# News this Week

Science  07 Oct 2005:
Vol. 310, Issue 5745, pp. 28
1. VIROLOGY

# Resurrected Influenza Virus Yields Secrets of Deadly 1918 Pandemic

1. Jocelyn Kaiser

As worries about a new flu pandemic mount, researchers have figured out the traits that made the 1918 influenza virus, which killed between 20 million and 50 million people, so virulent. Although a study on page 77 sheds new light on these questions, it raises a host of others because the researchers reconstructed the complete virus, which no longer existed anywhere on Earth.

The team resurrected the 1918 pandemic virus by using gene sequences fished from preserved tissue from a 1918 victim. The virus is as lethal as expected, killing mice more quickly than any other human flu virus known. Recreating the 1918 strain “had to be done, and it's produced some extremely interesting results,” comments flu researcher Robert Webster of St. Jude Children's Research Hospital in Memphis, Tennessee.

Although a scientific triumph, the experiment has stirred debate over safety procedures for handling such a deadly virus. Moreover, a new federal biosecurity board gave the paper an unusual last-minute review to make sure the merits of its publication outweighed the risks of releasing potentially dangerous knowledge. The board's green light is a relief to scientists who have worried about a clampdown on scientific information following the anthrax attacks 4 years ago. “The system is working,” suggests Massachusetts Institute of Technology molecular biologist Phillip Sharp, who wrote an accompanying editorial (p. 17).

The team, from the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, the Armed Forces Institute of Pathology (AFIP) in Washington, D.C., Mount Sinai School of Medicine in New York City, and the U.S. Department of Agriculture, says its work will provide crucial knowledge for heading off the next influenza pandemic, which could be brewing in Asia, where the H5N1 bird flu has killed more than 60 people. “This work has to be seen in a positive light,” says lead author Terrence Tumpey of CDC.

The research grows out of AFIP pathologist Jeffrey Taubenberger's efforts, begun in 1995, to sequence the genome of the 1918 flu virus. Working mainly with tissue from a victim found in permafrost in Alaska, he and others have been piecing together the virus's eight genes and characterizing their protein products.

Last year, this work revealed the structure of the 1918 hemagglutinin (HA), the crucial surface protein that flu viruses use to latch onto host cells (Science, 19 March 2004, p. 1866); in a separate study, Yoshihiro Kawaoka's group at the University of Wisconsin, Madison, showed that a virus containing this HA was unusually potent. This week in Nature, Taubenberger's group publishes the sequences of the last three genes, which together encode the virus's polymerase, the machinery for virus replication.

With those final sequences in hand, Peter Palese's team at Mount Sinai then stitched the eight 1918 genes into a regular flu virus genome contained within bacterial DNA. They shipped these inert plasmids to Tumpey at CDC, who inserted them into cells to make live virus.

In this issue of Science, Tumpey, Taubenberger, and collaborators report how the reconstructed 1918 virus behaves. In experiments at CDC, the virus killed mice in 3 to 5 days and caused severe lung inflammation reminiscent of that reported by doctors who examined 1918 flu victims. The team also studied viruses with various combinations of 1918 genes and regular flu genes, which showed that “without that HA, the virus was not virulent,” says Tumpey.

The 1918 flu had a couple of other tricks up its sleeve as well. One is that the virus doesn't need to rely on its host cells for the protease trypsin to cleave and activate the HA protein; instead, another surface protein, neuraminidase (NA), appears to help cleave the HA. That suggests the 1918 virus, like some highly virulent bird flu strains, can grow in any cell type, not just trypsin-laden lung cells. In addition, the 1918 flu's polymerase genes appear to allow it to replicate very efficiently in human bronchial cells. Probing these mechanisms may lead to the development of new antiviral drugs.

The virus also kills chicken embryos, unlike most human flu viruses. The polymerase genes are similar to those found in bird flu, including H5N1 in Asia, Taubenberger notes in the Nature paper. That means the 1918 flu likely arose from a bird virus and did not need to combine with a flu strain already adapted to humans to become so deadly.

