# News this Week

Science  19 Apr 2002:
Vol. 296, Issue 5567, pp. 444
1. CONSERVATION SCIENCE

# Caribou Study Fuels Debate on Drilling in Arctic Refuge

1. Jocelyn Kaiser

One week, experts say that oil drilling will harm caribou in the Arctic National Wildlife Refuge (ANWR). The next week, they say it won't. That is how the press and some lawmakers have portrayed a recent federal study and hastily done addendum by Department of the Interior (DOI) biologists that came out on the eve of a Senate vote on drilling. The apparent turnabout is the latest example of how Interior Secretary Gail Norton is manipulating science to promote the Bush Administration's views, drilling opponents say. But the scientists involved tell a more complicated story.

The analysis that triggered this furor is quite limited, says ecologist Brad Griffith of DOI's U.S. Geological Survey (USGS), who is its author. Griffith explains that a superior asked him to prepare an addendum to a major report on Alaskan wildlife focusing on one issue: how drilling in a scaled-back area might affect caribou. And he modeled just one behavior: calving. But everyone pounced on those details. Some caribou experts outside USGS, for example, say that DOI has erroneously concluded on the basis only of this calving study that drilling would be safe for caribou. “Other authors think [this] is an inappropriate use of the model,” says Ken Whitten, a retired Alaska state biologist who contributed to the original report. Griffith believes that his addendum is relevant—but only if drilling is actually limited to the scaled-back area.

The notion that caribou won't be harmed may prove pivotal in Congress. The Senate was expected to block drilling earlier this week and, together with the House, which passed a bill last summer allowing it, will now work out a compromise. The House bill says drilling can proceed only if there is “no significant adverse effect” on wildlife.

The USGS report sent to Norton 29 March, which reviews published papers and includes new peer-reviewed studies, says drilling could adversely affect a number of species such as polar bears and musk oxen, but it notes that many of these impacts could be reduced. However, the report raises serious concerns about the 123,000-strong Porcupine caribou herd, whose June calving ground in most years overlaps the 600,000 hectares in the north of the refuge, the so-called 1002 area, where drilling was originally proposed.

To prepare for this report, Griffith began working 6 years ago on a model to assess how oil development would affect calf survival. The model uses 17 years of radio-tracking data on where females calve in the 1002 area. It also incorporates data on how many calves survive in a given year, which depends on how much good forage the mothers had available and the abundance of predators. Using these data, Griffith developed an equation that predicts calf survival if the concentrated calving area were nudged in one direction by oil development. Griffith then ran this model, assuming that the caribou would behave like another herd to the west of ANWR, staying 4 kilometers away from oil pipelines and roads.

The initial USGS report released last month discusses the model's predictions mainly for just one scenario: developing the entire 1002 region. “That's what was on the table” when the report was prepared, Griffith explains. Development of 1002 could lead to an 8.2% decline in calf survival that would likely cause a decline in the herd population, the report says.

But a few days before the report was released, USGS director Chip Groat asked Griffith to model two new scenarios. These are based on a 2001 USGS report estimating that about 85% of the oil lies northwest of a geological fold, so drilling would likely be limited to this wedge of coast (see map) and some native lands. Griffith says that one need only look at the calving map to see that the impact would be minimal, as almost no concentrated calving occurs there. As expected, under these new scenarios the model predicted essentially no decline in calf survival.

Drilling supporters have trumpeted this result, which DOI spokesperson Mark Pfeifle says “concludes that energy production would have little to no effect on caribou.” But Whitten and other caribou biologists whose data went into Griffith's model say their work is being misinterpreted. Although the herd doesn't calve close to the coast, up to 19% of the herd congregates there a few weeks after calving to avoid mosquitoes and flies. If mothers spend energy avoiding the oil infrastructure, they could lose weight and produce less milk or fail to get pregnant the following year. “You've got to look at the other half of the picture”—after calving—says biologist Don Russell of the Canadian Wildlife Service, who like Whitten is a co-author on the original report's Porcupine herd chapter.

Griffith agrees, partly. Postcalving use of the land “could turn out to be unimportant or very important,” he says: “There's not enough data to evaluate it.” His own hunch is that “calving is most of the story.” But he notes that current legislative proposals don't limit development to the northwestern part of the 1002 area. If it were written into law, “I would feel a lot more comfortable as a scientist” saying that drilling won't harm caribou, Griffith says.

The USGS “reversal,” as some media reports have described it, has added fuel to allegations that Norton is distorting the science on ANWR. In a 4 April letter to Norton, Senator Joe Lieberman (D-CT), a drilling opponent, wrote that he was “gravely concerned” about Norton's request for the follow-up report and demanded an explanation for why she sought a new analysis that was not peer reviewed. For his part, Griffith—who once signed a letter (“as a citizen,” he says) urging that the 1002 area be protected permanently—hasn't felt pressured to come up with a particular answer and feels free to do his science.

But even Griffith is frustrated that the Porcupine herd is getting all the attention. Several scientific societies, most recently the Ecological Society of America, have weighed in against drilling because of the overall impacts on many species and the boreal ecosystem itself. “This issue is more than caribou. There's way too much hung on this one piece,” Griffith says. Unfortunately, that's not the way ANWR politics works.

2. ARCTIC DRILLING

# A Modest Drop in a Big Bucket

1. Richard A. Kerr

Geologists and resource economists are understandably loath to weigh in on the calving habits of caribou (see main text), but they have their opinions about the oil that may lie below the contested 1002 area of the Arctic National Wildlife Refuge (ANWR). In all likelihood, there's a good bit there, geologists say. However, add the economists, even if it were drilled, it would do little to improve the nation's energy security.

Geologists at the U.S. Geological Survey have estimated that the 1002 area of ANWR most likely holds 7.7 billion barrels of recoverable oil. But estimating as-yet-undiscovered oil is rife with uncertainty. Only one exploratory well has been drilled, so geologists fall back on wells outside the area, surface geology, and especially seismic probing of the subsurface. Folding in all the uncertainties, they estimate there's a 5% chance that area 1002 holds 11.8 billion barrels and a 95% chance that there are at least 4.2 billion barrels.

Whatever the actual amount of ANWR oil, say economists, it wouldn't insulate the United States from a volatile world oil market. In February, analysts at the Department of Energy's Energy Information Administration reported that in 2020, when production would be starting to decline if development were authorized this year, ANWR's estimated 7.7 billion barrels would reduce U.S. dependence on foreign oil from 62% to 60%.

“The energy security argument for drilling in ANWR is at best weak,” writes economist Michael Toman of the Washington, D.C., think tank Resources for the Future. Among a number of economic limitations, he says, the Organization of Petroleum Exporting Countries (OPEC) has the upper hand in the long term given its huge deposits of cheaply extractable oil. Whatever the fate of ANWR oil, he says, more efficiently using the oil we do consume is key.

3. ENTOMOLOGY

# New Insect Order Speaks to Life's Diversity

1. Elizabeth Pennisi

A graduate student sifting through collections in natural history museums has made the discovery of a lifetime: a new insect order. The last time the insect kingdom gained a new order was almost a century ago.

The new classification is based on just three known specimens. Two of them—one collected in 1909 and the other in 1950—have for the most part been languishing in museum drawers for decades, and the third is a 45-million-year-old fossil encased in amber. The discovery of these odd, sticklike, carnivorous creatures “is an extraordinary event,” says Harvard entomologist Edward O. Wilson.

The work, reported in a paper published online by Science this week (http://www.sciencexpress.org/), has spurred systematists and entomologists to comb their collections and search in the wild for additional members of this newly recognized group. Some living candidates have already turned up. Says David Grimaldi, an entomologist at the American Museum of Natural History in New York City, the naming of a new order “illustrates how poorly known the [small organisms] really are.”

A series of chance encounters led to the new classification. In June 2001, Oliver Zompro, a graduate student at the Max Planck Institute for Limnology in Plön, Germany, was visiting London's Natural History Museum as part of a project looking for new species among collections of preserved stick insects. A curator showed him one that had been a mystery since it was first collected in Tanzania in 1950. In the 1980s, Roy Danielsson, a curator at the University of Lund, Sweden, had spotted this baffling male insect among his museum's collections and shipped it to the London museum for study. Even there, no one had been able to figure out its place in the tree of life, and Zompro, too, was stumped.

Just weeks later, however, an amber collector sent Zompro a similar looking amber-encased fossil, and Zompro began to suspect that he had come across a new order. That suspicion was strengthened when he soon came across a third specimen, a female from Namibia, warehoused at the Berlin Natural History Museum since 1909. Zompro's connection of the fossil to modern insects was like unearthing long-hidden treasure. “How often do you get to investigate a fossil that has come to life?” says Christine Nalepa, an entomologist at North Carolina State University in Raleigh.

Zompro turned to two systematicists and anatomists at the Zoological Museum of the University of Copenhagen, Denmark, for help. Niels Peder Kristensen and Klaus-Dieter Klass, who is now at the Zoological Museum in Dresden, Germany, evaluated how closely related the three specimens were to each other and to other insects.

