for example, the annual growth rate is 2.3% and 2.8%, respectively. The direct manipulation of genes is seen as a key to boosting yields to provide the necessary food. “Asia needs to use every tool available to produce food for these growing populations,” Khush says.

Asia has in fact been a fervent believer in GM technology. Virtually every country in the region with any national research program has funded work on GM crops. Take China, which has set up several national labs specifically for the effort. By one count, researchers there have applied GM techniques to 47 plant species, using 103 different genes. Six plants are under commercial production, all but one developed within the country. Although China may have gone farther and faster than any other Asian country, Thailand, India, and the Philippines are following close behind.

Still, these same governments are at pains to demonstrate that they are protecting the citizenry. Their vigilance also provides an opportunity to stand up to international companies, a popular target.

Customs officials in China, for example, recently seized a shipment of a GM rapeseed variety not yet approved in the country. And India's biosafety protocol mandates a cost-benefit analysis of GM crops. This was done, says Rameshwar Prasad Sharma, a member of the Department of Biotechnology field trial review committee and a professor emeritus at the National Center on Plant Biotechnology in New Delhi, to hold down seed costs, “so that the interests of small and marginal farmers can be taken care of.”

But outright opposition to growing and consuming GM foods has emerged as an unexpected hurdle. In some cases, the opposition comes from outside Asia. For example, the Union of European Community Rice Millers Associations has warned the Thai Rice Exporters Association that Thai rice will not be welcome in the European Union if there are any traces of genetic modification.

## Homegrown opponents

But the bigger impact on the adoption of GM technology is coming from within Asia itself. There has been no organized opposition to GM crops or foodstuffs in China, thanks in part to the country's controlled press, which has paid scant heed to the controversies erupting in other parts of the world. In Indonesia, too, recent trials of so-called Bt corn, which carries a bacterial gene that makes it resistant to insect pests, went off without any significant opposition.

Other countries have not been so lucky. In November 1998, activists and farmers in the southern Indian state of Andhra Pradesh uprooted and burned Bt cotton planted in two small field trials by Maharashtra Hybrid Seed Co. (MAHYCO), a Monsanto affiliate. At the time, farmers' fears were centered on the possible introduction of the terminator gene, which renders second-generation seeds sterile, ensuring that farmers must buy new seed each year. Monsanto later pledged not to use the terminator gene in its products.

Meanwhile, MAHYCO persevered with preliminary trials. In June it won government approval for large-scale field trials of Bt cotton, the first transgenic crop to proceed this far in India. The approval is conditional on obtaining independent Indian laboratory certification that the plant does not contain the terminator gene, but even so, Vandana Shiva, director of the Research Foundation for Science, Technology, and Ecology in New Delhi and an ardent critic of GM technology, filed suit in India's Supreme Court seeking a halt to the trials.

She contends that the first-stage controlled trials and the required clearances were rushed through and that data supporting the safety have been simply “cooked up and fabricated.” The Supreme Court is scheduled to hear arguments next month. A ruling could take several months, however, and may come well after MAHYCO harvests the cotton, which is due for planting shortly. Regardless of the court ruling, Shiva vows to keep the debate at the top of the national agenda.

The Philippines has had an even harder time with trials. Last year, Pioneer Hi-Bred Philippines, the local affiliate of DuPont's Pioneer Hi-Bred International, and Agroseed, a Monsanto subsidiary, each won national approval for trials of Bt corn. They were planned for Bay, a town near Manila, and for General Santos City, on the southern island of Mindanao. However, the Bay town council subsequently voted to ban GM field trials.

Paul Teng, Monsanto's Asia-Pacific director of agricultural technology, says that for logistical reasons Agroseed had already decided to do only the General Santos trial anyway. But after it had begun, the General Santos council also adopted a moratorium on GM crop cultivation. A court suit seeking to have the crop destroyed was thrown out on a legal technicality, and Agroseed harvested the crop last spring.

View this table:

The Pioneer trials never got under way. The company initially delayed them until the rainy season, when the corn borer the Bt resists is more of a problem, and now, a Pioneer spokesperson says, they are on hold because of the local bans. Julieta Estacio, an official with the National Committee on Biosafety, says that such local laws would probably not hold up to court challenges.