Because of the sensitive nature of the work, the CDC lab's safety precautions received unusual scrutiny, says Tumpey, including review by several biosafety committees. Workers followed biosafety level 3 (BSL-3) practices, with additional enhancements, for instance, wearing battery-powered air purifiers with face shields and showering when leaving the lab. A year ago, Kawaoka's team drew fire for doing experiments with partial 1918 viruses under similar enhanced BSL-3 conditions, as opposed to the more stringent BSL-4 (Science, 22 October 2004, p. 591).

Since then, the government has weighed in, recommending in a draft biosafety manual that researchers use BSL-3 with additional measures for 1918 flu experiments. One reason BSL-4 isn't necessary, says government adviser Robert Lamb of Northwestern University in Evanston, Illinois, is that antiviral drugs are effective against 1918-like flu viruses. (CDC is also treating 1918 flu virus as a select agent, which means access is tightly controlled.)

Both the authors and Science's editors acknowledge concerns that terrorists could, in theory, use the information to reconstruct the 1918 flu virus. Similar fears erupted 3 years ago when Science published a paper on the reconstruction of a poliovirus. Science decided to publish the 1918 flu paper because it “could help prevent another global flu pandemic,” says Editor-in-Chief Donald Kennedy. That benefit “far outweighs the risk of working with this virus,” he says.

In addition to regular scientific review, Science required the authors to show that they had approval to publish from CDC Director Julie Gerberding and National Institute of Allergy and Infectious Diseases Director Anthony Fauci. After being briefed, Health and Human Services (HHS) Secretary Michael Leavitt also requested that his new National Science Advisory Board for Biosecurity (NSABB) review the Science and Nature papers “to make sure we'd touched every possible base,” said HHS spokesperson William Hall. After a flurry of e-mails and phone conferences last week, the panel suggested adding two sentences that underscore the stringent safeguards and the importance of the work in protecting public health.

The board's review surprised some scientists who expected NSABB to develop only general guidelines for journals. But Sam Kaplan of the University of Texas, Houston, publications chair for the American Society for Microbiology, says such reviews seem reasonable as long as they don't delay publication for months. “We certainly might turn to the NSABB” for a hot paper, he says.

2. U.S. BIOMEDICAL POLICY

# Acting FDA Head Drops NCI Post

1. Jocelyn Kaiser
1. With reporting by Jennifer Couzin.

Trying to calm an uproar after he took a second job, the chief of the U.S. National Cancer Institute (NCI) declared last week that he would take a leave of absence while he serves as acting commissioner of the Food and Drug Administration (FDA).

President George W. Bush's appointment of NCI Director Andrew von Eschenbach on 23 September to succeed FDA's Lester Crawford drew an outcry from cancer researchers and several members of Congress, who argued that both agencies would suffer and that the two jobs posed conflicts of interests (Science, 30 September, p. 2142). Giving up the NCI job seems to allay at least some of those concerns.

The temporary NCI boss will be John Niederhuber, who came to the institute last month and this week became its deputy director for translational and clinical sciences. Niederhuber will also serve as “chief operating officer to handle the day-to-day management at NCI,” according to memos von Eschenbach sent to FDA and NCI staff last Friday. Niederhuber, a surgical oncologist who has also studied cell signaling in tumors, most recently headed the department of surgery at the University of Wisconsin School of Medicine. Until July, he also was chair of NCI's National Cancer Advisory Board.

Niederhuber is “highly regarded in the oncology community,” says David Korn, a senior vice-president at the Association of American Medical Colleges. As dean of Stanford University medical school, Korn hired Niederhuber in 1991 to head the surgery department. “I think it's a terrific opportunity for him and for the NCI,” Korn says. Cancer biologist Tom Curran of St. Jude Children's Research Hospital in Memphis, Tennessee, is pleased as well. “John is an excellent choice for a challenging but important position at this critical time,” says Curran.

Speaking anonymously, some cancer researchers said they were not disappointed that von Eschenbach, a friend of the Bush family who came to NCI 3 years ago from the University of Texas M. D. Anderson Cancer Center, is stepping aside from the research institute for the moment. His plan to eliminate suffering and death from cancer by 2015 has been criticized as wildly unrealistic. And his proposals for achieving it—initiatives on nanotechnology, proteomics, and tissue banking—have drawn a lukewarm response from NCI advisers. Meanwhile, success rates for obtaining basic R01 research grants are steadily declining. “I'm not sure [his tenure] will be seen as a great period in the history of NCI,” said one academic researcher.