Klass found that all three specimens shared some characteristics with stick insects and an obscure group called ice crawlers. Unlike stick insects, for example, females lack a plate on the underside of the abdomen to cover the egg-laying appendages. They also look different because stick insects have elongated thoraxes, with a stretched-out middle segment, but the new specimens don't have this feature. Furthermore, when Klass dissected the female to look for further similarities and differences, he discovered that the stomach was full of insect parts; stick insects are vegetarians, not carnivores, says Kristensen.

Klass, Kristensen, Zompro, and Plön collaborator Joachim Adis therefore argue that the specimens are three new species that together make up a separate new order. They have named it Mantophasmatodea because of a superficial resemblance to the praying mantis and phasmids, the stick insects. “I am glad this group has a name and a place,” says George Poinar, a paleoentomologist at Oregon State University in Corvallis. Until now, he says, “anyone who looked at them really couldn't put them anywhere.”

With only three members, Mantophasmatodea is the smallest insect order yet known. Of the 32 other insect orders, only one has less than 20 members and another has more than 300,000. So far, entomologists have placed about 750,000 species into these orders, “but we're probably only halfway there” in finding and classifying the rest, says Wilson.

The three members of Mantophasmatodea may soon have company. “I bet you anything that there are more specimens lurking in museums,” Grimaldi predicts. Even more exciting, says Kristensen, Zompro and Eugene Marais of the National Museum of Namibia in Windhoek have just discovered two more species in Namibia. Zompro has brought living specimens of one back to his lab to study their behavior. All these finds just go to show, Kristensen adds, “that we are still very far from knowing the diversity of life on Earth.”

4. AMPHIBIAN DECLINE

# Ubiquitous Herbicide Emasculates Frogs

1. Jay Withgott*
1. Jay Withgott writes from San Francisco.

The most heavily used herbicide in the United States makes hermaphrodites of male frogs at concentrations commonly found in the environment, a new laboratory study reports. Its authors urge looking more closely at the possible role of atrazine and similar pesticides in amphibian declines, although a causal role has yet to be demonstrated. Atrazine is banned in many European countries, and some scientists expect this study to influence the U.S. Environmental Protection Agency's (EPA's) ongoing assessment of the chemical.

For more than a decade, scientists have watched with alarm as many amphibian populations have declined and some species have suddenly gone extinct. Although loss of habitat is clearly a culprit, many disappearances have occurred in undisturbed areas such as mountain rainforest reserves. Suggested causes for these mysterious declines include fungal pathogens, increased ultraviolet light, climate change, and pesticide residues.

Toxicologists had come to regard atrazine as one of the more benign pesticides around. Approximately 27 million kilograms of the chemical are applied annually to corn and other crops in the United States, and much of it makes its way into surface water, groundwater, and even rainwater. Past studies with amphibians had shown effects only at abnormally high levels. But researchers had not zeroed in on an apparent amphibian Achilles' heel: the hormone system, which can be disrupted by extremely low concentrations of compounds.

Now researchers led by developmental endocrinologist Tyrone Hayes of the University of California, Berkeley, report that in lab studies, male tadpoles develop extra gonads and become hermaphrodites at concentrations 30-fold lower than EPA's safe drinking water standard. The researchers raised tadpoles of the African clawed frog, Xenopus laevis—the lab rat of amphibians—in water with levels of atrazine varying from 0.01 to 200 parts per billion (ppb). The EPA standard is 3 ppb. At and above 0.1 ppb, 16% to 20% of the animals developed up to six gonads, including both testes and ovaries. In male adult frogs exposed to 25 ppb of atrazine, testosterone levels dropped 10-fold, to levels found in females.

“This study is ground-breaking,” says Val Beasley, an ecotoxicologist at the University of Illinois, Urbana-Champaign. It may well “give us an important piece of the puzzle of amphibian declines,” adds James Collins of Arizona State University in Tempe.

Atrazine concentrations used in the study are frequently encountered in the wild, affirms U.S. Geological Survey hydrologist William Battaglin. Atrazine is routinely present in streams, rivers, and reservoirs in the central portion of the United States at levels of 1 to 10 ppb in spring; peaks of 100 to 200 ppb have been recorded. Airborne atrazine is brought to earth in rainfall, sometimes at concentrations above 1 ppb. Because the herbicide is most often applied in the spring, its runoff peaks just as frogs are breeding and tadpoles developing—often in ditches and pools near agricultural fields.

Because Hayes and colleagues found no effects on mortality, growth rate, or external appearance, they argue that endocrine abnormalities might easily occur in the wild unnoticed. But critics point out that the current study doesn't reveal whether the abnormalities affect reproductive ability. It's also not clear whether atrazine-induced damage would lead to decreases in amphibian numbers. EPA biologist William Rabert adds that wildlife studies must demonstrate negative effects on populations before the agency will consider regulatory action.

As useful as Xenopus is in the lab, conservationists aren't trying to protect it, so Hayes and his group have been studying wild frogs in North America. Their unpublished data suggest that in northern leopard frogs the effects of atrazine are “even more dramatic than what we see in Xenopus,” Hayes says. Lab work with this species has shown similar gonadal effects, and field collections across the United States reveal that frogs in areas of high atrazine use show more endocrine damage than those in areas devoid of the chemical, he says.

Hayes and colleagues suggest that atrazine disrupts the endocrine system in a different way from compounds known to mimic hormones. They propose that atrazine activates the enzyme aromatase, which converts androgens to estrogen. “The testes have been co-opted by atrazine to make the wrong thing,” Hayes explains. Reproductive biologist Louis Guillette of the University of Florida, Gainesville, and his students first demonstrated this mechanism in atrazine-exposed alligators, whose testes produced hormones as ovaries do, and it has since been shown or suggested in several other vertebrates.

The new report, published in the 16 April issue of the Proceedings of the National Academy of Sciences, appeared the same week that EPA was to release its revised risk assessment for atrazine, a key step in its years-long process of reviewing the chemical's effects on humans, wildlife, and the environment. Although EPA officials refused to comment on the risk assessment before Science went to press, they confirmed that Hayes's results were forwarded to them before publication and were considered in the assessment.

5. SCIENTIFIC MISCONDUCT

# Beijing U. Issues First-Ever Rules

1. Yimin Ding*
1. Ding Yimin writes for China Features in Beijing.

BEIJING—China's most prestigious university has adopted the country's first explicit policy to root out research misconduct. The new policy, announced late last month, is distinctive for its sweeping range of offenses—and for having teeth.

For years the government here has tried to combat what is seen as a rising tide of questionable behavior in the scientific community (Science, 18 October 1996, p. 337; 5 March 1999, p. 1427). In keeping with that campaign, the new policy at Beijing University (also called Beida) goes beyond the universally accepted sins of plagiarism, fabrication, and falsification of research data to include much broader misuses of scientific information. Its definition includes “intentionally exaggerating the academic value and economic and social results of a research finding; publishing results without appraisals from school authorities or other academic organizations, … and disclosing research findings that should be kept confidential according to the country's laws and regulations.”

The rules, 3 years in the making, flesh out well-meaning but bland statements on ethical conduct that were issued recently by the Chinese Academy of Sciences and the Ministry of Education. “Our regulations are more practical compared with similar regulations published earlier,” says Zhou Yueming, who heads the university's department of human resources and who helped draft the document. In addition to the definition, the policy describes procedures for investigating allegations of misconduct and lays out a range of penalties for those found guilty.

Even before the policy was officially adopted, Beida officials had already applied it to a faculty member found to have plagiarized large amounts of material from a leading U.S. textbook on cultural anthropology. A university investigation found that Wang Mingming, a 38-year-old anthropologist, had used the material in his 1998 book Imaginary Alien Nation. Late last year, the university removed Wang from his post as director of the folklore study center, as well as from the sociology department's academic board and its anthropology teaching and research section. Wang is not allowed to recruit new doctoral students for 2 years, although he may continue advising those currently under his supervision.

Wang has declined to comment, but last fall he wrote about his situation to William Haviland, a retired University of Vermont anthropologist and author of the popular college text, Cultural Anthropology. “He said he'd done a terrible thing and asked for my forgiveness,” says Haviland. “In other words, he 'fessed up. I told him that it was wrong and that he shouldn't have done it. But I forgave him.”

Ironically, Haviland says that he gave Wang permission to translate the third edition of his textbook, which appeared in Chinese in 1987, and that Wang wrote him last fall asking for permission to translate the 10th edition, which had just appeared. “I was told that my text was the first Western anthropology textbook allowed in China in the post-Mao era,” Haviland says. “And although plagiarism is a serious offense, it is also the sincerest form of flattery.”

University officials say that media coverage of Wang's case this winter influenced the timing of the announcement. Three other Beida employees have been disciplined in recent years for misconduct involving improper crediting of research material. One teacher was moved out of the classroom, and two others were made ineligible for promotions.

Senior faculty members, some of whom were consulted on the policy, say they are pleased with the new rules. “I am a strong supporter of those regulations,” says Chen Dayue, deputy director of the college of mathematics science. “Research ethics have been passed on from teachers to students over generations at our university. But now a large group of faculty members are from other universities both at home and abroad. So we need a written document to guide and instruct our teachers and to prevent them from misconduct.”

6. SCIENTIFIC MISCONDUCT

# Australia Probes Kidney Researcher

1. Leigh Dayton*
1. Leigh Dayton writes from Sydney.

SYDNEY—The Australian government has frozen funding to a prominent medical researcher and clinician pending the outcome of an investigation into allegations that he committed scientific misconduct. The case has raised questions about the adequacy of the country's present system of investigating misconduct.