Meanwhile, a bigger threat, a bill to ban GM crops nationally that was introduced last year by Philippine Senator Gregorio Honasan, has been staved off. Scientists and officials from both the public and private sectors mounted a lobbying and education effort that has apparently killed any chance of the bill emerging from committee.

## A way forward?

Officials are cautiously optimistic that other regions will be more welcoming. Even so, IRRI is treading carefully. Its first planned transgenic trials involve a rice variety with a gene transferred from a different rice variety instead of from a foreign organism. William Padolina, IRRI's director of community relations, says they hope this will prove more acceptable to officials and the public in Los Baños, where the trial will be held.

Monsanto is even more optimistic. Its Agroseed subsidiary is now planning the next step toward approval for commercial use of Bt corn, which involves field trials in 18 locations. Teng agrees on the need for local support. “We don't want to go into an area that doesn't want this trial,” he says, adding that they plan “a major effort” in educating officials and citizens. But he believes the tide of public opinion has turned, thanks in part to the General Santos trial, where farmers, citizen groups, and the press could all observe the crop in the field, the harvest, and the postharvest destruction of remaining organic material.

Teng's assessment is not shared by groups opposed to GM organisms, however, who see a hardening of attitudes. “When people become aware of the [GM] issue, they become very concerned,” says Roberto Verzola, executive director of Philippine Greens, a Manila-based environmental group.

Indeed, the power of the consumer becomes most evident in Japan, the region's most technologically advanced nation, where early and well-funded research efforts have put a gardenful of transgenic plants into the development pipeline. But only one—a blue carnation—has proceeded to commercial cultivation.

Researchers and industry officials point to a simple reason: “There is extreme consumer resistance” to GM foods, says Go Kawamura, a director of Takano Foods Corp. Takano already uses only certified non-GM soybeans for its products and, like virtually all makers, puts that fact in bold characters on package labels.

That policy is in line with the results of a survey conducted last year by the government-affiliated Agriculture, Forestry, and Fisheries Finance Corp., which found that among 600 respondents, 80% were reluctant to buy GM foods. A labeling law that takes effect next April already has food processors substituting non-GM ingredients in products to avoid the stigma of a GM label.

Consumer preferences will inevitably affect the direction of research. “Without consumer acceptance, private companies will lose interest in developing GM plants,” says Takeshi Yoshida, director of the Innovative Technology Division of Japan's Ministry of Agriculture, Forestry, and Fisheries. “Eventually, that would influence the national institutes as well.”

A decline in research activity in Japan would reverberate through the region, particularly because Japan has been an important source of research collaborations and technical exchanges. Officials hope a new generation of GM plants that are better tasting, more nutritious, and remain fresh longer will have more consumer appeal. “Until now, GM technology only promised benefits for farmers,” says Naoki Katsura, director-general of Japan's National Institute of Agrobiological Resources in Tsukuba. “We hope consumers will realize the next generation of GM foods will have benefits for them as well.”

14. ECOLOGY

# Rift Over Biodiversity Divides Ecologists

1. Jocelyn Kaiser

An acrimonious dispute has broken out over whether the data on biodiversity are robust enough to inform public policy

A long-simmering debate among ecologists over the importance of biodiversity to the health of ecosystems has erupted into a full-blown war. Opposing camps are dueling over the quality of key experiments, and some are flinging barbs at meetings and in journals.

The dispute pits an outspoken group of ecologists against some of the leading lights in the field. In one camp are ecologists such as David Tilman of the University of Minnesota, St. Paul, and John Lawton of Imperial College at Silwood Park, U.K., who have devoted their careers to large and costly experiments that have indicated that healthy ecosystems depend on diversity. Some ecologists have long questioned the validity of these experiments, but what had been a relatively low-key dispute ignited last fall when the Ecological Society of America (ESA) distributed a pamphlet to Congress and federal agencies touting the importance of biodiversity—and citing the research in question.

Critics—including ecologists Michael Huston of Oak Ridge National Laboratory in Tennessee, Phil Grime of the University of Sheffield, U.K., and David Wardle of Landcare Research, an independent research institute in New Zealand—fired off a letter to the ESA's Bulletin, alleging that Tilman, Lawton, and colleagues are using inconclusive research to push their policy agenda. Some of these same scientists also take issue with a recent experiment this week in a Science Online Technical Comment (see www.sciencemag.org/cgi/content/full/289/5483/1255a). Huston calls the diversity studies “irrelevant” and “politically manipulated.” The critics even go so far as to allege bias at the major journals, which they say favor the more “politically correct” research plugging the value of biodiversity. “The results of these studies provide just the answers that many environmentalists want to hear,” says Wardle.