Within NCI, morale has slipped as budgets for intramural research have been trimmed and von Eschenbach built up a large personal staff that operated free of the established division directors, sources say. “It can't get much worse,” said one senior scientist.

Even so, David Johnson, deputy director of the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, worries about how NCI will fare under an acting director, which “is about the most powerless position you can be in.” Johnson wonders whether Niederhuber will “have the courage” to prioritize different NCI programs.

Von Eschenbach's memo says he “will not participate” in FDA matters involving NCI drug applications or clinical trials. But Johnson says that unless von Eschenbach resigns from NCI, his “residual interest” in the institution poses a potential conflict of interest. Another possible conflict, noted by The Cancer Letter, involves von Eschenbach's unpaid role as vice-chair of the board of C-Change, a nonprofit cancer advocacy organization headed by the president's parents, George H. W. and Barbara Bush. Its board members include drug industry executives.

3. NEUROSCIENCE

# Cancer Drugs May Help Injured Nerve Cells Regrow Their Axons

1. Greg Miller

The central nervous system in adult mammals is notoriously bad at healing itself. Once severed, the axons that connect one neuron to another can't regrow. That's why people regain little, if any, movement and sensation after a spinal cord injury. Neuroscientists are working hard on ways to coax adult neurons to regenerate axons, but progress so far has been slow.

On page 106, a Boston-based research team reports a surprising discovery that may be a substantial step forward. They identify a molecular signaling pathway that appears to prevent axon regeneration in rodent neurons and show that drugs that interfere with this pathway promote regeneration. “It's a really unexpected finding,” says Marie Filbin, a neurobiologist at Hunter College in New York City. She and other experts say they never suspected that this signaling pathway, which involves a cell surface protein called the epidermal growth factor receptor (EGFR), might have a role in thwarting regeneration. The study “identifies a novel target for therapeutic interventions,” Filbin says.

Even more exciting, says Ben Barres, a neurobiologist at Stanford University in California, drugs that inhibit EGFR signaling are already approved for treating lung cancer. “This raises the possibility of almost immediate application of EGFR antagonists in patients with spinal or other central nervous system injuries,” he says.

The new study was led by Zhigang He and Vuk Koprivica of Children's Hospital in Boston, Massachusetts. They and colleagues tested about 400 small molecules on cultured rat neurons, hoping to identify those that promoted the growth of new axonlike extensions. Most of the compounds did nothing, but several EGFR blockers had impressive effects, He says. To test the compounds on nerve injuries in live animals, the researchers crushed an optic nerve in adult mice and then packed the nerve with foam soaked with one of the EGFR blockers. Two weeks after the injury, the treated mice showed a ninefold increase in axon regeneration compared to untreated animals.

Until now, the primary role in the nervous system of epidermal growth factor, which activates EGFR, was thought to be signaling neural stem cells to divide. “Now it shows up in a very different context,” says Martin Schwab, a neurobiologist at the University of Zürich in Switzerland.

Additional work by He's team has provided clues about how EGFR blockers promote axon regeneration. Two types of molecular signals conspire to stymie regeneration in the adult nervous system: inhibitory molecules embedded in the myelin insulation on axons and inhibitory signals spewed out by astrocytes, support cells that form a scar around the site of injury. The team's experiments with cultured neurons suggest that EGFR signaling is necessary for both types of inhibition.

“To the extent to which we have to inhibit both pathways to get regrowth, this means that our chances of inhibiting all the bad actors [with a single drug] is that much greater,” says Marc Tessier-Lavigne, a neurobiologist at Genentech in South San Francisco, California, and collaborator on the current study. Genentech's drug Tarceva, which has FDA approval for treating non-small cell lung cancer, was one of the EGFR blockers tested on cultured neurons. Tessier-Lavigne says Genentech is now investigating the drug's effects on axon regeneration in a mouse model of spinal cord injury.

But even if those experiments yield good results, EGFR blockers alone may not be enough to heal spinal injuries, He cautions. Other research has suggested that compounds that actively promote axon regeneration may be needed as well. As with driving a car, He says, taking your foot off the brake only gets you so far—then you need to hit the gas.

