# News this Week

Science  05 Mar 2004:
Vol. 303, Issue 5663, pp. 1446
1. SCIENCE POLICY

# White House Denies Playing Politics With Science

1. David Malakoff

Long-simmering dissatisfaction with the Bush Administration's handling of scientific advice has come to a hearty boil. Stung by charges by more than 60 prominent researchers that the Administration has manipulated science to advance its political agenda, White House science adviser John Marburger this week moved to rebut what he calls a “troubling misperception” based on a “deeply flawed” report. “I'm quite irritated by the character of the report [and] concerned that so many respected scientists would sign on,” he says.

But the critics haven't backed off, and they say a White House decision to remove two academics from a bioethics panel only reinforces their concerns (see p. 1447). The debate is likely to stay hot, with a Senate panel due to examine the issue on 9 March.

Fueling the flames are two documents released by the Union of Concerned Scientists (UCS), a Cambridge, Massachusetts-based advocacy group, on 18 February. One is a two-page statement on “restoring scientific integrity in policy making” signed by 20 Nobel laureates, former President Bill Clinton's two science advisers, and five appointees of the Nixon and Eisenhower Administrations. (Reagan and George H. W. Bush appointees are conspicuously absent.) It accuses the current Bush White House of suppressing or simply ignoring technical findings that don't support its views. Tactics have included watering down documents, stacking advisory panels with ideological allies, and muzzling government scientists, the signers say.

“Across a broad range of issues, the Administration has undermined the quality of the scientific advisory system and the morale of the government's outstanding scientific personnel,” says lead author Kurt Gottfried, a professor emeritus of physics at Cornell University and chair of UCS. To restore order, the signers call on the White House to issue new rules and on Congress to pass legislation barring government censorship of findings that don't have security implications.

The second UCS indictment is a 31-page report that summarizes 21 incidents that UCS says illustrate “a well-established pattern of suppression and distortion of scientific findings by high-ranking Bush administration political appointees.” All of the incidents have been reported by Science and other media, including a decision to delete language on climate change from a report published by the Environmental Protection Agency (EPA) and moves to alter the membership of several advisory panels dealing with controversial lead pollution or ergonomics standards. The report also criticizes the White House for appointing Richard Russell, a former House Science Committee aide who holds a bachelor's degree in biology, as Marburger's top aide for technology, noting that past appointees to the position typically have had advanced degrees or extensive experience in industry.

When asked about the documents at two congressional hearings last week, Marburger said he had “a great deal of respect” for the researchers who signed the statement but “considerably less for the report.” It is “incomplete” and unable to “support the sweeping claim that is being made,” he said. He also called the attack on Russell “personal and … outrageous.”

“It is almost a conspiracy theory document. … There isn't enough information to suggest a pattern,” Marburger had told reporters earlier. In the case of the EPA report, for instance, all of the removed language—and more—was included in a climate science action plan released a short time later, he told lawmakers. In other cases, he says the report's authors highlighted interim documents but ignored final products. Marburger intends to include such “contextual” information in a detailed response that should be available within weeks. The added information “will make things look a lot less ominous,” he believes. “It's pretty easy to walk through every allegation and shred it,” adds Deputy Secretary of Energy Kyle McSlarrow.

So far, however, those who signed the statement are standing behind the report. (But at least one—Lewis Branscomb, head of the National Bureau of Standards in the Nixon Administration, who is now at Harvard University in Cambridge, Massachusetts—believes it should not have criticized Russell's credentials.) And both Branscomb and Gottfried dub Marburger's response “lame.” “We didn't say there is a conspiracy, some guru in the White House directing all this,” says Gottfried. Adds Branscomb: “Some [events] are pretty hard to explain away.”

Those events, and the report's credibility, are likely to get more attention next week, when Gottfried is scheduled to appear before Senator John McCain's (R-AZ) Commerce panel along with Bruce Alberts, head of the National Academy of Sciences, and possibly other scientists. So far, the panel hasn't asked Marburger to appear, which is fine with Administration critics who say he shouldn't shoulder the blame. “This wasn't an attack on [Marburger],” says Branscomb. “He's done the best he can, given the circumstances.”

2. FRENCH PROTESTS

# Impasse Continues, D-Day Looms

1. Barbara Casassus*
1. Barbara Casassus is a writer in Paris.

PARIS—Ringleaders of a nationwide protest earlier this week spurned a government bid to meet their demands for cash and jobs. As Science went to press, the opposing sides were huddled in talks aimed to avert a potential research meltdown.

Hundreds of lab directors have vowed to stop carrying out administrative duties beginning on 9 March if the French government does not pony up €200 million owed to science agencies and reinstate 550 permanent research jobs abolished in favor of short-term contract positions (Science, 13 February, p. 948). Their Internet campaign has now gathered more than 57,000 signatures. On 27 February, research minister Claudie Haigneré unveiled a raft of measures, including a promise to “unfreeze” €294 million from the 2002 and 2003 budgets—more money than the protesters had been demanding—create 120 permanent posts for scientists, engineers, and technicians, add 30% to contract salaries, and provide grants for 300 additional doctoral students and increase their value by 4%. “We have come a long way,” Haigneré said on 27 February.

The protest's spokesperson, however, has pooh-poohed the concessions. “They are derisory,” asserts cell biologist Alain Trautmann. The research union SNCS-FSU also had heaped scorn on the government, calling the proposals “window-dressing, a smokescreen, a budgetary masquerade.”

A major stumbling block, Trautmann says, is the government's refusal to restore all the permanent posts it had converted to contract positions. The protesters have also upped their demands, calling for an unspecified number of new academic jobs as well. “We need several hundred university posts,” says Trautmann.

Intense negotiations are under way to ward off next week's administrative walkout, which could grind many labs to a halt within weeks. To help end the standoff, Étienne-Émile Baulieu, president of the French Academy of Sciences, has offered to chair a committee that would organize a debate and a conference on the future of French research. Representatives of the protesters, the academy, and the government were discussing Baulieu's proposal earlier this week.

3. WHITE HOUSE

# Researchers Blast U.S. Bioethics Panel Shuffle

1. Constance Holden

In what appears to be a strikingly ill-timed move, the White House last week replaced two members of its Council on Bioethics with moral conservatives—just as the president's science adviser was rebutting charges of political bias (see “White House Denies Playing Politics With Science”).

On 27 February, the White House announced the departure of two council members whose views are generally favored by scientists: cell biologist Elizabeth Blackburn of the University of California, San Francisco, and ethicist William F. May, a professor emeritus at Southern Methodist University in Dallas, Texas. Blackburn and May were both in the minority in the most politically contentious issue to face the council: They voted that the cloning of human embryos for research should be permitted. Their departure and the appointment of two social scientists with conservative social views and a devout Christian brain surgeon immediately triggered cries of political foul play. Council chair Leon Kass insists that the changes are “in no way political” but rather designed to strengthen expertise in areas of brain and behavior the group wishes to explore next.

The new members are Benjamin Carson, a renowned black pediatric neurosurgeon at Johns Hopkins University in Baltimore, Maryland; Peter Augustine Lawler, a professor of government at Berry College in Mount Berry, Georgia; and Diana Schaub, a political scientist at Loyola College in Baltimore. The three seem to be on Kass's philosophical wavelength. Lawler, for example, has warned that biotech can't create happiness and could “isolate us from others even more.”

Several scientific societies have denounced the personnel change: The American Society for Cell Biology dubbed it the “Friday Afternoon Massacre.” Democrats including presidential candidate John Kerry accused the White House of playing politics with science. University of Pennsylvania bioethicist Glenn McGee notes that in dropping Blackburn, the group is losing its greatest authority on stem cells. “Whatever credibility presidential bioethics bodies had before this scandal, they certainly have less now,” he says.

Blackburn told reporters she'd had no warning that she was getting the boot. She has been at odds with the majority more than once. Last fall, she said she considered resigning to protest a council report on biotech that she felt was alarmist and had been rushed through without adequate feedback from the members. Now she says “the balance of the council is very dramatically changed. … If we look at what's been publicly said [by the new appointees], it seems their views will be very close to those of the chairman.”

Kass, who was clearly dismayed and annoyed by the fuss, says May had planned to step down when members' 2-year terms expired in January. May, a Democrat, says that he was actually willing to continue but had suggested to Kass that his age—76—might be a bar. In any case, he says, “there was no break between me and Leon.”

Kass won't say what role he played in the personnel shuffle but insists no one was vetted for their political views. He points out there are still “strong differences” within the council and that seven members disagree with President George W. Bush's stem cell research policies.