The allegations against Bruce Hall, a renal transplant physician and professor of medicine at the University of New South Wales (UNSW), have been made by three members of Hall's laboratory. In a series of submissions to university officials beginning last fall, they alleged that Hall misrepresented and fabricated experimental results, manipulated authorship credit in presentations and papers, and provided false data on a federal grant application. The work in question involves the role of CD4+ and CD25+ cells in organ acceptance and rejection as well as experiments involving monoclonal antibodies. Hall has declined to comment on any aspect of the case.

This month, in an attempt to put pressure on the university, the researchers—Clara He, Juchuan Chen, and Hong Ha—took their charges to ABC radio, which aired them last weekend. Two days after the ABC story ran, the UNSW Council, the institution's governing body, ordered an outside inquiry into the matter as well as an internal review of the university's procedures relating to possible misconduct. “The allegations are enormously disturbing,” says council member Jeremy Davis, a former dean of the university's management school and past president of the academic board. “If the allegations are true, all our deep processes have failed.”

Immediately after the show aired, John Ingleson, the university's deputy vice chancellor, issued a statement saying that the radio program “contained a number of serious inaccuracies.” The statement also asserted that “the university has taken all appropriate steps to investigate the complaints referred to in the program.” Ingleson said that its findings would be made public but did not give a timetable.

In a 16 January letter to UNSW officials, the National Health and Medical Research Council (NHMRC), the country's leading biomedical research funding agency, said that it was suspending a recently awarded grant to Hall—one of several he holds from the council—because of questions He had raised about the accuracy of the data upon which the application was based. “We don't have a view [on the truthfulness of the allegations],” says a council spokesperson. “But we take the matter very seriously, and we've asked that [the investigation] be done quickly.”

Australia has no national body to monitor, investigate, and prosecute allegations of misconduct. Instead, each institution sets its own procedures, which must follow relevant state employment or anticorruption laws. To receive federal funding, institutions must agree to a code of conduct written by NHMRC and a nationwide body of university vice chancellors.

But that system may be inadequate for the task, says Merrilyn Walton, an ethics scholar at the University of Sydney and a former state commissioner for health care complaints. While making no judgment on the allegations against Hall, Walton says it's unrealistic to require institutions to root out serious scientific misconduct that could damage their reputations and their bottom lines. “It's like asking police to investigate police,” she says.

7. CHEMISTRY

# To Net Big Molecules, Widen the Mesh

1. Robert F. Service

Some tradeoffs seem unavoidable. Industrial efforts to purify water or natural gas, for example, separate desired compounds from mixtures by passing them through membranes pocked with tiny holes. The smaller the holes, the more selectively the membrane lets molecules pass. But the tighter passage also slows the overall flow, requiring the use of higher pressures to push compounds through, an energy-intensive and costly proposition. But now a team of researchers from the United States and Australia has found a surprising way out of the dilemma.

On page 519, the researchers, led by Tim Merkel, a chemical engineer at Research Triangle Institute in Research Triangle Park, North Carolina, and Benny Freeman, a chemical engineer at the University of Texas, Austin, report that they have formed membranes with wide-open holes that, paradoxically, allow large molecules through far more readily than smaller ones. Normally, enlarging a membrane's pores opens the gates to a flood of molecules, both large and small. The new membranes are both more selective and faster acting than previous versions.

“This is a very interesting result” that could open new industrial uses for membranes, such as separating gases like oxygen from air, says Narcan Bac, a chemical engineer and membrane separations specialist at Northeastern University in Boston, Massachusetts. Bac adds that extending the same approach to other membranes may make current industrial separations cheaper. “Any time you can improve the efficiency of separations, you are improving the economics of the process,” says Bac.

Merkel, Freeman, and their collaborators were aiming to get that efficiency boost by spiking a conventional membrane polymer with tiny particles. That combination isn't novel: For years, other groups had been adding small, porous particles called zeolites to membranes to try to increase their selectivity. Because zeolites come riddled with various-sized pores, they can serve as filters to allow slim molecules through while blocking their hefty cousins. But zeolite particles themselves are at least a micrometer across, making them “like giant boulders” compared with the polymer chains in the membrane around them, Freeman says. When the particles are added to polymer films, the tiny polymer building blocks pack tightly around the zeolites and produce dense films that make it difficult for gases to make their way through, leaving the hulking zeolites as the primary passageways through the membrane.

“We wondered what would happen if the particles were on the same size scale of the polymer chains,” Freeman says. Because smaller zeolites weren't available, the researchers opted instead for a type of fine-grained sand called fumed silica, each particle of which was only 13 nanometers across, roughly the same size as a polymer chain. They mixed their fumed silica with rigid polymer chains, each akin to a strand of uncooked spaghetti. The small sand particles acted like meatballs strewn among the stiff spaghetti strands.

“That forced the polymer chains apart and increased the permeability” of the membrane, Freeman says. The arrangement gave the membranes an array of gaping holes, which by all accounts should sieve molecules quickly. The researchers braced themselves for the seemingly inevitable influx of chemical intruders.

It never came. In fact, the new membranes proved twice as good as previous versions at allowing larger gaseous organics such as benzene to pass through while straining out smaller gases such as hydrogen. The counterintuitive result, Freeman explains, occurs because molecules move through a membrane in two stages. First they must dissolve into the membrane, and then they must wiggle their way through it. And whereas smaller molecules are faster wigglers, larger molecules are quicker to dissolve. In densely packed membranes, that knack for dissolution doesn't turn large molecules into speed demons, because they still get hung up on their way through. But thanks to the wider holes in the new membranes, Freeman says, the bigger molecules have the elbow room they need to take full advantage of their head start and zip across before the smaller molecules.

The new membranes aren't perfect. One conventional membrane made from a polymer abbreviated PTMSP remains more permeable than the new variety. But PTMSP membranes degrade quickly in the presence of gaseous hydrocarbons such as methane, making them poor candidates for separating unwanted compounds from natural gas. The new hybrid version uses a far more stable polymer, abbreviated PMP. Merkel, Freeman, and colleagues are now testing whether their new membranes will separate out unwanted compounds commonly found in natural gas. If so, the hybrid membranes could open the door for energy companies to exploit vast natural gas reserves that currently harbor too many unwanted gases to be useful.

8. PARKINSON'S DISEASE

# Coincidence or Connection?

1. Richard Stone

When actor Michael J. Fox revealed in 1998 that he has Parkinson's disease (PD), it caused a stir: a celebrity in his prime afflicted with a degenerative disorder associated with old age. Now a new twist to the story has emerged, and scientists are debating what, if anything, it means. A Canadian TV documentary has reported that three people who worked with Fox at a TV studio in the late 1970s also have been diagnosed with Parkinson's. One, like Fox, first showed symptoms in her 30s.

The cluster of four cases out of a 125-person production crew may not have a common cause. Indeed, disease clusters often turn into scientific dead ends. But the two instances of the rare early-onset form, in particular, have experts intrigued. “When you start seeing young patients, the odds increase dramatically” that a cluster is not due to chance, says J. William Langston, scientific director of the Parkinson's Institute in Sunnyvale, California.

A handful of PD experts have known about the cluster for roughly a year. It first came to public light in a documentary, “The Parkinson's Enigma,” aired last month by Canada's CTV. Fox and the three others had worked together in Vancouver, Canada, when the actor was taping the short-lived Canadian Broadcasting Corporation (CBC) sitcom Leo and Me. All of the patients except Fox are being treated by PD specialist Donald Calne, former director of the Neurodegenerative Disorders Centre at the University of British Columbia (UBC) in Vancouver.

Scientists have long known that PD, characterized by tremors and muscle rigidity, results from cell death in the substantia nigra, a brain region that produces the neurotransmitter dopamine. The vast majority of PD cases, many researchers believe, occur when genetic or environmental factors accelerate a gradual die-off of nigral neurons. Gene mutations are thought to be responsible for many cases of the early-onset form.

Calne and some others, however, argue that a brief environmental exposure, or “event,” may kill some neurons in the substantia nigra and damage many others. “As these wounded soldiers die, you start to see symptoms,” says Calne, who argues that a toxin or a virus could trigger such a cascade. Calne believes that the Fox cluster fits that hypothesis. All four patients first showed symptoms 7 to 13 years after working together—a lag one would expect to follow an event, he says. In addition, Calne says, “concern has been expressed about the ventilation” in the new, CBC sound-insulated studio they were working in at the time. CBC confirms that it has called in a UBC epidemiologist to examine this concern. To Calne, these facts represent “intriguing straws in the wind that the cause could be viral”—although he cautions that a toxin or other environmental factor is equally plausible.

The explosive mix of Michael J. Fox and speculation about a possible PD virus proved irresistible for many news organizations, including CNN. The coverage has triggered a “deluge” of inquiries, says Langston, who is also chief scientific adviser to the Michael J. Fox Foundation for Parkinson's Research in New York City. The foundation has posted a statement on its Web site, signed by Langston, that plays down a viral link. “Lacking strong scientific evidence, … the viral theory is not widely held by PD researchers and clinicians,” the statement asserts.