4. ECOLOGY

# Satellite Tracking Catches Sharks on the Move

1. Elizabeth Pennisi

With the speed of a tuna and the homing instinct of a salmon, the great white shark—once considered a homebody—is proving a transoceanic traveler. And not to be outdone, a less fearsome cousin called the salmon shark has now shown up in Hawaii, far away from its supposed home in Alaska.

Two studies in this week's issue document these unexpected sea trips. Two species “we have previously considered to be largely coastal in their movements have a much greater ecological link with the open ocean than previously thought,” says Barry Bruce, a marine biologist at the Commonwealth Scientific and Industrial Research Organisation in Hobart, Australia. These findings complicate conservation efforts, he adds, as multiple countries must take part in protecting the species.

Over the past decade, satellite technologies have enabled marine biologists to follow the oceanic travels of animals tagged with transmitters. On page 100, a team led by Ramón Bonfil of the Wildlife Conservation Society in New York, New York, reports using such technologies and visual markings on fins to observe 32 great white sharks over 15 months. “These researchers have gone where others have feared to tread,” says Barbara Block of Stanford University Hopkins Marine Station in Pacific Grove, California, referring to the danger and challenges of tagging these beasts.

An electronic device attached to the dorsal fin sent data about geographical coordinates whenever a tagged shark surfaced, enabling Bonfil and his colleagues to plot a shark's journey. Another device, fastened by a releasable pin, recorded depth and temperature. When the pin snapped as planned, the device surfaced and relayed these data “directly to the office,” says Bonfil. In addition, the researchers equipped the sharks with acoustic transmitters and tracked the animals' finer scale movements using microphones scattered in certain South African bays.

Bonfil's work extends earlier studies by Block's group, which found that great white sharks around the California coast periodically headed more out to sea. Bonfil's data showed just how far this species could travel. One female sped across the Indian Ocean and back at 4.7 kilometers per hour, covering 20,000 kilometers in less than 9 months. Other tagged great whites, thought to be looking for prey, regularly took 2000- kilometer trips up and down South Africa and into the waters off Mozambique.

In a separate study, reported on page 104, Kevin Weng, working with Block and others, used remote-sensing satellites to track 48 tagged salmon sharks based in Prince William Sound, Alaska. The salmon sharks also migrated long distances. After wintering off Alaska, some headed south, sometimes going as far as Hawaii or Baja California before returning to Alaska. One covered 18,220 kilometers in just 640 days, Block's group reports. As with the great whites, the salmon sharks took multiple trips but always seemed to return to familiar territory. “[Both] sharks use entire ocean basins as home ranges and show remarkable fidelity to areas,” she says. “These two papers represent great leaps in our understanding of how top predators utilize the world's oceans,” says Andrew Martin, an evolutionary biologist at the University of Colorado, Boulder.

Block's group also discovered that two cardiac proteins may enable the salmon shark to withstand water temperatures cold enough to stop a polar bear's heart. She and her colleagues now report that salmon sharks have excess SERCA2 and Ryanodine receptors—proteins key to keeping the heart beating—just as hibernating animals do. In the heart's muscle cells, these proteins help control the flow of calcium and consequently the rate of contraction. This result “advances Block's developing story about how physiological adaptations allow niche expansion,” says Martin.

The unexpectedly large ranges for both sharks revealed by the new studies have a downside: The more spread out a species is, the harder it is to protect. Great whites are particularly vulnerable. For example, great whites protected by South Africa are fair game for Mozambique fishers. “They are so much more exposed to being caught because they cover a much wider area,” says Andre Boustany of the Hopkins Marine Station. Thus, “conservation management of this species and other highly migratory species must occur on an international level.”

5. CONSERVATION POLICY

# House Revises Endangered Species Act

Legislation that would remove a controversial provision of the U.S. Endangered Species Act (ESA) was passed last week by the House of Representatives. The bill, introduced by a longtime opponent, was pushed through at a whirlwind pace despite pleas by moderates for more time. Critics are now looking to the Senate to correct provisions that they say will weaken protection of species.

Representative Richard Pombo (R-CA) and other critics argue that the 1973 act, last amended in 1988, hurts landowners while not adequately helping endangered species. They say only 1% of 1268 species listed have ever been removed after recovering. But supporters say that the act's main achievement has been to prevent extinctions. As chair of the House Resources Committee, Pombo moved his bill through committee in just 4 days—a pace that some legislators and officials at the Fish and Wildlife Service (FWS) say precluded adequate analysis. On 29 September, the House approved it by a vote of 229 to 193.