4. UNIVERSITY-INDUSTRY RELATIONS

# Pitt Takes Over a Struggling Genetic Technology Firm

1. Yudhijit Bhattacharjee

Nobody raises an eyebrow these days when a high-tech company is spun out of research done at a university. But now comes the reverse: a “spin-in” company that's struggling in the marketplace and retreats to the shelter of academe. The University of Pittsburgh Medical Center (UPMC) pioneered the idea last month by taking over an independently founded biotech firm to beef up its academic research.

UPMC officials say the university is acquiring RheoGene, a Philadelphia-based company that manufactures gene expression technologies, to help its researchers make advances in gene therapy and regenerative medicine. They also hope the company will develop commercial therapeutics. The acquisition comes a year after UPMC joined with other investors to buy a division of PPL Therapeutics in Blacksburg, Virginia—part of the financially strapped Scottish firm that created Dolly the cloned sheep. The goals were similar: to get access to research tools and possibly make a profit.

Observers say the RheoGene transaction is a new milestone in the forging of close ties between academia and industry. “It reflects an increasing integration of universities into the innovation economy,” says Ashley Stevens, director of the Office of Technology Transfer at Boston University (BU). Patent owners have donated their property to universities for development before; Stevens says the donation of a company is a logical next step.

RheoGene fell into UPMC's lap after its parent company, Rohm and Haas, decided to get rid of it but couldn't find a buyer. Researchers at UPMC's McGowan Institute for Regenerative Medicine had been using RheoGene's technologies—which allow for precise control over the expression of multiple genes and are therefore attractive for experiments in cell therapy and tissue engineering—in an academic collaboration. When he learned that the company was in distress, McGowan's director, biological chemist Alan Russell, persuaded Rohm and Haas to donate the entire firm, including its patents, 20-member staff, and facilities, to the university. The Pennsylvania state government chipped in with a 5-year, $1.5 million grant to UPMC to help facilitate the takeover. Rohm and Haas can get a tax write-off on the donation, whose value it estimates at$30 million.

UPMC doesn't see any parallels between the RheoGene acquisition and BU's fateful investment in the biotech company, Seragen, from 1987 to 1998, which ended up costing BU over $45 million. “We are a 20-hospital system with an annual budget of$5 billion,” says UPMC treasurer C. Talbot Heppenstall Jr. “Can we afford this company? Yes. Do we think it's worth the risk? Absolutely.”

Although UPMC sees RheoGene as a profitmaking venture in the long term, its more immediate goal is using the company's resources to accelerate basic research at the McGowan Institute and the University of Pittsburgh Cancer Institute. Russell says the acquisition will provide UPMC researchers greater access to RheoGene's technologies. Information exchange will be more “straightforward,” says Russell, now that UPMC is RheoGene's owner as well as a collaborator.

The benefits will be mutual, says RheoGene CEO Tom Tillett, who hopes that the relationship will help the company customize its technologies for the development of human therapeutics. And in the short term as well, RheoGene expects to reap some financial dividends from the partnership by collaborating with UPMC on grant proposals. Even so, Tillett does not anticipate that the company will become profitable anytime soon. Last year, it generated $400,000 in revenue including licensing income and government grants—an undisclosed fraction of operating costs. This year he hopes it will do better. 5. PLANETARY SCIENCE # A Wet Early Mars Seen in Salty Deposits 1. Richard A. Kerr WASHINGTON, D.C.—The low, light-colored outcrop that the Opportunity rover stumbled upon in an enticing sea of dark sand was going to be just a bonus, a sideshow to the rover's mission to follow the water on Mars. But this week the outcrop turned out to be the big payoff: strong evidence that eons ago water flowed across Mars, ponded over hundreds of kilometers of the surface, and then returned to the atmosphere, leaving behind a 300-meter-thick layer of minerals leached from the land. “We've found our ancient water on Mars,” says rover science team member Harry McSween of the University of Tennessee, Knoxville. The new findings don't prove that the water ever sustained life on Mars or even that Mars was ever as warm and wet as Earth has been. They do mean that at least in one place the size of Oklahoma, water soaked the rock—an ocean floor or subterranean strata—for age upon age, which is what martian life would have needed. From high above in orbit, the attraction at Opportunity's future landing site appeared to be a surface layer of dark, coarse-grained debris that spectra obtained from orbiting spacecraft suggested was rich in the iron-oxide mineral hematite. The$410 million Opportunity came to check out this hematite and any accompanying minerals to see whether it formed in a warm, wet environment—such as a lake bottom or subterranean aquifer—that was suitable for life. But sticking up here and there through the 10-meter-thick hematite layer was a lighter rock. Where it outcropped, it could be seen to be 300 meters thick and layered on the scale of meters. By sheer chance, Opportunity—encased in its landing air bags—rolled to a stop inside a 20-meter crater where the impact had exposed what may well be a tiny bit of the underlying stratum. From the ground, the half-meter section was finely layered, on the scale of millimeters.

At a press conference at NASA headquarters on 2 March, rover principal investigator Steven Squyres of Cornell University ticked off the four lines of evidence for a soaking wet Mars that he and his team had developed from Opportunity observations of the previous couple of weeks. The first two involve the structure of the outcrop. The round balls 2 or 3 millimeters in diameter seen weathering out of the rock are concretions formed in place, they decided, not blobs of molten rock that fell onto a soft lake bottom. Concretions grow by the chemical precipitation of minerals, implying that lots of mineral-laden water was around when they formed. The second kind of structural evidence is vugs, “very weird-looking, tabular holes,” in Squyres's words, that riddle the rock. They are probably the voids left by now vanished crystals of gypsum—to judge by their shape—that grew from mineral-laden water.

The third line of evidence is mineralogical. The rover's Mössbauer spectrometer found high concentrations of jarosite, an iron-rich mineral “you have to have water around to make,” said Squyres. And the fourth sign of water was chemical. The rover's alpha-particle x-ray spectrometer (APXS) found “an enormous quantity of sulfur in this rock,” said Squyres. “It must be full of sulfate, a telltale sign of liquid water.” The rover's mini-thermal emission spectrometer also saw signs of sulfate in the infrared colors of the rock. There seems to be up to 40% salt in the outcrop, much of it probably magnesium sulfate, the familiar Epsom salts. “This is an astonishing amount of salt,” said Benton Clark, a science team member at Lockheed Martin in Denver. On Earth, such an abundance of salts typically makes a rock an evaporite. They most often form when water carrying dissolved material pools and then evaporates away, concentrating the dissolved salts until they precipitate and fall to the bottom. In fact, the APXS found different compositions at the bottom and top of the outcrop, reminiscent of the way evaporite composition varies as salts become more and more concentrated in the water.

The official line on all this salty water on early Mars (a few billion years ago is the best guess) is twofold. It all happened either underground in a porous rock aquifer or at the bottom of a lake or an ocean. Either would be a suitable habitat for life. In the first scenario, water percolated through a buried bed of volcanic ash, altering the rock and depositing salts. In the ocean or lake scenario, water flowed across the surface, picking up salts from the rock. It then pooled in a depression and evaporated away, leaving the salts. If it were particularly cold then, as scientists have been concluding of late, the ice could have sublimated away to leave salts as well.

Squyres is not yet leaning toward either scenario, but sedimentologist John Grotzinger of the Massachusetts Institute of Technology—another team member and press conference panel member—admitted to Science that “it's hard to avoid the thought that” the ocean/lake scenario is now the dominant hypothesis. The aquifer would have needed both a heat source, such as volcanic activity, and a source of sulfur, he notes, neither of which is evident. Opportunity is now marching down the outcrop again, this time throwing all its analytical power at selected sites in an effort to find out whether it was surface standing water or groundwater. “We may never know,” said Squyres, “but we're going to give it our best shot.”

6. GENETICS

# Hybrid Mosquitoes Suspected in West Nile Virus Spread

1. Jennifer Couzin

West Nile virus has walloped the United States each year since it arrived in 1999. Mysteriously, however, there have been few human outbreaks in Europe—even though the virus is endemic there, and the birds that harbor it and the mosquitoes that transmit it are similar to those in the United States.

Now, genetic analyses of mosquitoes from five continents suggest a controversial explanation for this mystery: U.S. mosquitoes that transmit West Nile virus may be hybrids of two strains. In Europe, some researchers believe, mosquitoes normally specialize in either birds or mammals. The hybrids, according to the new theory, feast on both, spreading the virus from one species to another.