The Fox cluster may turn out to be mere coincidence, but neurotoxicologist Peter Spencer of Oregon Health & Science University in Portland says a search for potential toxins or pathogens “should be vigorously pursued. Sure, it could theoretically have been something in the building, but TV crews eat, drink, and perhaps experience other things together.” Langston agrees. If you could unravel just one cluster, he says, “boy, you could learn a tremendous amount.”

9. ENVIRONMENTAL HEALTH

# National Tracking Plan Picks Up Speed

1. Jocelyn Kaiser

Parkinson's disease, autism, childhood leukemia, lupus, asthma: They are all chronic diseases caused by multiple factors—including, some suspect, environmental pollutants. Now an ambitious, $200-million-plus-per-year national plan to ferret out such disease links is gaining momentum among agencies and Congress. At a public meeting last week in Washington, D.C.,* the proposal met with enthusiastic support, although a few participants voiced caveats—such as the need to define environment broadly to include lifestyle factors as well as chemicals. The Nationwide Health Tracking Network, as it's known, was first proposed as a federal project 2 years ago by a group of environmental health researchers funded by the Pew Charitable Trusts. They wanted to find ways to firm up suspected links between diseases like cancer and pollutants such as heavy metals and pesticides. “We need to move away from speculation about disease to interventions and action,” says commission member Lynn Goldman of the Johns Hopkins School of Public Health in Baltimore, former chief of the pesticides office at the U.S. Environmental Protection Agency (EPA). To do this, the Pew commission proposed that the federal government spend$275 million a year to build or expand mandatory state registries of diseases such as cancer, Parkinson's, and autism. The money would also be used to add more pollutants to databases such as EPA's inventory of chemical releases by industry. It would add more local data and more contaminants to existing exposure studies, such as a Centers for Disease Control and Prevention (CDC) national survey that measures levels of lead and other pollutants in participants' blood. And it would train a corps of experts to investigate whether potential environmental disease outbreaks are linked to the hazard data that has been amassed. The data would be available (with privacy protections) to the public and researchers. But just how the various databases would be connected “is still in evolution,” says Shelley Hearne of the Trust for America's Health, a nonprofit in Washington, D.C., promoting the network.

View this table:

CDC has put its weight behind the plan and received $17.5 million in 2002 as an earmark from Congress. Richard Jackson, head of CDC's National Center for Environmental Health, says the agency will fund pilot projects such as state tracking of immune diseases. The plan has also won the support of lawmakers such as Senator Hillary Rodham Clinton (D-NY), who in March co-introduced a bill to establish a national network that mirrors the Pew report (see table). Clinton says it “will help get to the bottom of” problems such as unusually high cancer rates in Fallon, Nevada, and on Long Island. At the meeting last week, several participants, who included attorneys and toxicologists, cautioned that environment in the strictest sense could miss the bigger picture, because diet and lifestyle factors such as occupation and smoking are just as likely to contribute to these chronic diseases. “We may miss the actual” trigger if the network assumes that pollutants are to blame, said Carol Henry of the American Chemistry Council, an industry group. Others worried that epidemiology simply can't deliver the kinds of answers policy-makers want, because it may be impossible to pinpoint cause and effect for some diseases. “Some of the promises we're making make me a bit uneasy,” said EPA toxicologist Harold Zenick. At a logistical level, participants also pointed to the difficulty of coordinating activities in at least a half-dozen agencies. Some said that a federal-level committee is needed. “This is a very broad and complex initiative, a very ambitious idea. It's going to take a lot of patience and time, not just one or two symposia,” said Sam Wilson, deputy director of the National Institute of Environmental Health Sciences. Those familiar with the Clinton proposal say it already addresses most of these concerns: For example, it mentions collecting lifestyle data. “It's all been thought of,” says Susan Polan of the Trust for America's Health. Supporters are hoping that Congress will allocate$100 million for 2003.

• *Environmental Health Indicators, sponsored by the Roundtable on Environmental Health Sciences, Research, and Medicine, Institute of Medicine, 10–11 April.

10. BIOMEDICAL RESEARCH

# Dexter to Step Down at Wellcome Trust

1. Melissa Mertl*
1. Melissa Mertl is a freelance writer in London.

LONDON—The Wellcome Trust, the $16 billion charitable foundation that dominates British biomedical research, has a year to find a new leader. Mike Dexter has announced that he will not extend his 5-year term. Dexter, 57, was a respected cancer researcher and newly named director of the Paterson Institute in Manchester when he took the reins of the trust in 1998, after a sale of holdings in the Wellcome drug company turned it into the world's largest medical charity. Many observers say the trust under Dexter's leadership used its money to help save British science, often shaming the government into increasing its own support. Over the next 5 years the trust plans to spend about$4.3 billion, 85% in the United Kingdom, supporting biomedical research and related activities. “[Now] is the right time to begin the search for a successor,” Dexter said in a statement about his decision not to seek an optional 2-year extension.

John Bell, head of Oxford University's Department of Clinical Medicine, calls Dexter's decision “a healthy way to run biomedical science. You find people of real quality, but they shouldn't be there forever. A lot was done in 5 years.” Dexter has made no plans for what to do next and is “not going to think about it until [his term ends] next year,” says a Wellcome spokesperson.

Observers give Dexter credit for charting the trust's recent course, which has included improving salaries and career paths for scientists and coaxing the government into matching an $800 million initiative for modernizing research infrastructure in British universities after years of neglect. Dexter also emphasized the importance of public awareness, says Diana Garnham of the Association of Medical Research Charities. “[The trust] has played an important role in building public confidence in medical research,” she says, and has been outspoken on behalf of the use of animals in research and embryonic stem cell research. But Dexter's work to secure Britain's place in international genomics and large-scale biology may be his most significant accomplishment. Under his direction, the trust pumped hundreds of millions into the Sanger Centre, now Europe's largest sequencing and biological computing facility. The Sanger Centre, in Hinxton, U.K., predates Dexter's arrival, but he “had the vision” to continue pushing for large-scale biology funding, says Bell. Sanger director Allan Bradley says Dexter's presence “played a key role” in his decision to move from the Baylor College of Medicine in Houston. The biggest challenge facing the trust may be sustaining its planned growth. The trust had allocated at least$160 million to expand its genome-research campus outside Cambridge, where the Sanger Centre is located, but the local council rejected the initial plans on environmental grounds. A new plan proposes to build a smaller postgenomic research facility with a greater emphasis on basic research and less space for start-up companies.

11. UNITED KINGDOM

# Hard Sciences in Terminal Decline?

1. Kirstie Urquhart*
1. Kirstie Urquhart is U.K. editor for Science's Next Wave.

LONDON—Physical scientists may not yet be extinct in the United Kingdom, but they are rapidly becoming an endangered species.

This week a high-profile government report* describes how enrollment in physics, engineering, and chemistry courses at British universities fell sharply between 1995 and 2000, despite a rise in the number of graduates across all disciplines. The decline is rippling through the whole supply chain of scientists: Schools cite a dearth of physics teachers, while universities and companies complain of a lack of physical science talent at all experience levels. The United Kingdom is “seriously in danger” of being unable to sustain world-class science, argues Peter Cotgreave of the pressure group Save British Science.

Concerned about the supply of research talent, the Treasury commissioned the report last year and tapped physicist Gareth Roberts to lead the study. Roberts, president of Wolfson College in Oxford, found a scientific community out of balance. Worldwide, only France, New Zealand, and Finland produce more science and engineering graduates per capita than the United Kingdom. But that lead is built upon a 49% rise in the past 5 years in biology, which has masked a 7% decline in physics and engineering graduates and a 16% drop in chemistry over the same period. Such losses have led to “a number of serious problems,” says Roberts. Not least the fact that about two-thirds of physics teachers in British schools have no training in physics.

The report calls for a thorough overhaul of the U.K. educational system. One “very urgent” recommendation, Roberts says, is for schools to recruit local university students as teaching assistants, which he calls a better use of their expertise than “filling supermarket shelves.” The idea has been kicking around for awhile, but Roberts says it might be taken seriously if the assistants are paid.

The report also urges the Treasury to raise pay for physical scientists at all levels. “It is vital that Ph.D. stipends keep pace with graduate salary expectations,” Roberts says. Whereas a new graduate entering employment can expect to take home on average $17,000, a physical scientist staying on in academia gets only$11,000. Postdocs also need a leg up to permanent academic posts, says Roberts, who wants the government to provide funding for 200 new 5-year university fellowships each year. “They should be focused very much on shortage areas,” he says.

While welcoming the report, Cotgreave is disappointed that “it doesn't put any figures on how much it's going to cost” to implement. That omission, he says, will make it very difficult to judge the Treasury's response. Science Minister David Sainsbury has promised that the government “will consider” the recommendations in an upcoming spending review, and he notes that the looming shortfall of physical scientists is plaguing many other industrialized nations. “The country that gets this right,” Sainsbury says, “has a real opportunity.”

12. GLACIAL RESEARCH

# Melting Glaciers Release Ancient Relics

1. Kevin Krajick*
1. Kevin Krajick is the author of Barren Lands: An Epic Search for Diamonds in the North American Arctic. He lives in New York City.