Tilman calls such charges completely “off base.” Although he and others acknowledge that the experiments have limitations, they argue that the evidence is still convincing.

Other ecologists safely outside the fray say there is more at stake in this dispute than personalities and egos. Beyond the legitimate scientific question about how much can be learned from the experiments is the nagging question—by no means limited to biodiversity—of when scientific data are strong enough to form the basis of policy decisions. “There's a lot of unease” about how this research is being used, says ecologist Daniel Simberloff of the University of Tennessee, Knoxville. Even so, others defend its merits. “Scientific criticism is good, but rather than trash these experiments, we need to say, ‘What do we need to do to learn more?’” says ecologist David Hooper of Western Washington University in Bellingham.

## Strength in numbers?

At the heart of the debate is the notion that the loss of plant or animal species will bring an ecosystem closer to collapse. Ecologists have long pondered how species contribute to ecosystem stability; in the early 1970s theoretician Robert May concluded that diversity has no consistent effect. Just 6 years ago, experimental evidence indicated the opposite.

One study, the Ecotron experiment, investigated what happens to plots of plants as more species are added. As reported in Nature in 1994, Shahid Naeem and others on Lawton's team at Silwood Park planted various plants in enclosed chambers, added insects and worms, and measured how biomass—simply the leaves, roots, and other organic matter produced by plants—changed with the number of species. To the surprise of much of the ecological community, they found that the more species there were, the more biomass the plot yielded—hence, the more productive the ecosystem was.

That same year, Tilman's group at the University of Minnesota published in Nature results from their grassland plots at Cedar Creek, 65 kilometers north of Minneapolis, showing that species-rich plots were more resistant to drought than were species-poor ones. The upshot, Tilman and other ecologists concluded, was that the more species the better, in terms of buffering ecosystems against disruptions.

But the studies soon came under heavy attack. Scientists including Huston and Grime charged in letters to Nature and in subsequent papers that the experiments were flawed: Variables other than species number could explain the rise in productivity, they argued. For example, the Ecotron team planted taller plants in more species-rich plots than in the sparser plots, which made the diverse patches more productive. Even experiments such as those at Cedar Creek that added species randomly suffered from a “statistical artifact,” critics claimed: The higher productivity seen with more species could be explained by simply adding a few highly productive species to the mix, a phenomenon known as the “sampling effect.” To show a real benefit from diversity, these ecologists argued, the plots would have to demonstrate “overyielding”—put simply, productivity would have to be greater than that of the single most productive species grown in isolation (see sidebar).

The BIODEPTH experiment was supposed to resolve these problems. “We were partly prompted by criticism of earlier work that didn't separate [the effects of] biodiversity from other processes,” says Andy Hector of Imperial College at Silwood Park, a protégé of Lawton and lead author on this massive study, which involved 34 authors in eight European countries. The 2-year experiment, reported in Science last year, found that in plots of up to 32 species, productivity rose in step with diversity (Science, 5 November 1999, p. 1123). Moreover, in many plots, the researchers saw the much-desired overyielding. In a Perspective accompanying the piece, Tilman, who was not an author on the study, called it a “landmark.”

But rather than resolve the debate, BIODEPTH added more fuel to the fire. In this week's Technical Comment, Huston, Grime, and 10 other critics argue that the BIODEPTH experiment also suffers from technical problems. On closer inspection, they say, the sampling effect does explain most of the productivity gain. The critics attribute the few cases of overyielding that the study authors report to an obvious explanation—addition of a legume. That “is a well-known phenomenon, and it occurs at very low species numbers,” Huston says. “There's no evidence from this experiment that 200 species is any better than 50 species.” Hector agrees that BIODEPTH results could benefit from more detailed analysis. “There are some good points, and I'm working on some of them now,” he says. “But I think technically the work was correct, and there was nothing [in the Technical Comment] to change our conclusions.”