Some West Nile experts enthusiastically endorse the proposal, described on page 1535, saying it could help solve several nagging puzzles about how the virus spreads. But others are not convinced. “The evidence here is anything but solid,” says entomologist Andrew Spielman of Harvard School of Public Health in Boston. Like many researchers, he believes that “naïve” populations of birds and people in the United States have never been exposed to the virus and are thus more susceptible to it, whereas Europeans have been exposed for centuries.

The paper's authors, led by Dina Fonseca of the Smithsonian Institution's National Museum of Natural History in Washington, D.C., who was working with Richard Wilkerson of the Walter Reed Army Institute of Research in Silver Spring, Maryland, focused on a complex of mosquitoes called Culex pipiens. It includes at least two species, Cx. pipiens and Cx. quinquefasciatus; both are suspects in U.S. West Nile epidemics. In northern Europe, some mosquitoes in the complex live above ground, and others flourish beneath it. The name Cx. molestus has been used to describe the subterranean dwellers, but scientists have squabbled for years over whether molestus is a species in its own right.

Fonseca and her colleagues examined mosquito samples from 33 sites in countries including Australia, Britain, Germany, Italy, Japan, Jordan, and the United States. Eight genetic markers in above- and belowground mosquitoes from Britain and Germany showed that “boom, these are different” from one another, she says. Despite residing in the same geographic area and appearing to be virtually identical, the mosquitoes were not exchanging DNA in the marker regions. (In Japan, Australia, and the Middle East, distinct above- and belowground populations aren't thought to coexist.)

The genetic markers told a different story in U.S. mosquito samples: More than 40% of the Cx. pipiens mosquitoes were hybrids, mixing genetic material that, in Europe, was segregated in above- or belowground mosquitoes. In southern Europe, no more than 10% of the mosquitoes sampled were hybrids; almost none from northern Europe were.

“It's a very enticing theory, [and] it really fits with what we've been seeing,” says Laura Kramer, director of the arbovirus laboratories at the New York State Department of Health in Albany. Risk analyses had led researchers to conclude that the Cx. pipiens species was transmitting West Nile virus to humans—which was strange, because the insects had long been considered “bird-biters.” Given the new study, Kramer tentatively concludes that “what we've been calling pipiens are a hybrid.”

Still, the scientists haven't shown that genetic hybrids of what they suggest are bird- and human-biters like biting both. There's also disagreement over whether Cx. pipiens complex mosquitoes are the dominant type in transmitting West Nile virus to humans. In the United States, says Paul Reiter, an entomologist at the Pasteur Institute in Paris, West Nile has been isolated from 38 different mosquito species.

While Kramer, Fonseca, and others explore whether hybrids are behind West Nile virus's spread in the Western Hemisphere, Fonseca is also hoping to examine the genetics of mosquitoes involved in Eastern Hemisphere outbreaks, including one in Romania in 1996, and other recent outbreaks in Israel.

7. U.S. UNIVERSITIES

# Foreign Graduate Student Applications Drop

1. Yudhijit Bhattacharjee

The specter of long delays and uncertainties in obtaining a visa appears to be dissuading a sizable number of international students from applying for graduate study in the United States.

A survey* conducted by five higher education organizations and released last week found that 47% of the 250 colleges and universities that responded received fewer graduate applications for fall 2004 compared to last year. Among them are 19 of the 25 U.S. research institutions that enroll the largest number of international students. Thirty-eight percent of respondents reported no change in application rates, and 14% reported an increase. “The declining rates are clearly connected to a series of actions taken by the U.S. government to make it progressively more difficult for people to enter the country,” says Victor Johnson of NAFSA: Association of International Educators, one of the organizations that conducted the survey.

The point was underscored by a report from the General Accounting Office (GAO), issued on the same day, that documented delays in visa processing for science students and scholars. Based on a study of 71 cases, GAO found that it took an average of 67 days to review applications requiring an extensive security check, or Visas Mantis—aimed at preventing the transfer of sensitive technologies. Consular staff interviewed by GAO said that they were unclear which cases needed to be subjected to a Visas Mantis check, which often involves additional scrutiny by the FBI and other agencies. “Consular officials seem to be applying Visas Mantis very broadly to protect themselves against the charge of not being vigilant enough,” says Johnson, noting the increase in Mantis reviews from 1000 in 2000 to 20,000 in 2003. State Department figures also show a drop in visas issued (see table).

View this table:

The growing effort by universities in Australia, the United Kingdom, and Canada to attract international students may have contributed to the U.S. decline, says Peter Syverson of the Council of Graduate Schools. But, he adds, “The climate in the U.S. is more challenging for international students than before because of the general need to fill out more forms on campus, to be re-registered every year, and so on.”

• † The others are the American Council on Education, the Association of American Universities, the Council of Graduate Schools, and the National Association of State Universities and Land-Grant Colleges.

8. STEM CELL RESEARCH

# Harvard Enters Stem Cell Fray

1. Andrew Lawler

BOSTON—Harvard University intends to raise on the order of $100 million in the next few years to create a stem cell research institute. The initiative will focus on bringing work on such cells out of the lab and into the clinic, and it will operate without federal funding to avoid government restrictions. Harvard will also draw on faculty members outside science to address the thorny ethical, business, and policy aspects of the controversial research. Harvard's foray into the field was underscored by a report this week that Douglas Melton, a co-director of the new effort, and colleagues have created 17 new human embryonic stem cell lines (Science, 7 November 2003, p. 983). In 2001, President George W. Bush declared that federal funds could be used for research only on then-existing cell lines. Melton says his team used private funds to develop the new lines because “we were not convinced that the numbers and quality available to do our research” were sufficient. The new cell lines, described in the 25 March issue of The New England Journal of Medicine, can be more easily grown and used in the lab than existing lines, he adds. Harvard's new institute and cell lines are the latest signs that restrictions on federal funding are doing little to dampen enthusiasm among scientists eager to work with stem cells. From New Jersey to California, researchers and politicians are scrambling to finance stem cell research privately. The Harvard institute will exist as a virtual center until a new building is constructed, which likely will take 5 years or more. Harvard officials decline to provide financial details, but one says that$100 million is the “crude figure” necessary to power the institute and that at least one donor has already been found.

The competition for both dollars and researchers is sure to be fierce. Stanford University, the University of California, San Francisco, and the University of Wisconsin, Madison, already are pulling in substantial private funds for stem cell research. Meanwhile, California enthusiasts are pushing a ballot initiative for November that would issue $3 billion in bonds for the research over a decade (Science, 16 January, p. 293). It follows a state law promoting stem cell work. In New Jersey, a new state law does the same, and the governor is backing a 5-year,$50 million research fund that would combine state and private monies.

Harvard's institute will focus on issues such as why some stem cells don't transplant successfully and which disease processes might be halted by stem cell therapies. “Maybe what we're doing isn't unique, but we make up for that in our depth and breadth,” says David Scadden of Massachusetts General Hospital, who will co-direct the new effort. “I think it will have a major impact on stem cell biology,” says Leonard Zon of Children's Hospital in Boston and president of the International Society for Stem Cell Research, who is on the institute's executive committee. In addition, the institute will turn to Harvard schools of government, law, business, and divinity for advice on issues related to stem cell research. More details should be forthcoming in April, when Harvard plans to host a scientific conference on stem cells.

9. CELL BIOLOGY

# How Cells Endure Low Oxygen

1. Jean Marx

As researchers unravel the biochemical system by which cells register and respond to hypoxia, they're coming up with potential new strategies for treating cancer, heart attack, and stroke

Cells can't exactly gasp for breath when they are deprived of oxygen. But they do have their own way of coping: a highly efficient system for turning on a host of genes that can counteract the effects of low oxygen levels, or hypoxia. Recently, researchers have learned a great deal about how this intricate system works, and the results have surprisingly broad implications: Drugs that target this system could potentially lead to better therapies for diseases from cancer to heart attacks to inflammation.

One key discovery revealed the heart of the system: a family of related proteins called hypoxia-inducible factors (HIFs). HIFs are transcription factors that turn up the activity of a variety of genes when oxygen becomes scarce, which can happen in a variety of both normal and pathological conditions. Some tissues, including the placenta and hard-working muscles, naturally have to deal with low oxygen concentrations, whereas in other cases—say, during a heart attack or stroke—HIFs can help mitigate the damage caused by a cutoff of blood flow to critical tissues.