Animal and human remains frozen for thousands of years are melting out of glacial ice—and scientists are rushing to capture them before they decay

Gerald Kuzyk was hiking on a snowy Yukon peak in summer 1997 when the wind lashed an unexpected barnyard stench his way. He followed his nose to a square kilometer of fresh, ankle-deep caribou dung melting from a perennial ice bank—but caribou had not been seen there for generations. Kuzyk, a wildlife technician for the Yukon Department of Renewable Resources, had stumbled on the alpine equivalent of King Tut's tomb: Melting ice was releasing a treasure trove of ancient relics. During a few summer weeks of working at this spot and nearby ones like it, Kuzyk and colleagues found not only rivers of dung but also remains of large mammals, whole freeze-dried birds and rodents, and human artifacts including a long wooden projectile shaft complete with sinews, feathers, and ochre paint. Radiocarbon dating showed that the ice held a more or less continuous biologic record for 8300 years, reaching almost to the present.

As alpine glaciers around the world succumb to warming, scientists are reaping grand harvests of frozen organic objects—and with them previously unavailable information on past wildlife, human culture, genetics, climate, and more. Tissues with intact DNA and archaeological objects of wood and bone provide pictures that stone tools only hint at, and because they can all be radiocarbon dated, there is little guessing about chronology. Up to now, such well-preserved objects from the last 10,000 years—after the retreat of the last great ice sheets—had been vanishingly rare in most parts of the world.

Because the frozen objects are so valuable—and decay so fast once exposed—a growing cadre of scientists is trying to predict and comb fertile spots. “The potential for discovery in many fields is tremendous,” says Yukon Territory wildlife biologist Rick Farnell, who is based in Whitehorse and heads an interdisciplinary team that now regularly harvests Yukon ice. “It's one of the few positive things to climate change.”

## Vanishing ice

Glaciers have been thinning and retreating since the mid-19th century—Switzerland's have declined a third in volume since 1860—but now the pace is accelerating and with it the urgency to collect stranded perishables. Many regions have not been this warm for 8000 years or more, and so some frozen objects may be at least that old. In March, the University of Colorado published a report by glaciologist Mark Dyurgerov estimating that mountain glaciers worldwide are losing 90 cubic kilometers of ice a year, with those in Alaska, the Andes, and central Asia dwindling particularly fast. Glaciologist Lonnie Thompson of Ohio State University, Columbus, says that the Qori Kalis glacier in the Peruvian Andes, which has retreated by 4.7 meters a year since the 1960s, has suddenly started wasting that much in a week and that the famous snows of Kenya's Mount Kilimanjaro may be completely gone by 2015 (Science, 2 March 2001, p. 1690). “This is a really good time to expand the search for any kind of objects,” says Dyurgerov.

Until now, scientists assumed that just ice, snow, and plowed-up rocks collect in glaciers, but clearly animals, plants, and people do, too. David Hik, a wildlife biologist at the University of Alberta in Edmonton, has studied the 40,000 square kilometers of mountain ice fields linking the Yukon with coastal Alaska—North America's largest glacial expanse—and says that many animals stray there, including wolves, bears, mountain goats, and especially rabbitlike pikas, which live on rock islands in the ice kilometers from other land. Many eventually end up in the deep freeze. Dozens of bird species migrate over the ice fields and surprisingly often crash by the flockful, later to turn up in snowbanks like raisins in a fruitcake. Even whole forests are sometimes encased by advancing ice, as shown by largely intact ancient trees washing out of glaciers in Alaska and Switzerland. “Ice is a gold mine of dead stuff,” says Hik.

Humans have also crossed glaciers far more often than previously thought. In recent years ethnographers and aboriginal elders of the interior Southern Tutchone and coastal Tlingit tribes have drawn maps showing the seemingly impassable Yukon-Alaska ice fields crisscrossed with once-lively trade routes. Some natives and later travelers—including countless 19th century gold prospectors—starved, froze, or plunged down the emerald-shaded depths of crevasses. “Some of these people have a long way to go, but we'll see them again,” says Gerry Holdsworth, a glaciologist at the University of Calgary, Alberta.

Until now most finds have been accidents, such as the 5300-year-old “Iceman of the Alps” (Science, 28 September 2001, p. 2373), spotted by European hikers in 1991 and still under study. Another, much younger ice man surprised sheep hunters in British Columbia in 1999 (Science, 8 October 1999, p. 229).

But Kuzyk's 1997 find has spawned sustained operations. The following year Farnell led a team that combed the high country west of Whitehorse for more so-called “ice patches” like Kuzyk's, which generally cover a square kilometer or less and are no more than 50 meters deep—technically too small to be called glaciers, but perfect for artifact hunting because they are susceptible to fast annual melting. So far the team has visited two dozen patches by helicopter during summer melt season, and in more than half team members have found bones, animal tissues, human artifacts, and, everywhere, lots of dung. (Not all animals died in the ice, but many left calling cards.) Farnell says in retrospect it's no mystery why the patches hold such riches: Today, wherever caribou are found, they can be seen wallowing in similar perennial ice to escape summer heat and insects. “Hunters, I'm sure, knew this,” he says, and they killed prey in these dependable spots for thousands of years.

Practically every ice-preserved object has scientific value. The humble dung contains not only pollen but large chunks of undigested plants and lichens easily identifiable by species, revealing what was growing and therefore the climate during various periods. Wood also provides climate clues; last year in the journal Holocene, a Swiss group reported a highly detailed 9000-year chronology of climate based on tree trunks and peat salvaged from melt streams in the Alps.

Farnell's group is still unraveling the chronology of the Yukon finds, but he says that ancient caribou ate more shrubs and mosses than caribou consume today, an indication of drier, colder times. Other Yukon animal remains include Dall sheep; mountain goats; elk; about 60 largely intact shrews, voles, and birds; and a 4000-year-old lemming. And Darlene Balkwill, a zooarchaeologist at the Canadian Museum of Nature in Ottawa, got a big surprise when analyzing the team's harvest: the horns, teeth, and dung of bison, suspected but never proven to have lived at high altitudes.

Alan Cooper, director of the Ancient Biomolecules Center at Oxford University, plans to analyze the DNA of the caribou and compare them with modern ones in other parts of the mountains. This, he says, will tell him whether today's animals are descended from the frozen ones or, as he suspects, caribou have been periodically extinguished from the region by climate change or humans and later replaced by outsiders. Previously Cooper has been able to study DNA from animals 15,000 to 60,000 years old preserved in permafrost (Science, 22 March, p. 2267). But until now, the warmer period of the past 10,000 years has yielded few remains. “The ice patches give us a DNA window into a period rarely seen,” he says.

## Long Ago Person Found

The more recent record is doubly important, says Cooper, because that's when humans probably entered the region. Frozen objects may help resolve many questions about them and their interactions with animals. So far, the artifacts are stunning. There are wooden weapon shafts of birch, spruce, and willow up to 2 meters long, some with antler projectile points attached. One point still has caribou blood on it. There is a finely serrated ivory blade of unknown purpose. “This is unique,” says Yukon government archaeologist Greg Hare. “Usually we get just stone points and try guessing what they mean. Now we have the whole thing.” He says radiocarbon dating on the wood proves that hunters used the patches from at least 7300 years ago right into the mid-19th century, when the first Europeans arrived.

The weapons also help address a long-running debate about when bows and arrows appeared in the Americas. Some argue that they were used as far back as 10,000 years ago, but Hare says the shafts show that in this locale, until 1300 years ago the weapons were all spears designed to be thrown with a device called an atlatl; only the younger ones are arrows. The group has even found two bows of maple, apparently carried over the glaciers 80 kilometers from Alaska, where maples grow.

The Canadian iceman himself, found just south of the Yukon, wore a squirrel-fur cloak and finely woven hat much like those seen in the region today and carried a bone-and-metal knife, a spear, and a snack of dried fish in a leather bag. About 20 when he died, he was dated to “only” about 550 years ago—disappointing scientists but delighting northwestern Native Americans, because he could be someone's great-ancestor. Scientists in the area cooperate closely with aboriginal people, an unusually amicable arrangement that comes partly because the Champagne and Aishihik First Nations control rights to cultural artifacts in the region, and nothing gets done without their assent.

The Native Americans dubbed the frozen mummy Kwaday Dan Ts'inchi—Long Ago Person Found—and started their own DNA analysis project to see to whom he might be related. Says Diane Strand, heritage officer for the Champagne-Aishihik: “We want to know as much about him as we can. That's what science is for, right?”

Maria Victoria Monsalve, a pathologist at the University of British Columbia in Vancouver, is running separate DNA tests and says the iceman is tied to far-flung living native people, including the Haida off the British Columbia coast, the Quecha of Guatemala, and the Amerindians of Brazil. “His lineage is all over [today],” she says. “It bolsters the idea that humans [originally] came from Asia.” Some moved south, whereas the ancestors of the Long Ago Person Found stayed up north. Her results are in press in the American Journal of Physical Anthropology.

The only thing missing: the Long Ago Person Found himself. After making sure scientists had enough samples, in July 2001 Indians held a potlatch, cremated him, and had his ashes airlifted by helicopter close to where he died. Archaeologist Al Mackie of the Royal British Columbia Museum in Victoria says that return visits to the vicinity have continued to yield objects apparently from other travelers, including notched sticks, a leather thong, and fragments of an atlatl, as well as insects, birds, and a moose.