## Propaganda blitz?

The last straw for Huston and other critics—and what drove the dispute beyond science—was ESA's pamphlet on the importance of biodiversity to ecosystem functioning. A section of the pamphlet summarized work from Ecotron, Cedar Creek, and BIODEPTH—with scarcely any mention of doubts raised about the experiments, skeptics say. Part of a series called “Issues in Ecology” aimed at policy-makers, students, and the public, the pamphlet was written by a panel of ecologists led by Naeem, now at the University of Washington, Seattle, and was translated into lay language. Copies were sent to members of Congress and agencies. Tilman was the series editor and one of the 12 co-authors. Finding that “both the magnitude and stability of ecosystem functioning are likely to be significantly altered by declines in local diversity,” it recommends “the prudent strategy of preserving biodiversity in order to safeguard ecosystem processes vital to society.”

Huston and the other critics hit the roof. In a commentary published in the July 2000 ESA Bulletin, which goes to all 7700 ESA members, they mince no words, charging that the pamphlet is “biased,” “states opinions as facts,” and sets “a dangerous precedent”—especially as it appears to represent the position of the entire society. It is “a propaganda document,” they claimed, “and an advertisement for some authors' research.” By promoting “unjustifiable actions” based on a “house of cards,” they wrote, “scientific objectivity is being compromised.”

In response to this broadside, some of the pamphlet's authors are backtracking. In a written response, Naeem defends the report as “objective.” But, he told Science, he argued for including some material that would have made the piece more balanced, such as a graph showing conflicting studies. It was lost in the condensing process. Tilman, for his part, says he strove to satisfy two sides—ecologists who wanted more decisive language, and others who felt it should be more cautious. In the end, he concedes, “nobody was happy.” Tilman says that in retrospect a scientist from “the other side” should have been invited to review the document; he has since added another layer of review to the series.

Ecologists who are less critical of the disputed studies argue that a different line of research might be more fruitful. Hooper suggests that rather than simply counting numbers, experimentalists should devote more attention to what a plant does—whether it sequesters a mineral for other plants, or how deep its roots are. “Composition matters more than diversity,” he says. Wardle, too, suggests that a better way to get at what might happen to ecosystems as species are lost is to remove plants from established plots, rather than study plots started from seed.

In spite of the temperature of this dispute, Tilman doesn't believe the two sides are that far apart: What's different, he says, is the ardor with which they disagree. “We have a case where everybody is partly right, and some people are vehemently partly right.”

If there's any hope for ecologists to reach some sort of consensus about what diversity experiments mean and how best to study the issue, it may come this December. Calling a cease-fire, Michel Loreau, a French member of BIODEPTH, has invited both sides to a meeting in Paris. “The opinions are so disparate, I don't think it's likely that everyone will converge,” says Hector. “But we can maybe clear away some of these issues.”

15. ECOLOGY

# When Do Many Species Matter?

1. Jocelyn Kaiser

Ecologists agree that experimental plots of grasses are sometimes more productive when they harbor more species. But some disagree passionately about whether it matters—in other words, whether this proves that biodiversity is critical to ecosystem health (see main text).

If the rise in productivity is simply due to a phenomenon known as the “sampling effect,” then it is a meaningless statistical artifact, argues Michael Huston of Oak Ridge National Laboratory in Tennessee. The sampling effect is an arcane term to explain a rather simple process: As more species are randomly added to a plot, the odds rise that one of those species will be productive—because it's leafier or uses nutrients more efficiently, for instance. And just a few highly productive plants can drive up the overall productivity of a plot. So, say Huston and others, this does nothing to prove that an array of species is any better than planting a monoculture of the most productive species.

Not necessarily so, answers David Tilman of the University of Minnesota, St. Paul, who argues that the sampling effect is a legitimate explanation for why more species make an ecosystem more productive and resilient. Even if a few more productive species were thrown in the mix, it is not certain that the entire plot would be more productive, because some species might outcompete each other, he says.

Both camps agree that the most convincing evidence that biodiversity is beneficial would come from a demonstration of an effect called “overyielding.” This means that the productivity of a species mixture has to be higher than the productivity of any individual species within it grown in isolation. If it is, then something synergistic is at work. One plant might fix nitrogen for the other plants, for example, or a tall plant might provide shade for a sun-intolerant species. But to demonstrate that high numbers of species are beneficial, one has to show overyielding with many species, not just a few, asserts Phil Grime of the University of Sheffield, U.K.

Tilman says the latest results from his grassland plots, now 6 years old, may help bring the two sides together. Overyielding “totally dominates the patterns,” a result that, he says, would be “a lot more interesting biologically” than the sampling effect.