The genes controlled by the HIFs include those coding for proteins that stimulate red blood cell production and angiogenesis, the formation of new blood vessels, as well as for glycolytic enzymes that can produce energy from glucose without the aid of oxygen. “HIF-1 is a sort of master switch that allows cells to respond to falling oxygen,” says William Kaelin of Harvard's Dana-Farber Cancer Institute in Boston.

HIFs have also been linked to disease. Many kinds of cancers carry elevated levels of the proteins. This change may contribute to the cancers' ability to grow and spread, partly because it revs up angiogenesis, which in turn provides tumors with new blood vessels that fuel their growth. As a result, scientists in both industry and academia are looking for compounds to inhibit HIF activity. Conversely, drugs that increase HIF activity may be useful for treating victims of heart attacks and strokes.

Much more work will be needed, however, first to develop drugs that act on HIFs, and then to see if they are safe to give to patients. One indication of the enormous interest HIFs are generating: The first-ever conference on hypoxia will be held at the end of the month at a Keystone Symposium in Steamboat Springs, Colorado.

## A multitalented protein

Researchers first identified HIF-1 about 12 years ago, when they were trying to figure out how the body controls production of erythropoietin (EPO), a protein that stimulates production of red blood cells and is now widely used to prevent anemia in patients with chronic kidney failure. Oxygen deficiency stimulates EPO production, and Gregg Semenza's team at Johns Hopkins University School of Medicine in Baltimore, Maryland, had set out to discover how this happens. The researchers found that a particular sequence in the EPO gene plays a critical role, and when they then looked for proteins that bind to that sequence, they came up with HIF-1.

The protein's functions in the body have turned out to be surprisingly broad. Semenza estimates that perhaps 5% of the human genome comes under its control, although the exact suite of genes regulated varies depending on the cell type. In addition to genes involved in glycolysis and angiogenesis, HIF-1's targets include those involved in controlling cell growth, division, survival, and mobility. Whereas only a few cell types produce EPO, HIF-1 “worked in all cells, irrespective of whether they make EPO. That was extremely unexpected,” says Peter Ratcliffe of the Henry Wellcome Building of Genomic Medicine at the University of Oxford, U.K.

Consistent with its broad impact on gene regulation, HIF-1 plays major roles both in embryonic development and in adults. The protein consists of two essential subunits, called HIF-1α and HIF-1β. About 6 years ago, Semenza's team and also that of Randall Johnson at the University of California, San Diego, showed that knocking out the gene for the α subunit causes mouse embryos to die around the tenth day of gestation. The embryos' many abnormalities included defective blood vessel and heart development, presumably because normal angiogenesis doesn't occur without functional HIF-1.

Subsequent work by Celeste Simon's team at the University of Pennsylvania (Penn) School of Medicine in Philadelphia showed that HIF-1 is also needed for the placenta to establish normal blood connections in the uterine lining. “Virtually all aspects of the vascular system are fine-tuned by this [HIF] system,” Simon says.

Because embryos lacking HIF-1 die early in gestation, they provide few clues to the protein's role in more mature tissues. Recently, however, researchers have produced so-called conditional knockouts, in which they inactivate the protein in specific cell types. Using such an approach, Johnson and his colleagues have found that macrophages and neutrophils—immune cells whose activity can lead to inflammation—depend on HIF-1, probably because they often operate in hypoxic conditions, such as in wounds and abscesses. “Knocking out HIF in macrophages and neutrophils basically blocks inflammation,” Johnson says. One obvious implication: Drugs that inhibit HIF-1 activity might be useful for treating inflammation, he suggests.

## Maintaining control

While researchers were making these discoveries, they were also finding that the body keeps HIF-1 activity under tight control. Within the past few years, they've started to figure out how that control is achieved, with a particular focus on HIF-1α as HIF's oxygen-sensitive component.

Early work showed that cells maintain relatively constant concentrations of the β subunit, but that HIF-1α concentrations vary, going up when oxygen levels are low and down when they are normal. These HIF-1α fluctuations are achieved partly by regulating destruction of the subunit. As shown by Jaime Caro of Jefferson Medical College in Philadelphia and others, when oxygen levels are normal, the protein is targeted for destruction by addition of a small protein called ubiquitin. But a fundamental question remained, says Kaelin: “How do cells know they are hypoxic and should leave HIF alone?”

A big clue came in 1999 when Ratcliffe's group showed that cells lacking the von Hippel-Lindau (VHL) tumor suppressor protein do not degrade HIF-1α properly. There was already good reason to suspect a link between HIF and VHL. Patients who have VHL gene mutations develop numerous cancers, particularly renal cell carcinomas—tumors that not only are copiously supplied with blood vessels but also have abnormally high levels of HIF-1. And Kaelin's group had previously found that cells harboring VHL mutations show signs of increased HIF activity. The reason for that became clear when Ratcliffe, Kaelin, and others showed that the VHL protein attaches ubiquitin to HIF-1α. The mutations prevent that addition, allowing HIF-1α to build up.

The link to oxygen levels came in 2001, when three groups, one led by Ratcliffe and Christopher Schofield of the University of Oxford and the others by Kaelin and Frank Lee at the University of Pennsylvania School of Medicine, showed that HIF-1α must have hydroxyl groups tacked onto two specific residues of the amino acid proline before it can be ubiquitinated by VHL. Shortly thereafter, Ratcliffe's team and, independently, Steve McKnight and Richard Bruick of the University of Texas (UT) Southwestern Medical Center in Dallas identified the prolyl hydroxylase enzymes required for the hydroxylation reaction, which requires oxygen.

A second oxygen-dependent enzyme came into the picture the following year. Murray Whitelaw of the University of Adelaide in Australia, Bruick, and colleagues discovered that FIH-1, a naturally occurring HIF-1 inhibitor identified in Semenza's lab, uses oxygen to add hydroxyl groups to an asparagine residue near the carboxy end of HIF-1α. This prevents HIF-1α from interacting with other transcription factors to regulate gene activities.

Many, perhaps most, of the researchers working on HIFs now think that the prolyl and asparaginyl hydroxylases are themselves the “oxygen sensors” that keep HIF-1 turned off when cells have plenty of oxygen. “They provide a direct interface with molecular oxygen,” Ratcliffe says.

But other researchers think the enzymes come into play later, in response to the actual sensor. This group includes Penn's Simon and Paul Schumacker of the University of Chicago, who have proposed that the sensor may instead be located in the mitochondria, the organelles that provide most of the cell's energy when oxygen is abundant.

They base this suggestion partly on their finding that cells lacking functional mitochondria don't respond to low oxygen levels by activating HIF. The missing ingredient in such cells may be the so-called reactive oxygen species (ROS) that mitochondria produce when oxygen concentrations are low. Schumacker's group has found that adding reactive oxygen in the form of hydrogen peroxide stabilizes HIF-1α. In contrast, overexpression of catalase, an enzyme that helps cells eliminate ROS, abolishes that response.

The issue of the oxygen sensor's identity is sure to be a hot topic at the upcoming Keystone Symposium. “The central question regarding HIF-1α is what the oxygen sensor is,” Schumacker says.

## The cancer connection

Oxygen-sparked degradation of HIF-1α isn't the only way cells regulate the protein's concentration, however. Work by Semenza, Amato Giaccia of Stanford University School of Medicine, and others has shown that activation of two of the major pathways that stimulate cell growth leads to increased production of the protein even when oxygen levels are normal. It's apparently a preemptive strategy that allows tissues—and tumors—to cope with decreased oxygen concentrations as they expand. This response can be buttressed, however, by inhibition of HIF-1α breakdown due to hypoxia. “The combination results in very high levels of [HIF-1α] expression,” Semenza says.

Elevated HIF activity may contribute to the development of human cancers. HIF-1α has a relative, HIF-2α, which was discovered in the late 1990s by McKnight's team. Exactly what HIF-2α does is an outstanding question, although recent results from Joseph Garcia, also at UT Southwestern Medical Center, and his colleagues suggest that it may help protect cells against oxidative damage. Whatever it does, HIF-2α, like its cousin HIF-1α, has been linked to cancer.

Researchers have found that many human cancers, including common ones such as breast, colon, and lung cancers, have much higher levels of either HIF-1α or HIF-2α than do surrounding tissues. The changes in gene expression triggered by HIF-1 can promote cancer in a variety of ways. They foster the formation of new blood vessels, promote the spread of cancer cells to new sites by providing molecules needed for cell motility, and inhibit the programmed cell death that might otherwise eliminate abnormal cells.