## Ice spotting

No one knows exactly how old the rich ice patches may be, nor how much longer they will last. “We should be out there with 10 helicopters every summer, because these places may go fast,” says Gordon Jarrell, curator of the frozen-tissue collection at the University of Alaska, Fairbanks, where many of the Yukon finds are stored. He says that flesh starts rotting within hours of exposure—and ravens and other alert scavengers may not mind eating even 8000-year-old meat.

To get ahead of the curve, scientists are now trying to pinpoint good prospecting spots. “We know things melt out, but the real problem is predicting exactly where they'll appear,” says archaeologist James Dixon of the University of Colorado Institute of Arctic and Alpine Research (INSTAAR).

Dixon and glaciologist William Manley, also of INSTAAR, have spent the last 3 years assembling a Global Information System model to map potentially fruitful areas in Alaska, which they hope to apply to other areas of the world. Their charts overlay glaciologic data, such as the altitudes below which particular glaciers are melting, with information such as trade routes, ancient stone quarries, mineral licks, and other places where people and animals may have been.

Last summer Dixon and Manley tested their model in Alaska's Wrangell-St. Elias Park—and hit the jackpot. Landing by helicopter and ski plane, they found 36 sites with a mind-boggling array of melted-out material. In addition to the ever-present feces, they found fleshy remains of Dall sheep, caribou, assorted carnivores, many birds, and even a complete, perfectly preserved fish, perhaps hauled in by a human. Other leavings of people included an antler projectile lying near a punctured caribou scapula, a piece of cut wood, and a pile of horse-hoof rinds (the part of the toenail cut off to reshoe the horse) with rusty nails still attached. Dixon assumes these last are from a 1902 gold rush in which prospectors foolishly tried crossing the glaciers.

“The organic content of glaciers is amazing, and it has profound implications for everything from paleontology to water quality,” says Dixon. Water quality? “Yes,” he says, pointing out that many glaciers provide drinking water. One small example: A hotel near his Colorado home has a drinking fountain labeled: PURE WATER DIRECTLY FROM ARAPAHOE GLACIER. “I wince, thinking about what's probably in there.”

13. IMMUNOLOGY

# Gently Soothing a Savage Immune System

1. Jennifer Couzin

Autoimmune disease and transplant researchers are teaming up in their search for ways to make the immune system tolerate tissue it's attacking

The immune system is a shifty character, displaying the faces of Dr. Jekyll and Mr. Hyde. Most people encounter only its benevolent side, charged with protecting against disease. But in others, the immune system bares its teeth. For organ transplant recipients, efforts to quash a beastly, overactive immune system have defined treatment for a generation. That may be about to change, as researchers search for ways to tame the immune system without obstructing it entirely.

The new approach, called immune tolerance as opposed to immune suppression, is driven by work in the transplant field, but experts in autoimmune diseases such as multiple sclerosis (MS) and type I diabetes are also getting into the game—in their case to modulate attacks on the patient's own tissue. Results from animal studies have generated promising findings, such as mice cured of diabetes and off all medication and monkeys with new kidneys who don't need immunosuppressants. Spurred on by such successes, dozens of clinical trials are now under way or gearing up.

“I'm very optimistic that [immune tolerance] is going to be a big step forward,” says Fritz Bach, a transplant surgeon at Harvard Medical School in Boston. “I've been in this a long time, [and] I've never taken this view before.”

But in humans, the work remains highly experimental. Along with some promising preliminary results, a handful of trials have screeched to a halt due to deadly adverse effects—a reminder of how exquisitely sensitive the immune system can be, and how much about it is left to learn.

## Friendly fire

Transplant surgeons have been battling host rejection for decades with drugs such as cyclosporine, which massively suppresses the immune system. This approach has allowed an impressive 90% to 95% of organ transplant recipients to retain their new organ for at least 1 year. But rejection numbers rise sharply with time. Despite continued use of immunosuppressants—patients must take them for life—by 10 years after transplant, the immune systems of roughly 50% of patients have rejected the organ. Even when immunosuppressants keep working, they can have harmful side effects, including infections and cancer.

If immune suppression is a sledgehammer approach, immune tolerance is more akin to a massage. By coaxing subtle shifts, researchers hope to train the system to accept tissue it's trying to destroy. Strategies vary. In some cases, researchers administer experimental drugs to suppress only those immune system cells causing problems. Other approaches put patients through risky stem cell transplants, which usually require toxic chemotherapy. The hope is that those transplants will destroy renegade immune cells or mingle a patient's immune system with a donor's so that the body accepts the donated organ. Research is showing that tissue rejection mechanisms can be quite similar, whether in autoimmune diseases or transplants, and some of the same drugs are being tested in both types of patients.

So far, tolerance treatment has helped a subset of individuals on whom it's been tested; they can get by on lower drug doses or respond to standard treatments they once resisted. But very few have met the strictest test of tolerance: an immune system that no longer recognizes tissue from the donor or, in the case of autoimmune diseases, their own tissue as foreign once drugs are withdrawn.

## In with the new

One way to revamp an immune system is with a bone marrow or stem cell transplant. It can come from a matched donor such as a sibling or from cells taken from the patient and later reintroduced. Commonly used to treat life-threatening blood disorders and leukemias, such transplants are performed after large doses of chemotherapy and radiation destroy existing marrow. The marrow contains infection fighters such as T cells as well as other immune cells and the stem cells that produce them. Once the marrow is gone, doctors infuse a new dose of bone marrow extracted from the donor's hip or stem cells taken from the blood. If all goes well, the new cells will churn out blood and marrow free of disease.

But such treatments carry serious risks. Chemotherapy and radiation regimens are toxic enough to kill. If the patients survive, their new marrow may attack their bodies, a sometimes deadly complication called graft-versus-host disease (GVHD). Still, researchers have improved the technique substantially in recent years, and some believe that the potential benefits of stem cell transplants outweigh their risks and justify extending the treatment to those with autoimmune disease or transplants.

At Stanford University 18 months ago, immunologist Samuel Strober began combining stem cell and kidney transplants in humans. Years of lab research had convinced him that a mix, or chimera, of a patient's immune system cells and the donor's could prevent organ rejection. He crafted a low-toxicity regimen that includes drugs and radiation and destroys some cells in the bone marrow to make room for new ones.

Four patients have signed on, receiving cells that should generate T cells identical to the donor's; the patients also retain some of their own T cell-producing stem cells. The volunteers will be allowed to stop taking immunosuppressants if they exhibit chimerism, no rejection, and blood markers of tolerance to the donor. The first patient went off medication after 1 year. Strober will present an update at meetings of the American Association of Immunologists and the American Society of Transplantation this month.

Immunologist Megan Sykes and colleagues at Massachusetts General Hospital (MGH) in Boston have pioneered additional chimerism protocols. Sykes has performed transplants on three people with both bone marrow cancer and kidney failure who were not eligible for standard kidney transplants; two are off immunosuppressants. She's also experimenting in animals with adding antibodies to the mix. The antibodies would in theory disable T cells in the patient, doing some of the work of radiation and chemotherapy without their side effects; they also attack T cells from the donor, reducing the risk of GVHD. Both the MGH and Stanford groups have used living organ donors, although both say it's possible to extract stem cells along with organs from cadavers.

Tolerance treatment has also been tried in autoimmune patients. European scientists are tracking about 400 patients in Europe, Asia, and Australia who suffer from diseases such as rheumatoid arthritis and MS and have received stem cell transplants. By administering chemotherapy before the transplant, researchers such as Alan Tyndall, a rheumatologist at the University of Basel in Switzerland, and Richard Nash, an oncologist at the Fred Hutchinson Cancer Research Center in Seattle, believe they are reducing the number of overactive T cells, B cells, and other immune cells. Then the patients receive an infusion of stem cells previously extracted from their own blood. That way, the theory goes, the immune system can “turn back the clock,” as the stem cells produce new cells that haven't yet gone bad.

Early results found that a majority of patients initially stabilized or improved after the transplant, but between 20% and 70%, depending on the disease, of the European cohort later relapsed. Many of them, though, continue to respond far better to standard treatments they once resisted, says Tyndall, who's coordinating the study, run by the European Group for Blood and Marrow Transplantation and the European League Against Rheumatism.

About half of the U.S. transplants for autoimmune patients are overseen by doctors at the Fred Hutchinson Cancer Research Center, who are coordinating a multicenter trial on more than 50 people with MS and scleroderma. For scleroderma, severity on average has been reduced 50%, says Daniel Furst, a rheumatologist at the University of California, Los Angeles. “In any other studies, the max is 20%,” he says.

Promise aside, these treatments—like all stem cell and bone marrow transplants—carry a risk of death. In the European studies, 28 autoimmune patients have died from transplant-related complications, as have four in the Hutchinson protocol. Although researchers initially performed transplants on the sickest patients, they found that too many succumbed to the rigors of the transplant. The teams have since shifted to patients with poor prognoses—in the Hutchinson protocol, the scleroderma patients are deemed to have a 50% chance of living 3 to 5 years—but relatively good health currently. “If it's done in the right patients, it gives them the best chance,” says Tyndall.

Still, such transplants remain a drastic treatment for both organ recipients and autoimmune patients. Their toxicity and their reliance, so far, on living donors has prompted questions about how widespread the treatment can become.