The bill (H.R. 3824) would eliminate so-called critical habitat provisions, land or water that FWS designates as necessary for a species to recover. The designation brings several legal protections into place, but it also generates many lawsuits (Science, 30 September, p. 2150). FWS maintains that it's not necessary because those legal protections are redundant, but many environmentalists say that in practice critical habitat bolsters conservation efforts.

Pombo's bill would also require FWS to quickly evaluate any proposed projects that might harm an endangered species. If the agency doesn't finish within 180 days, the proposal would get an automatic green light. Environmentalists worry that FWS's long backlog will result in many harmful projects going forward. Finally, if FWS determines that land shouldn't be altered, then the agency must compensate landowners. The Congressional Budget Office estimated that amount at $10 million per year initially, but critics say it's likely to be much higher and could wind up bankrupting FWS's$143-million-a-year endangered species program.

Representative Sherwood Boehlert (R-NY), chair of the House Science Committee, and several others proposed a floor amendment that would avoid these concerns by neither giving automatic approval to projects nor compensating landowners. The amendment would have abolished the critical habitat provisions and replaced them with a similar and enforceable type of habitat designation. Although he lost by a vote of 206 to 216, Boehlert said the slim margin of defeat “showed the Senate that the House would be willing to pursue moderate reforms of the Endangered Species Act.”

The Senate is unlikely to work on a companion bill until next spring. The subcommittee responsible for ESA is chaired by Senator Lincoln Chafee (R-RI), a moderate who has expressed reservations about making significant changes to the act.

6. FRANCE

# Reform Law Fails to Impress Researchers

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

PARIS—French scientists will be more competitive, young scientists will be paid better, and the public and private sectors will work together more closely, say government officials, thanks to a long-awaited draft science reform law unveiled last week. But research leaders who have protested against current policies say the reforms don't go far enough, urging the government to do more to create jobs and improve prospects for young scientists. “The system is becoming more complex and more opaque,” says chemist Jacques Fossey, head of the main research union SNCS.

In the reform bill, due to be published on 5 October, the government earmarks an extra $23 billion in public funds for research between 2004 and 2010. It will award young researchers in public labs an 8% pay hike in both 2006 and 2007, allow university lecturers to spend fewer hours teaching, and provide incentives for companies to hire more postdocs. The government will also create a 24-member agency to evaluate labs, research teams, and individuals so as to improve the distribution of funds. Universities and government research agencies would be offered subsidies to join forces on projects from neuroscience to nanotechnology. The draft law, which is expected to be adopted by Parliament in February, is “symbolic” of the government's research reforms, says junior research minister François Goulard, because it has already set up the grant-giving National Research Agency this year (Science, 26 August, p. 1316) and will soon form a blue-ribbon council to advise the French president on research priorities. But Fossey says that the government must go further. France needs 9000 new public scientific posts and a$6-billion-a-year jump in spending to reach the European Union goal of 3% of gross domestic product spent on research by 2010.

Goulard won't make any guarantees, saying only that this figure is “accessible” and that “the weak link is the private sector.” Even the government's commitment is short-term, however, given that national budgets are drawn up annually and presidential and parliamentary elections are due in 2007. Cochin Institute biologist Alain Trautmann, a leader of the protest movement, wishes it were otherwise. “Governments can and should make long-term moral commitments beyond the next elections,” he says.

7. PHYSIOLOGY OR MEDICINE

# Triumph of the Ulcer-Bug Theory

1. Martin Enserink

A simple but revolutionary finding, perseverance in the face of opposition, and scientific salesmanship were the ingredients enabling two Australians to win the 2005 Nobel Prize in physiology or medicine. On Monday, the Nobel Assembly at the Karolinska Institute in Stockholm, Sweden, announced that Robin Warren and Barry Marshall have been recognized for their discovery that an easily treatable bacterium called Helicobacter pylori—and not stress, spicy foods, or a host of other factors—causes most peptic ulcers. “With tenacity and a prepared mind,” the duo “challenged prevailing dogmas,” the assembly said in a press release.