Although HIF-2α's activities may be different, recent work by Kaelin's team shows that it is the chief culprit behind the growth of renal carcinoma cells in which the VHL gene is mutated. Normally, addition of the normal VHL gene to such cells inhibits their ability to form tumors when transplanted into mice—as would be expected for a tumor suppressor. But as the researchers reported in the December 2003 issue of the Public Library of Science Biology, this doesn't happen if renal carcinoma cells have an altered form of the HIF-2α gene that doesn't respond to VHL. Conversely, suppressing HIF-2α activity in the cells suppresses tumor growth.

Taken together, Kaelin says, the results show that suppression of HIF-2α is both necessary and sufficient to arrest the growth of these renal carcinomas. The work has caused a shift in his thinking. Previously, Kaelin says, “I thought that the tumor outgrowing its blood supply was causing up-regulation of HIF. Now I have to think it is the other way around”—that up-regulation of the HIF genes causes the tumors.

Less clear is whether HIFs alone can lead to the growth of cancers not linked to VHL mutations, although McKnight says they “probably have a very, very substantial role.” Among other things, researchers including Semenza, Giaccia, and Adrian Harris of the Churchill Hospital in Oxford, U.K., have linked the elevated HIF levels seen in many cancers to a poor prognosis for patients. The finding is consistent with something oncologists have known for years: Hypoxia makes tumors resistant to both radiation and many chemotherapeutic drugs. “Hypoxic cells need three times as much radiation to kill as normally oxygenated cells,” Giaccia says. What's more, he adds, “many chemotherapeutic agents target rapidly proliferating cells. Hypoxia inhibits proliferation.”

The involvement of HIFs in cancer has touched off an intensive search for drugs that can prevent the proteins from performing their normal functions. The work is still in its early stages. So far, researchers have come up mainly with agents that work indirectly rather than by specifically inhibiting HIF. One such effort comes from Giovanni Melillo of the National Cancer Institute in Frederick, Maryland, and his colleagues. They screened roughly 2000 compounds for anti-HIF activity and identified four, including a known cancer drug, they reported in 2002 in Cancer Research. It's an inhibitor of the enzyme topoisomerase, which aids in the unwrapping of the DNA double helix during gene transcription. The drug may therefore work by blocking HIF's effects on gene activity.

Some other known anticancer drugs, including Herceptin and Gleevec, may work partly by inhibiting HIF action, but their effects are also likely to be indirect. For example, they may inhibit the growth pathways that stimulate HIF-1α synthesis.

Other researchers have come up with new drugs that target HIF. For example, Garth Powis of the Arizona Cancer Center in Tucson and his colleagues identified a compound called PX-478 that reduces HIF levels in cancer cells, although the mechanism is still unclear. The compound, he says, has “exceptional antitumor activity” in animal models. Powis, who started a company called Prolex to develop cancer drugs, hopes to move PX-478 into clinical trials soon.

Still, researchers prefer direct—and presumably more specific—HIF inhibitors that might have fewer side effects than drugs with broader actions. Those efforts are going slowly. “Targeting transcription factors [such as HIF] is attractive but very difficult,” says Melillo. The problem is that it's harder to block protein-protein interactions than, say, the active site of an enzyme.

For that reason, it may be easier to develop drugs that bolster HIF action, which might be useful for treating conditions such as heart attack or stroke. Such drugs might be developed, for example, by finding inhibitors of the prolyl hydroxylases that mark HIF-1α for degradation.

Still, researchers note that many obstacles will have to be overcome before any drugs that target HIF find their way into the clinic. One recent note of caution comes from Johnson. Working with Gabriele Bergers's team at the University of California, San Francisco, he found that HIF-1α-deficient tumors that are derived from astrocytes, a type of neuronal support cell, behave differently depending on their location in the body. When transplanted under the skin of mice, an environment low in blood vessels, the tumors, as expected, grew poorly compared to those with active HIF-1. But when transplanted into the much more vessel-rich brain—where astrocytomas normally form—just the opposite occurred. The HIF-1α knockout cells grew even faster than those with the protein, and they spread much more extensively throughout the brain. The results suggest that clinicians will need to understand the precise biology of their patients' tumors before attempting anti-HIF therapy, although this is a problem for cancer therapies generally.

Even at best, however, blocking HIF activity may not be sufficient to wipe out tumors. Giaccia notes that in animal models anti-HIF therapy usually doesn't kill all the tumor cells, and the survivors can begin growing again. “Just inhibiting HIF may not be the panacea for cancer everyone thinks it will be,” he says.

Finally, there are concerns about possible harmful side effects of drugs that target HIF, given the proteins' widespread effects in the body. Researchers hope that HIF inhibitors will be less toxic to normal cells, which usually have plenty of oxygen, than they are to tumor cells, which tend to be hypoxic, but that remains to be seen. Conversely, there are worries that giving HIF potentiators to stroke or heart attack victims might promote tumor growth.

Even with all the uncertainties about potential clinical applications, researchers are already pleased by what they've learned about how cells cope with hypoxia. “Almost everything about HIF makes sense,” McKnight says.

10. ECOLOGY

# Science Center on Jordan-Israel Border Aims to Bridge the Rift

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

Groundbreaking will start next week on a project involving Stanford and Cornell universities that will focus on the ecology of the arid border region

The bleak, fortified desert border between Jordan and Israel seems the last place on Earth for an ambitious multidisciplinary science institution, but the two states plan to break ground on 9 March for just such a venture. The Bridging the Rift science center, a “free academic zone” planned to straddle a literal gap in the fence, will host researchers from both countries and eventually other Middle Eastern nations. Its first project will be a comprehensive catalog of the genomics and ecology of the Dead Sea region. Spinoffs might include advances in Middle Eastern agriculture—to say nothing of politics. “Obviously the symbolism is as important as the science,” says Marc Feldman, a Stanford University population geneticist who, along with colleagues at Cornell University, will help run the program. “We'll be bringing together people who don't normally have the opportunity to work together.”

The center is the brainchild of Mati Kochavi, a New York City-based Israeli magnate involved in fiber optics and defense industries. Kochavi already has pledges of several million dollars—from his own funds and private donors'—toward a total cost estimated at tens of millions of dollars. No government money is involved. “Very few people in these two countries talk to each other,” says Kochavi. “We want to start by speaking the common language of science. Then we will build the language of partnership.” The location is significant: 80 kilometers south of the Dead Sea in the Wadi Arabah, an extension of the African Rift. Once the frontier between the ancient Hebrew kingdom of Judah and its enemy, Edom, it is rich in history, culture, and archaeology—so much so, UNESCO is pushing to make it part of a World Heritage site.

The announcement of the project on 24 February took many by surprise. According to sources involved, Kochavi invited Stanford and Cornell 4 years ago and enlisted Israeli Prime Minister Ariel Sharon and Jordan's King Abdullah. (Abdullah is a voice of moderation in the region; the countries signed a peace treaty in 1994.) Negotiations were slowed by the ongoing Palestinian uprising—many Jordanian scientists are of Palestinian descent—and were kept secret to avoid publicity that might torpedo the project. Recently tensions heightened with Jordan's bitter criticism of a vast new Israeli security barrier now going up along the West Bank. Finally, in late 2003, Kochavi told Sharon and Abdullah the project would fold unless it moved forward now; the countries then agreed to cede 30 adjoining hectares each. According to a signed agreement, researchers will have free access to both countries through the portal.

Researchers hope to assemble a picture of all organisms around the Dead Sea—initially, plants and microbes—with an emphasis on how they handle the extreme heat, aridity, and salinity. Stanford-sponsored scientists will focus on collecting organisms and mapping their populations and ecology; Cornell will sequence genomes and create new computing technologies to integrate the vast trove of data into a single user-friendly system, the Library of the Desert. Researchers aim to figure out how organisms survive and exist together, says James Haldeman, director of international programs for Cornell's College of Life Sciences. Potential applications include environmental engineering and crop design for dry, saline Middle Eastern soils. “This would be a springboard for all sorts of research from which surrounding nations would benefit,” he says.

The facility will take 3 to 5 years to build. It will have space for perhaps 150 staff members. Plans call for Israeli and Jordanian Ph.D. candidates to attend Cornell and Stanford for 2 years on scholarships, then return to the desert for fieldwork. The initial cadre of a dozen students should arrive in the United States in January 2005, with numbers growing in succeeding years. Students from neighbors such as Egypt and Lebanon—and possibly the Palestinian territories—will be invited later.