## Divide and conquer

Another way to thwart immune cells is to isolate them. A strategy called co-stimulatory blockade stops communication between specific immune receptors, which stud the surface of all sorts of immune cells and help govern their behavior, and the T cells on which particular receptors reside. Ideally, this prevents a defined subset of T cells from causing inflammation, while leaving everything else untouched. MGH's Sykes co-opted this approach when she added antibodies to her chimerism approach, but it can also be used alone.

One co-stimulatory blockade drug is anti-CD3, which interferes with so-called CD3 receptors and alters their ability to signal to T cells. The drug inactivates a subset of helper T cells thought to be involved in type I diabetes. These T cells apparently destroy insulin-producing islet cells in the pancreas. French scientists, led by Lucienne Chatenoud at the Necker Hospital in Paris, reported in 1997 that giving mice anti-CD3 cured diabetes, even after the drug was stopped. Now Kevan Herold of Columbia University, Jeff Bluestone of the University of California, San Francisco, and others are testing it in newly diagnosed diabetic patients, with the hope that such patients may still have islet cells left to save. Other antibodies are being explored for diseases ranging from psoriasis to MS to rheumatoid arthritis as well as kidney transplants.

## Discouraging works

For tolerance researchers, safety issues loom large. In the past few years, a handful of trials have caused enough harm to be halted, and others, such as stem cell transplants on autoimmune patients, have recorded higher-than-expected mortality rates for reasons not understood, says Roland Martin, chief of the cellular immunology section at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

Martin still does not understand exactly what went wrong in his MS trial, supported by Novartis in Basel, Switzerland, and the biotech firm Neurocrine Biosciences in San Diego, California. It ended disastrously in 2000, after three of the eight volunteers suffered exacerbated MS symptoms apparently linked to the peptide-targeting drug supposed to temper immune attacks. One patient began the trial with a few brain lesions and ended up with 91, and another exhibited large tumorlike lesions he'd never had before. It's still not clear what caused the lesions—which were successfully treated with standard MS drugs—although Martin theorizes that the dosing may have been too high, somehow sending immune cells into overdrive instead of quelling their activity.

“[Immune tolerance] is a matter of tipping the balance,” says Elaine Collier, chief of the autoimmunity section at the National Institute of Allergy and Infectious Diseases in Bethesda. “We may be tipping one set of regulatory cells the way we want, and another set the way we don't want.”

Fine distinctions in the immune system or among different diseases may help explain the startling variations in response to treatments, says Tyndall. Clues to what distinguishes subsets of patients could come from the tiny number of transplant patients who stopped taking immunosuppressants but somehow kept their organ. Kenneth Newell, a kidney and pancreas surgeon at Emory University in Atlanta, Georgia, is hoping to identify roughly 40 kidney patients in the United States and Europe who fit the bill; a group at the University of Pittsburgh in Pennsylvania is doing the same for liver recipients.

Fully “curing” disease by inducing true tolerance without the help of drugs remains the holy grail of the field. But those involved say that, given the mysteries that still surround the human immune system and the devastation it can produce, a more realistic, short-term goal may fall somewhere between broad immune suppression and total tolerance.

14. DANIEL PAULY PROFILE

# Going to the Edge to Protect the Sea

1. David Malakoff

Fisheries biologist Daniel Pauly has carved out a colorful—and controversial—career with fresh and frank insights into marine fisheries

Daniel Pauly still remembers his youthful encounter 30 years ago with what he calls “the living papers.” A graduate student in Germany, Pauly watched the field's royalty with awe at his first major fisheries conference. “Names I knew only from the literature were suddenly parading before me like kings,” he recalls. “I was terrified.”

These days, the 55-year-old Pauly—tall and graying—is a bit of a living paper himself. A professor at the University of British Columbia (UBC) in Vancouver, he is arguably the world's most prolific and widely cited living fisheries scientist, with recent headline-grabbing papers in Science and Nature. He's also an architect of a leading fish database and a popular ecological modeling program.

Despite these accomplishments, Pauly remains something of an outsider. His offbeat approach to the science is part of the reason. Whereas colleagues have built careers by using complex mathematics to crunch massive data sets, Pauly has worked mostly in data-deprived developing nations, and he says he can't stomach “enormous equations.”

The $4 million investment paid quick returns. A year later, Pauly's team—many plucked from ICLARM—scored again with a paper (Science, 6 February 1998, p. 860) that analyzed world catch data. It argued that fishers had systematically overfished larger, more valuable predatory fish, such as cod and groupers, forcing them to shift to less desirable species lower on the food chain. This “fishing down the food web,” Pauly said, would eventually leave people with a diet of “jellyfish and plankton soup.” Such hyperbole, and the statistical gyrations of Pauly's team, drew groans from some colleagues. FAO staff argued that Pauly had skewed their data to make his case (Science, 20 November 1998, p. 1383). In response, Pauly's team said that FAO's suggested corrections—such as accounting for aquaculture—only made the trend worse. A similar exchange followed a recent Nature paper (29 November 2001) with UBC colleague Reg Watson that suggested that China had intentionally inflated its catch statistics to match its economic targets. The reality, Watson and Pauly found by comparing the claims with the fish-producing capacity of Chinese waters, was that China's overblown numbers had masked a slight decline in FAO's global catch estimates. In a lengthy response (www.fao.org/fi/statist/nature_china/30jan02.asp), FAO researchers noted—accurately—that they had long ago asked China to correct the problem. And they decried press suggestions that they had intentionally fudged data to hide fisheries problems. “We welcome efforts to improve the accuracy of our data,” says Richard Grainger, FAO's fisheries chief. “That's why we've worked hard to make it available to researchers such as [Pauly].” Both papers “put FAO in a very difficult spot,” says Andrew Rosenberg, dean of life sciences at the University of New Hampshire, Durham, and the former top U.S. fisheries biologist. “Some people may [already] have known these things. But [Pauly] puts them together in a way that makes sense.” Pauly's notoriety has generated a flood of speaking invitations and helped attract a publisher for a long-planned volume called Darwin's Fishes. The title is a play on Darwin's famous finches, although Pauly says, “Darwin actually wrote far more about fish.” Being a celebrity is like hanging onto the side of a fast boat, he remarks: “It's nice to talk to the waves, but it's dangerous as hell.” Still, Pauly seems incapable of staying away from the edge. In recent speeches, he's told fisheries biologists that they need to win over the public—or else. “If fisheries science doesn't consummate a marriage with conservation,” he says, his discipline—and the oceans—will suffer. 15. DANIEL PAULY PROFILE # Science Helps Pew Push Its Oceans Agenda 1. David Malakoff From scientific conferences to Congress and the courtroom, the Pew Charitable Trusts has emerged as a major force in marine fisheries research and conservation. Over the last 4 years, the$4.3 billion philanthropy, based in Philadelphia, Pennsylvania, has channeled more than $12 million to Daniel Pauly and other marine scientists to study the impact of human activities—in particular fishing—on the seas. The findings have fueled landmark lawsuits, sparked policy changes, and raised awareness of the precarious state of the world's oceans. Pew relishes its reputation as a results-oriented, hands-on funder. But Josh Reichert, head of Pew's$45-million-a-year environment program, rejects the whispers among some scientists that Pew is looking for predetermined results. “There is no contradiction between our pursuit of conservation goals and sound science,” says Reichert. “We have a bias, but we never dictate results.”

That bias can be seen in its research portfolio. Pauly's $4 million project stems from Reichert's interest in how fishing is influencing ocean ecosystems. Another team of researchers, led by Larry Crowder of Duke University in Durham, North Carolina, and Ransom Myers of Dalhousie University in Halifax, Nova Scotia, are studying the impact of “long line” fisheries on nontarget species, such as turtles and sea birds. Other researchers are studying how other types of fishing gear, such as bottom-dragging nets, affect sea habitats. The results of these studies “can't solve problems by themselves,” says Reichert, who will disburse about$12 million to marine-related efforts this year. But they provide ammunition to a growing network of Pew-molded advocacy groups, including the education-oriented SeaWeb and the newly created Oceana, a “supergroup” that will pursue litigation, lobbying, and media coverage.

16. AMERICAN CHEMICAL SOCIETY MEETING

# Science Invades the Magic Kingdom

1. Robert F. Service

ORLANDO, FLORIDA—With nine major theme parks dominating the landscape here, fantasy reigns supreme. But nearly 14,000 chemists, materials scientists, and physicists tore themselves away from wild roller coaster rides long enough to present some 6500 papers. Among the highlights: a color-switching molecular motor, a novel scheme for improving hybrid organic-inorganic solar cells, and a safer way to make an antismog fuel additive that's more environmentally friendly than the most widely used additive, MTBE.

## Nanomotor's Rainbow Connection

Nanotechnology's forte—manipulating matter at near the atomic scale—is also its biggest weakness. Several research groups, for example, have built tiny rotary motors that spin in circles. But getting those motors to do work that makes a difference in our macrosized world has been hard. At the ACS meeting, Ben Feringa, a chemist at the University of Gröningen in the Netherlands, reported progress that puts the nano-to-macro transition in a new light.