“It's fantastic,” says microbiologist Francis Mégraud of the Hôpital Pellegrin in Bordeaux, who heads France's national reference center for Helicobacter. “Their work has made a huge difference in the lives of millions of people.” In the past, ulcer patients underwent stomach operations or took medicines for life, he says; thanks to Warren and Marshall, a simple course of antibiotics is often enough to cure them completely. Warren says that he and Marshall had long hoped for a Nobel but worried that “a bug in the stomach might not be romantic enough.”

Warren, 68, a pathologist who retired from the Royal Perth Hospital in 1999, first observed small, curved bacteria in biopsies from ulcer patients' stomachs in the early 1980s. He also noticed that they appeared to cause inflammation. Marshall, now 54 and a researcher at the University of Western Australia in Nedlands, was a young clinical fellow at the time, looking for something interesting to do. He teamed up with Warren and managed to culture an unknown bacterium from the biopsies. In a 1984 paper in The Lancet, the two first suggested that the microbe, which they then classified as a new Campylobacter species, played a role in causing ulcers.

Most gastroenterologists rejected the idea out of hand, and it took a decade of many more studies, including treatment trials with antibiotics, to win over the field. “Many people had been spending a lot of time on all kinds of hypotheses, and all of a sudden there was a very simple answer,” says gastroenterologist Loren Laine of the University of Southern California's Keck School of Medicine in Los Angeles. Although Warren was “a little bit shy,” Mégraud says, Marshall “fought very hard” to get the idea accepted. He traveled the world, pleaded his case endlessly, and even experimented on himself, swallowing a Helicobacter culture to show that it caused inflammation. Warren agrees that Marshall is the “better salesman” of the two: “I just don't think I would have been able to convince people on my own.”

H. pylori is also implicated in two types of stomach cancer, other researchers have discovered, and the microbe's epidemiology is now much better understood. About half the world's population may be infected permanently, even if only one in 10 hosts develops ulcers. Infection rates are highest in the developing world but have gone down in wealthier nations during the 20th century because of improved hygiene and increased antibiotic use. Several tests are now available for rapid diagnosis of H. pylori infection, including a 20-minute breath test co-developed by Marshall.

Not all debate about H. pylori has ended, though. A few researchers believe that the bug may confer some benefits to its host along with the risks. New York University's Martin Blaser, for instance, says there may be a causal relationship between declining H. pylori infection rates and the rising incidence of acid reflux disease and a deadly type of esophageal cancer. Doctors may one day reintroduce Helicobacter strains into some patients' stomachs to take advantage of its protective effects, he predicts. The question is hotly debated among gastroenterologists, but “in a peculiar type of irony,” Blaser says, he finds himself in the same underdog position as Warren and Marshall 20 years ago. “I guess he could be right,” says Warren. “But I don't think he has as much evidence as we did.”

8. SCIENTIFIC PUBLISHING

# Withdrawn Parasite Paper Stirs Criticism of Cell

1. Constance Holden

Many biologists are protesting a decision by the editors of the journal Cell to retract a paper without the authors' assent or any allegations of misconduct.

In July 2004, a group at the University of Brasilia published a widely noted paper claiming that experiments in chickens and rabbits showed that the parasite (Trypanosoma cruzi) responsible for Chagas disease actually transfers DNA to the host genome. They even reported that parasitic DNA integrated into DNA of patients with heart damage from the disease. The unexpected finding offered a possible wayto explain why the disease, prevalent in Latin America, can damage a person's organs decades after the parasite is gone.

In June, Cell editor Emilie Marcus wrote the research team, headed by Antonio Teixeira of the Chagas Disease Multidisciplinary Research Laboratory, that “subsequent re-analyses” by a reviewer she did not name “do not support the claim” of DNA integration. Although the Brazilian team offered detailed rebuttals, Cell published a one-paragraph retraction in the 23 September issue. The retraction has generated a flurry of indignant correspondence, including a protest letter from the Brazilian Society of Protozoology. Cell editors so far have stayed mum.

Scientists agree that the paper, which was the first to claim integration of parasite DNA into a host genome, is controversial, and some doubted the finding from the start. Nonetheless, many biologists are alarmed at the failure of the journal to supply the evidence on which the retraction was based. “This is not the way science should be done,” says Roberto Docampo, a cellular biologist at the University of Georgia, Athens. “I am very concerned with the editor's power to retract papers based on opinions without publishing the basis for the retraction. … If an editor starts to do that, maybe half of the literature will start to disappear.”