By late February, border fencing at the site had already been razed; but other joint ventures suggest that the project still confronts many challenges. Along the Gulf of Aqaba, where the Jordanian and Israeli coasts meet, marine researchers from the two nations have pooled data under a U.S.-sponsored program, but politics have prevented much physical contact and each team has worked its own side (Science, 27 July 2001, p. 627). More recently the Wadi Arabah project, a cross-border coalition of archaeologists, has tried fostering joint excavations. Things looked promising until the Palestinian uprising started in 2000. Relations dried up, and a conference planned for Jerusalem last November had to be moved to the neutral ground of Atlanta, Georgia. Joint fieldwork “would be very unrealistic at this point,” said co-leader Katharina Galor, an archaeologist at the W. F. Albright Institute of Archaeological Research in Jerusalem. The group has compiled a badly needed map of the region's 6000 known sites, she says; it's a start.

Similar tensions are evident with Bridging the Rift. Sharon and Abdullah will hold groundbreaking ceremonies—but separately, in Jerusalem and Amman. And no Israeli or Jordanian university is involved. Ron Elber, an Israeli computer scientist heading Cornell's Library of the Desert, says there was no choice: Scientists on both sides are eager to work together but cannot afford to be seen as collaborating directly. Avishay Braverman, president of Ben-Gurion University of the Negev, disagrees. The university has been quietly working with individual Jordanians for years, he says, and the time for direct, public engagement has come. He wants a role for Ben-Gurion: “We would like to contribute as much as we can to science and as much as we can to peace.”

11. POLAR EXPLORATION

# A Year to Remember at the Ends of the Earth

1. Richard Stone,
2. Gretchen Vogel

Researchers charting a course for an International Polar Year in 2007–08 are hoping to recapture the glory of a similarly ambitious venture a half-century ago

CAMBRIDGE, U.K., AND BERLIN—When Les Barclay and 20 intrepid fellow voyagers set out for Antarctica in November 1956, they knew they were embarking on the scientific adventure of a lifetime. After 5 weeks at sea, the radiophysicist and his colleagues on the International Geophysical Year (IGY) Antarctic Expedition put in at Halley Bay, then Britain's new toehold on the Antarctic Peninsula. They had lugged all the equipment they could possibly need there until the next ship called a year later. “We went down without recourse to any facilities back home,” says Barclay.

For the next 2 years, he and counterparts across Antarctica and at the other end of Earth, in the High Arctic, made some of the first high-latitude measurements of the ionosphere and its most spectacular phenomenon, the aurora. Barclay also teamed with W. Roy Piggott to pioneer the use of radio waves for measuring the thickness of ice shelves, a technique that led to ground-penetrating radar. Other major finds of the $1 billion IGY of 1957–58 include the discovery of the Van Allen radiation belts and radical new estimates of ice volume on Earth's surface. “We learned a tremendous amount about the world,” says Barclay, who now runs a consulting firm in Chelmsford, U.K. Nearly a half-century later, researchers are marshalling forces for another major assault on the poles. Under the auspices of the International Council of Scientific Unions (ICSU), the World Meteorological Organization (WMO), and more than a dozen other scientific groups, an ambitious plan is taking shape for an International Polar Year (IPY) to kick off during the Arctic spring of early 2007 and extend through the Antarctic fall of early 2008. “We want a real quantum jump in our understanding of how the poles work,” says Chris Rapley, director of the British Antarctic Survey and chair of ICSU's IPY planning board. Rapley and other organizers now face the daunting task of convincing countries to pitch in funding and logistical support beyond that already committed to ongoing polar programs. The overall investment could easily top$1 billion, organizers say, as dozens of countries sign up to multilateral agreements that will govern IPY projects.

The will be no shortage of ideas in search of funding, for unanswered questions of polar research are legion. IPY's planning board will try to winnow the field to a few major themes that promise to have deep scientific impact and broad public resonance. “One of the goals is to get people to realize that … the cold ends of the sphere we live on really do influence us,” says ICSU IPY planning vice chair Robin Bell of Columbia University's Lamont-Doherty Earth Observatory in Palisades, New York. And, like their predecessors, they intend to leave a lasting legacy. “We want to design a way to take the pulse of the poles in 2007 and 2008,” Bell says, “but we also want to leave a heart monitor in place so we can continue to see what's going on.”

## From Cape Horn to Sputnik

The polar year of 2007–08 will follow in the footsteps of illustrious predecessors, each of which overhauled our understanding of global processes. The first IPY, in 1882–83, was largely the brainchild of Karl Weyprecht, an Austrian naval lieutenant who commanded a ship during the Austro-Hungarian Arctic Expedition of 1872–74. He argued that polar exploration required more than geographic discovery and called for the establishment of a network of research stations in the polar regions. The idea caught fire, and during the first polar year, 11 nations established 14 stations—two at Cape Horn and South Georgia Island in the South Atlantic and a dozen in the Arctic—to record data on everything from meteorology to terrestrial magnetism and the aurora, findings that shaped later theories of the ionosphere. “It was the first big meteorological experiment,” says Cornelia Lüdecke, a science historian at the University of Hamburg, Germany.

The second IPY took place 50 years later, in 1932–33. Despite a global economic depression, 44 countries teamed up on nearly two dozen dedicated expeditions to the Arctic and the Southern Hemisphere, although like the previous IPY the effort did not reach as far south as Antarctica. Technology had come a long way: Telephone, aircraft, and radio sounding all were at the disposal of researchers. A major achievement was obtaining detailed measurements of the upper atmosphere, including the first maps of the jet stream.

Grand as those efforts were, they paled in comparison to the massive undertaking of 1957–58. Lloyd Berkner of the Carnegie Institution of Washington aired the IGY idea at a dinner party at the home of space physicist James Van Allen in the spring of 1950. The suggestion snowballed into one of the biggest global scientific undertakings ever. Still, it was the depths of the Cold War, and politics was never far from the surface: The Soviet Union in 1956 announced that it would put the first satellite in orbit during the IGY (Sputnik duly went up the next year), and China withdrew from the effort after Taiwan was brought aboard. Antarctica was seen as a potential Cold War battleground, with countries laying claim to slices of the continent. An international research effort, some hoped, would ease tensions—and indeed, the IGY is credited with fostering the political climate for the Antarctic Treaty, in which signatories agreed to share the continent in the name of “peace and science.” In all, roughly 80,000 scientists and support staff from 67 countries took part in the IGY.

“It was a thrilling time,” recalls David Limbert, who confesses that as a 29-year-old meteorologist he left several girlfriends in England to join the Royal Society's IGY advance team, dispatched in late 1955 to build the Halley Bay camp. “We were there as pump primers,” he says. For the first several weeks he and the other expedition members slept in tents as they built Halley beam by beam. Halley and many of the other few dozen Antarctic bases established during the IGY continue to produce world-class science. The IGY, says Rapley, “set the standard for what can be achieved.”

## The next frontier

The IGY will be a hard act to follow. But the half-century of polar science it ushered in has only deepened scientists' appreciation of the complexity and importance of polar processes. What happens at the poles is inextricably tied to patterns of cold and warmth, rainfall and drought. To have any hope of understanding what is happening to global climate today, and what might happen in the future, scientists need a better picture of conditions at the poles and how they interact with and influence ocean and air currents.

So far scientists have only the vaguest clues to how those interactions work. “We know the climate models don't get the polar regions right, and there is a lot of work going on to understand why that is,” Rapley says. One puzzle, he notes, is that the models have largely failed to predict the dramatic melting of the Antarctic ice shelf. And even state-of-the-art models vary widely in their predictions for the severity of the warming that might occur in the Arctic.

One challenge is that the polar regions seem to be reacting more dramatically than other latitudes to global climate changes. The three fastest-warming regions in the last 2 decades have been Alaska, Siberia, and parts of the Antarctic ice sheet, notes Rapley. But whether that is the start of a long-term trend or a normal fluctuation is unclear. Figuring this out “is directly related to our ability to collect data,” Rapley says.

One likely project for the upcoming IPY will be updating an array of monitoring stations strung across the Russian Arctic during the IGY. In the last decade alone, many of those stations have fallen silent, depriving meteorologists of key data on temperature and rainfall, for example. According to the Russian Academy of Sciences, only 45 polar hydrometeorological stations were functioning in 2002, a two-thirds reduction over the past decade. Refurbishing the stations is a top priority, says Eduard Sarukhanian, WMO's IPY coordinator. However, adds Rapley, “what we're keen to do is make sure that doesn't just focus on meteorology and hydrology but opens up new vistas on other research—from any field that people can convince us is worthwhile.”