Feringa and his colleagues in Gröningen and at Tohoku University in Sendai, Japan, used nanomotors to alter the orientation of liquid crystals, molecules commonly used in computer displays. That orientation change, in turn, altered the color of light the crystals reflected, allowing the Dutch team to generate a spectrum of different colors from a display without the need for the electronic circuitry that currently drives such devices.

The results—also published in the online edition of the Proceedings of the National Academy of Sciences—are unlikely to lead to quick commercial applications, Feringa cautions. Nevertheless, the work is impressive, says George Whitesides, a chemist and nanotechnology expert at Harvard University in Cambridge, Massachusetts. “It's a terrific example of trying to couple molecular-scale stuff to something real,” he says.

Feringa says that's exactly what he was hoping to accomplish. Three years ago his group reported making one of the first examples of a light-driven molecular motor. These compounds harbor two separate three-ring groups that rotate relative to one another. A full 360° spin occurs in four separate steps. First, the top half of the molecule absorbs a photon, causing it to turn 90° and adopt an energetically unstable orientation. The molecule stabilizes itself by making another quarter-turn, a reaction that occurs spontaneously because it is energetically favorable. Those two steps are then repeated, causing the molecule to spin in one direction.

The early molecular spinners were less than ideal. Among other drawbacks, the reactions that drove the spin worked only at high temperatures. Now the researchers have tweaked the structure of their motors to allow them to work at room temperature and to spin much more quickly than previous versions, making them potentially more powerful. They have also added the new-model motors to a thin film of rod-shaped molecules, called cholesteric liquid crystals. These molecules tend to stack like pencils lying flat one atop the other. Each layer is slightly offset from the one beneath it, so that collectively they twist upward like a spiral staircase.

Researchers have long known that the spacing between the molecules in a liquid crystal can change the color of light it reflects—tightly packed liquid crystals reflecting short wavelengths such as blue, widely spaced molecules reflecting longer wavelengths such as red. Feringa's team found that shining light on their motor-spiked liquid crystals caused the motors to turn, increasing the pitch of the liquid crystals and forcing them to move apart slightly (see diagram). The resulting color change wasn't instant. It took 10 seconds of illumination for the crystals to turn from violet to blue, and nearly a minute and a half to cross the entire visible spectrum. The speed of the color change is likely to underwhelm displaymakers looking for ways to scrap energy-hogging electronic components used by current setups. But Feringa says his efforts are just getting started. “This is the first demonstration that a molecular motor can be used to control the movement of many molecules and have a macrosized effect,” he says. And that could give nanotechnology a whole new strength.

## Stellar Way to Catch More Rays

Star-shaped plastics may just help the sunshine go a bit farther. Although most plastics are made from chainlike molecules, in recent years researchers have come up with a bevy of techniques for coaxing polymers to grow into tiny balls called dendrimers. Groups are looking at using dendrimers as everything from drug carriers to catalysts. At the ACS meeting, chemist Jean Fréchet of the University of California, Berkeley, reported that dendrimers may also help solar cells squeeze more electricity out of sunlight.

Fréchet's group has been working to improve a type of solar cell that uses an organic dye to collect the energy in sunlight and generate an electrical current. The researchers created dendrimers packed with light-harvesting compounds and added them to the solar cells. The dendrimers acted as antennae to capture more light, greatly enhancing the cells' light absorption.

“It's a promising approach” to improving conventional solar cells, says Mary Ann Fox, a chemist and the chancellor of North Carolina State University in Raleigh, whose group is pursuing similar research. Dendrimers currently are prohibitively expensive for high-volume applications, Fréchet notes. But if they yield promising light-absorbing compounds, researchers may be able to mimic the effect with cheaper conventional polymers.

Most commercial solar cells today use only inorganic semiconductors, such as silicon and the alloy cadmium telluride, to convert sunlight into a steady stream of electrons that can serve as a power source. But in 1991, Michael Grätzel of the Swiss Federal Institute of Technology in Lausanne devised a novel hybrid solar cell made from both organic and inorganic components. The device uses a rhodamine-based dye to absorb sunlight, which excites electrons in the dye and gives them enough energy to hop around. The mobile electrons quickly jump to a network of neighboring inorganic particles of titanium dioxide, which ferries them to an electrode that is connected to an external circuit, allowing them to power lights, toasters, or other electrical equipment. Grätzel cells, as they have come to be known, are cheap to make. But most such cells convert only about 6% of the energy in incoming sunlight to usable electrons, far below what many pure inorganic solar cells can accomplish. Hence Fréchet's interest in using dendrimers to increase that efficiency.

Unlike chainlike polymers, dendrimers have a branching structure that gives them a large surface area, perfect for attaching light-harvesting groups. Fréchet's group created dendrimers shrouded with coumarin 2 dyes, which readily absorb ultraviolet light, then added them to the mix of light-absorbing organics in a Grätzel cell and turned on a test lamp. “We get a huge enhancement” in the absorbed light, Fréchet says—enough to boost the electrical efficiency of the device by a couple percent.

Fréchet is quick to note that the current tests were done with ultraviolet lamps in the lab. But the Berkeley group is getting ready to repeat the tests with dendrimers designed to capture natural light. If all goes well, a few polymeric stars may hold the future to harnessing the power of the sun.

## Cleaning Air While Sparing Water

Kermit the Frog was right: It's not easy being green. The United States Clean Air Act requires that smog-ridden municipalities such as Los Angeles add oxygen-rich compounds to gasoline to help it burn more cleanly and thereby reduce smog-forming exhaust. However, cries for banning the most widely used additive, methyl tertiary-butyl ether (MTBE), are growing. MTBE readily dissolves in water and has fouled groundwater supplies around the country. A possible MTBE replacement, called dimethyl carbonate (DMC), does an even better job at helping gasoline burn cleanly. But the most prevalent scheme for making it carries its own environmental baggage, and alternatives are more costly.

At the ACS meeting, however, researchers led by chemist Yiling Tian at Tianjin University in China reported a potentially greener and cheaper approach to making DMC. The key is a new catalyst that turns carbon dioxide and cheap, nonhazardous starting materials into DMC. “It's a very interesting result,” says Michele Aresta, a chemist at the University of Bari, Italy. He cautions, however, that because proprietary concerns kept Tian silent about details of the new catalyst, the process's commercial prospects are hard to assess.

Even though DMC is nontoxic and therefore a potentially benign fuel additive, it has been anything but benign to make. Most producers start with a poisonous gas called phosgene, which requires expensive equipment to keep it contained. To make matters worse, generating DMC from phosgene produces chlorinated byproducts that can damage wastewater streams, says Chang-jun Liu, a chemist at Tianjin University, who is not affiliated with Tian's project.

Cleaner schemes do exist. One, which uses a catalyst to carry out a reaction between methanol, carbon dioxide, and ethylene oxide, has already been commercialized. But the reaction is still too expensive to be useful for making DMC in high volumes, Tian says.

Seeking a cheaper, more effective alternative, Tian and colleagues devised a catalyst containing two different metals that makes DMC from methanol, dimethyl ether—a cheap methanol derivative—and a pressurized form of CO2 called supercritical CO2. What is more, Tian says the reaction works under mild conditions and turns out DMC in high yield. That combination, Liu says, should make the process easy to scale up to generate DMC in the high volumes needed to bring the price down.

The new process could have other environmental benefits as well, Tian contends. Not only are the starting materials and byproducts nontoxic, but the process could be designed to tap CO2 present in oil fields, instead of releasing it to the atmosphere, and thereby help prevent the buildup of greenhouse gases. According to Tian, the Chinese energy giant Sino Petroleum, which funds part of his work, is considering scaling up the new process. If it succeeds, petroleum companies may have an easier time hewing to Kermit's hue.

## Snapshots From the Meeting

Electronic nose for liquids. Researchers around the globe are perfecting strategies for making polymer-based sensors that detect an array of different gases and produce an electrical signal. At the meeting, physicist Ananth Dodabalapur and colleagues at Lucent Technologies' Bell Labs in Murray Hill, New Jersey, reported the first conducting polymer transistors that work in liquids to detect a wide variety of compounds. Look for these to be integrated with microfluidic devices to automatically detect compounds coming from handheld medical diagnostic equipment.

Circular polyethylene. Virtually all common plastics are made from hydrocarbon groups linked together in long chains, like boxcars in a train. In a few exotic varieties, however, researchers have linked the ends of these polymer chains together to form large circles. At the meeting, chemist Robert Grubbs of the California Institute of Technology in Pasadena reported that his group has created a catalyst that turns one of the most common linear polymers, polyethylene—the stuff of grocery bags—into polymer circles. Watch for studies that show whether the new circular polyethylene has unique properties that push the ubiquitous polymer into new markets.

More on drug pollution. The U.S. Geological Survey came out with a widely publicized study last month showing that a handful of prescription and over-the-counter drugs could be detected in U.S. waterways, raising concerns that they pose a new threat to fish and other aquatic life. Padma Venkatraman and colleagues at Johns Hopkins University in Baltimore reported here that the problem could be much more widespread. To guide future studies, they tracked sales and prescription data for the 200 most popular prescription drugs and fingered numerous antimicrobials, anticonvulsants, antidepressants, and anticancer compounds that could further endanger aquatic life. Results from ongoing field studies by the group will better define the true magnitude of the threat.