Opening new vistas may well be the driving theme of the IPY. “There are subglacial lakes and the spreading ridges under the Arctic that have never been explored,” Bell says. And while biologists have barely begun to catalog life in polar oceans, there are hints that here, too, the frozen ends of Earth have a global influence.

One theory suggests that the Southern Ocean might have been a source of much of the biodiversity in the deep oceans worldwide. When the Antarctic continent broke away on its own, a girdle of swift-moving ocean currents formed around it, trapping species in the chilly waters of the Southern Ocean and forcing them to adapt to extreme conditions, Rapley explains. Those creatures, then, may have hitched a ride to other oceans. Brigitte Hilbig of Ruhr University in Bochum, Germany, recently identified several worms in 5000-meter-deep waters off Angola that are nearly identical to one first identified in the Southern Ocean, 5000 kilometers away, suggesting that there may be important connections between the life forms of polar oceans and seabed habitats worldwide. To probe this further, Hilbig and colleagues have proposed taking a zoological and genetic census of the Southern Ocean as part of the IPY.

The Arctic waters, too, likely hold new surprises. An expedition in 2001 to the Gakkel Ridge, where the continental plates bearing Europe and North America are spreading apart, turned up much more hydrothermal activity than scientists expected, says Jörn Thiede of the Alfred Wegener Institute for Polar and Marine Research in Bremerhaven, Germany. As part of the IPY, he and his colleagues hope to send a remote-controlled sub to survey the region.

IPY organizers also hope to attract interest from astronomers who can use polar summers for uninterrupted views of the sun; medical researchers who study human responses to extreme conditions; and social and political scientists who could study the impact of Arctic warming on northern Russia, Canada, and other Arctic Rim nations.

In an initial call, organizers received nearly 150 proposals. “It's taking off like gangbusters,” Rapley says. The ICSU committee and its partners will settle on a handful of flagship projects by autumn, he says. (Contributions are still welcome; see Editorial, p. 1437.) Rapley says that ICSU might try to coordinate three to five large-scale efforts, such as major transects across the poles or large-scale atmospheric or ocean surveys. He hopes the effort will inspire a wellspring of multinational projects around the globe organized by other scientists.

It's not yet clear whether such efforts will add up to the $1 billion infusion the last IGY enjoyed. Karl Erb, director of the U.S. National Science Foundation's Office of Polar Programs, estimates that NSF might contribute up to$50 million in research funding and logistical support for IPY-specific activities, from its nearly $400 million annual budget. Given the formidable base that the field is building on, a smaller investment than that plowed into IGY could have just as profound an impact, argues Chad Dick of the Norwegian Polar Institute in Tromsø, Norway. The onus will be on organizers to choose projects with far-reaching payoffs. “If all we do is have a blast for 2 years and nothing changes in our ability to monitor the poles for the long term, we will have failed,” he says. Considering the track record of the first two IPYs and the IGY, failure would appear to be only a remote possibility. 12. POLAR EXPLORATION # An Otherworldly Place to Hunt for Other Worlds 1. Gretchen Vogel High on Antarctica's frozen desert, astronomers have found some of the best conditions on Earth for peering into space. The calm, cloudless skies above Dome C, 3233 meters above sea level in the middle of the main Antarctic ice sheet, make the isolated spot a stargazer's dream. The site is the location of the newest permanent year-round station in Antarctica, a joint French-Italian project called Concordia. The main buildings, which will host 16 people over the 9-month winter and twice as many in summer, are expected to be finished by the Antarctic winter of 2005–06, in ample time for the station to participate fully in the International Polar Year (IPY) to begin in 2007 (see main text). Concordia, perched on an ice dome, should entice scientists from a range of disciplines. For example, researchers who use ice cores to decipher clues to past climates expect to look deep into the last Ice Age thanks to nearly 500,000 years of snow accumulation at Dome C. And as the third permanent station on the continent's interior, located more than 1000 kilometers from its nearest neighbor, the United States' Amundsen-Scott South Pole Station, Concordia will help fill gaps in measurements of Earth's magnetic and gravitational fields and the continent's seismic activity. Concordia is also set to rival the South Pole as a premier astronomical outpost. Although there are not yet any full-size telescopes at the site, measurements suggest it is an outstanding place for optical and near-infrared astronomy. The air can be so still, says Eric Fossat, an astronomer at the University of Nice in France, that smoke rings from tractors at the construction site often linger for tens of seconds before dissipating. The lack of wind and heat currents makes the atmosphere extremely clear, cutting down on the shimmer that disrupts Earth-based views of stars. Thus astronomers can look forward to some of the best “seeing” anywhere on Earth. “The indications are that the seeing may be absolutely extraordinarily good,” says astronomer Tony Stark of the Harvard-Smithsonian Center for Astrophysics, who has worked extensively at the South Pole. That quality, combined with the site's aridity and average ambient temperature of −50°C, makes it a great spot for infrared astronomy—perhaps the best on Earth for searching for planets similar to our own, Fossat says. In the infrared, planets show up brighter and stars dimmer, allowing astronomers to discern planets more easily. And, he notes, there is half as much cloud cover as at the already impressively clear South Pole Station. Astronomers are still securing funding, but they hope to have the first telescope in place for the IPY in 2007. An array of telescopes could come further down the road. Concordia may even help humans reach for the stars. To simulate the effects of long-duration space flight, researchers plan to study how staff members cope with the Antarctic winter (Science, 15 August 2003, p. 906). Fossat himself says he won't winter there. “I'm too old for that kind of sacrifice,” he says. But with Concordia's astronomical attributes, don't expect any shortage of volunteers. 13. CLIMATE CHANGE # A Eurasian Tiger Threatens to Maul Kyoto 1. Paul Webster* 1. Paul Webster is a writer in Toronto, Canada. A new U.N. report is likely to strengthen the case of hard-liners intent on ditching Russia's commitment to ratifying the climate treaty Two years after the United Nations began putting the heat on Russia to ratify the Kyoto Protocol, enthusiasm in Moscow for the global plan to tackle climate change has cooled rapidly. In recent months, senior Russian government officials have repeatedly challenged U.N. greenhouse gas forecasts suggesting that Russia would benefit from a key treaty sweetener, the sale of billions of dollars' worth of emissions credits. Now Moscow's Kyoto doubters are about to get a boost from a surprising source: the U.N. itself. According to a draft report for the secretariat of the U.N. Framework Convention on Climate Change in Bonn, Germany, the data underlying the U.N.'s emissions forecasts for Russia are full of holes and out-of-date. “It's a problem in general with the U.N. estimates,” says Kremlin economist Peter Kaznacheev. “They tend to base their estimates on old data.” The future of the Kyoto Protocol is in Russia's hands. For the treaty to come into force, it must be ratified by countries whose greenhouse gas emissions total more than 55% of global output in 1990. With the world's biggest greenhouse gas emitter, the United States, having renounced the treaty, Russia is crucial to slipping over the 55% bar. For a while, things were looking up for Kyoto backers: Russia had long signaled its intention to ratify the treaty. Its carbon emissions plummeted in the 1990s as decrepit Soviet-era plants and factories ground to a halt. But a rip-roaring economy of late has prompted some Kremlin insiders to claim that Russia may not have any carbon credits to sell in 2008, when the Kyoto treaty is supposed to come into force. Indeed, they warn, Russia may end up having to cut back on fossil fuel consumption to stay below 1990 emissions levels, as Kyoto requires. One of the more outspoken adherents of this view, Andrei Illarionov, Russia's presidential adviser on economic issues, last week compared the Kyoto Protocol to the notoriously unrealistic Five-Year Plans imposed by Soviet authorities. Speaking to a forum of European Union officials lobbying Moscow to ratify the treaty, Illarionov drew an unflattering parallel between what he calls “Kyotism” and Marxism: “During the 20th century, Russia seriously suffered from another ideology that came from Europe,” he mused. “Not only Russia, but the whole world suffered.” With the treaty's fate hanging in the balance, researchers on both sides of the debate have been scouring Russia's emissions data for ammunition to better press their case. Russia's third national communication, mandated by the climate change convention, would appear to support the Kyoto cause. It notes that Russia's greenhouse gas emissions—not counting perturbations from land-use changes—declined 38% in the decade following the dissolution of the Soviet Union, from 3 million metric tons of “carbon dioxide equivalent” in 1990 to 1.9 million metric tons in 1999. Moreover, the third communication, submitted to the U.N. in November 2002, predicts that greenhouse gas emissions would not surpass 1990 levels before 2015. That backs U.N. forecasts made in 2000 that Russian emissions would remain 20% below 1990 levels through 2012 (see graph). The new review for the U.N.'s climate change secretariat casts doubt on those scenarios. Russia's third communication does not include emissions data from important energy sources, notes the draft report, prepared by a team that included experts from Spain, Hungary, Ecuador, and the International Energy Agency. One major shortcoming is Russia's failure to account for the potential impact of its plans to almost double coal production by 2020. “We questioned whether emissions would not increase more than they are saying [they would],” says one analyst who has seen the report. And due to insufficient funding, the report says, emissions from waste incineration, aviation, and many other industries were not evaluated. Another weakness is that the third communication contains emissions data only through 1999. Since then, the U.N. reviewers note, Russia's economic growth of 6.5% per year on average suggests upward pressure on greenhouse gas emissions. Russian and U.N. officials declined to respond in detail before the review is released later this month or early in April. But the Russian government has acknowledged deficits in its emissions reporting and has begun to improve its data collection, notes deputy foreign minister Yuri Fedotov. The coordinator of the U.N.'s 2000 emissions forecasts for Russia, Nebojsa Nakicenovic, an economist at the International Institute for Applied Systems Analysis in Laxenburg, Austria, acknowledges that Russian emissions could exceed Kyoto limits earlier than predicted late in the next decade. But he doubts that Russia can sustain its current rate of economic growth. Nakicenovic also argues that the rate of growth of emissions will begin to tail off to about half the economic growth rate if Russia follows through with long-awaited investments in energy efficiency. “Russia is not likely to exceed Kyoto limits even if its economy doubles during the next 10 years,” Nakicenovic says, “and the doubling of the economy would indeed be an incredible achievement.” That assessment is shared by Alexander Golub, an emissions economist at the nonprofit organization Environmental Defense's Washington, D.C., office. In a study for the World Bank in 1999, Golub, one of Russia's representatives on the U.N.'s Intergovernmental Panel on Climate Change, was among the first to warn that solid economic growth without significant energy efficiency reforms might propel Russia beyond its Kyoto emissions limits far sooner than the U.N. had predicted. Now, however, Golub argues that a close analysis of energy usage suggests that the rate of growth of greenhouse emissions is not keeping pace with economic growth. That means Russian emissions will remain well within Kyoto limits, he claims. The wild card, Golub says, is coal. He worries that if Russia more than doubles its coal output to feed domestic energy needs while exporting its natural gas, greenhouse gas emissions could skyrocket past Kyoto limits. Although Golub considers Russia highly unlikely to increase coal production so rapidly, Illarionov says that Russia intends to go full throttle in tapping coal reserves. The new U.N. report, observers say, will play into the hands of Kyoto skeptics. In a speech in late January, Illarionov advocated rejecting Kyoto on the basis of studies by the Institute of Economic Analysis (IES) in Moscow, a think tank he headed before joining Russian President Vladimir Putin's staff. “We've got newer, better data indicating our actual emissions are much higher than the U.N. forecasted,” says Kaznacheev, an economist on Illarionov's Kremlin team. The IES studies, Kaznacheev says, indicate that increases in Russia's greenhouse gas emissions have nearly matched the percentage increases of its economic growth since 1999, a trend that suggests Russia should surpass its 1990 emissions levels within 2 years after Kyoto is implemented in 2008. The raw data that IES tapped are from a 2002 report from the U.S. Department of Energy's (DOE's) Energy Information Administration. The report states that Russian oil and coal production have been booming since 1999, with carbon emissions largely unchecked. “I don't really think they are willing to slow growth in that industry to head off environmental impacts,” says David Correll, a Russia analyst at DOE Headquarters in Washington, D.C., who was involved in the DOE study. “We don't see those kinds of policy initiatives.” The bottom line, Kaznacheev says, is that Russian policymakers no longer see Kyoto as a cash cow. “It's unlikely Russia will make profits from carbon dioxide quota sales,” he says. And meeting Kyoto targets is out of the question: The targets “are hardly affordable,” says Kaznacheev. Russia's rising fortunes, therefore, could be the Kyoto treaty's ultimate misfortune. 14. ARCHAEOLOGY # Earthquake Allows Rare Glimpse Into Bam's Past--and Future 1. Andrew Lawler A massive effort to rebuild this Iranian city should give scientists a chance to learn a great deal about the world's largest mud-brick complex BAM, IRAN—When the earth shook in the early morning of 26 December in this rough frontier town near the Pakistan border, it buried alive perhaps half of the city's 100,000 people. The devastating quake took more than lives: It also laid waste to the city's restored old town and massive fortress—the largest mud-brick complex in the world—and unearthed ancient bones, pottery, and architectural features that had long been buried. Amid the terrible destruction, researchers see a unique chance to study Bam's largely unknown past and to find ways to improve mud-brick architecture. “Bam is now a laboratory for archaeology, urban development, and conservation,” says Junko Taniguchi, UNESCO's representative in Tehran. In the coming months, an international team of engineers and scientists will put together a plan to map, excavate, and eventually restore the complex called the Arg-e-Bam, with money from Japan and, possibly, Italy. The task is daunting. The Arg-e-Bam, most of which dates from the 18th and 19th centuries, was built entirely of fragile mud, straw, and date palm logs. Dominated by its imposing citadel, the several-square-hectare city was an important trading center on the eastern edge of Persian influence. Abandoned a century ago during political upheavals, the city was restored over a 40-year period beginning in the 1950s. A few test trenches were dug in the mid-1990s, but no extensive archaeological work has ever been done here. The restored old town was a source of immense civic pride for this remote city in the southeastern desert with an unsavory reputation for smuggling, kidnapping, and widespread drug use. But it took only a few minutes for the earthquake to destroy nearly every structure in the complex. Today, visitors must scramble over the shattered walls and high gates of the city to view the countless piles of rubble, and aftershocks are a constant threat. Fortunately, there were few casualties in the old city: Two guards were killed, and one official for the Iranian Cultural Heritage Organization was trapped for 7 hours under debris, says Fallah Afar, an ICHO engineer who works for the newly created Arg-e-Bam project and whose immediate task is to examine the extent of the damage. That exploration may be a boon for archaeologists. “Prior to the earthquake, we didn't know much about Bam's past,” says Chahryar Adle, a historian and archaeologist with France's basic research agency CNRS in Paris who recently visited the site. “How far back it goes has been a matter of speculation, since we've had no archaeological proof.” Early Arab texts mention Bam, which likely was fortified during the Sassanian period before Islam swept across the region in the 7th century C.E., according to Adle. He says that sections of the citadel that collapsed revealed earlier layers dating possibly from the great Achaemenid empire of the 5th and 4th centuries B.C.E., which stretched from Greece to Afghanistan. “The mud bricks we can now see suggest that period,” but he adds that intensive research is necessary to confirm that finding. Adds Taniguchi, “Ironically, the earthquake has added to the value of the site.” Using aerial photography and a laser camera, Adle plans to spend 6 months assembling a detailed three-dimensional reconstruction of the citadel. The map will be used for archaeological and, ultimately, restoration purposes. An April meeting in Bam will allow specialists to hash out a long-term research plan, says M. H. Talebian, director of the Arg-e-Bam project. Aside from conducting archaeology and preparing the way for restoration, Talebian and his team also hope to analyze the relative strength and flexibility of various structures—critical information in a land where the vast majority of village dwellers still use mud brick. During a recent tour of the site, Afar pointed to traditional arcades that fared better than nearby flat roofs, and noted that stone foundations and more arches helped protect the homes in the richer area near the citadel. “We know now that the ruling class was aware how to build in a safer fashion,” he says. Guidelines are needed, he adds, to determine where concrete or baked brick—more expensive building materials—should take the place of mud brick. Afar says he doesn't know how long restoration of the site will take: “We have to be very careful and patient.” Three teams are being organized to sort out the status of the area inside the walls, the towers and walls, and the citadel. Restoration costs are expected to run into the millions of dollars. UNESCO provided an emergency fund of$50,000 to come up with the initial plan, and the Japanese government has pledged \$500,000 for the project. Italy, meanwhile, is considering providing additional money. UNESCO will work with ICHO to coordinate the international effort.

Although humanitarian efforts deserve the highest priority in a city where most residents live in canvas tents and disease is a constant threat, local support for the restoration project is expected to be strong. “Some people here were as upset by the Arg-e-Bam's destruction as they were in losing family members,” says one amazed Iranian. Adds Afar: “Even when people were mourning, they came to see the Arg-e-Bam.”