Microbiologist David Engman of Northwestern University School of Medicine in Chicago, Illinois, adds that he knows of “maybe a dozen” people in parasitology alone who have written Cell editors to protest. On the other hand, parasitologist Dmitri Maslov of the University of California, Riverside, says he “was not surprised at all” that the report's “extraordinary” claim had been retracted. Cell editors “provided a compelling rationale, … namely, that the integration sites' sequences have not been properly characterized, and some other data did not support the integration unequivocally,” says Maslov.

Cell's action appears to fall within policies Marcus explained in testimony submitted to the British House of Commons Committee on Science and Technology in March 2004: “Editor-instigated retractions occur when the Editor receives correspondence from a third party who cannot reproduce the original data.” In such a case, she wrote, “the authors are invited to respond in writing, and both sets of data are then evaluated by independent reviewers.” Teixeira claims, however, that he was never shown any experimental evidence to contradict his findings.

Teixeira says he's not going to let the matter drop: “I shall fight back to show that the data in our paper is correct.” But regardless of how the matter is resolved, Cell may face repercussions. Engman says a colleague asked by Cell to review a paper is now wondering if he should bother because the paper “may be reversed postpublication.”

9. PHYSICS

# Quantum Optics Shines in the Photon's Centenary

One hundred years ago, Albert Einstein hypothesized that although light behaves like a wave, it consists of particulate bits or “quanta.” On the centennial of Einstein's revolutionary insight, the 2005 Nobel Prize in physics honors three researchers who have pioneered the frontier between the wave and particle views of light and laid the foundation for the field of “quantum optics.”

Theorist Roy Glauber, 80, will receive half the $1.3 million prize for mapping out the conceptual connection between assemblages of individual photons and classical waves of light. Experimentalists Theodor Hänsch, 63, and John L. Hall, 71, will share the other half for developing exquisitely precise techniques to manipulate laser light, which is a quantum-mechanical torrent of photons. Their work has opened new avenues of research and led to the development of ultraprecise frequency standards. “Hänsch, Hall, and Glauber—what a wonderful combination!” says physicist Marlan Scully of Texas A&M University in College Station and Princeton University in New Jersey. “I think it bodes well for quantum optics that these heroes are getting the recognition they deserve.” In the early 1960s, Harvard University's Glauber tackled a fundamental problem with the quantum theory of light: A randomly produced bunch of photons behaves more like a hail of bullets than a graceful “classical” light wave. To appear more wavelike, the individual photons must be coordinated or synchronized to create a so-called coherent state, in somewhat the same way that a pointillist painter organizes colored dots into a complete image. That much was already known. But Glauber studied in detail the properties of such coherent states and their interactions with detectors. Coherent states “were treated as a curiosity,” Glauber says. “Some [hints from experiments] gave me the thought that their role was much more fundamental.” Glauber's work explained surprising phenomena that occur only in experiments that probe the quantum nature of light. For instance, depending on the circumstances, individual photons can tend either to clump together or to avoid each other. Known as “bunching” and “antibunching,” those phenomena may be useful for conveying information in streams of individual photons. This year's prize also lauds Hänsch of the Max Planck Institute for Quantum Optics in Garching, Germany, and Hall of JILA, a research institution run jointly by the University of Colorado, Boulder, and the National Institute of Standards and Technology, for work on stabilizing and manipulating laser light. “It's a very rich reward for the excellent work they've done for a very long time,” says physicist Stephen Lea of the National Physical Laboratory in Teddington, U.K. A laser produces a beam with a narrow range of frequencies by coaxing atoms to emit light in concert. But there is always some variation in frequency because of the inherent uncertainty in the emission of light by the atom and the mechanical instabilities of the laser. Hänsch and Hall independently developed techniques to greatly reduce that uncertainty by using a “resonant cavity”—essentially an optical bell that rings with light—to stabilize the laser. These efforts led to the invention of the frequency comb, an ultraprecise frequency standard that might someday replace the current atomic clock as the ultimate timekeeper. The comb consists of a highly stabilized laser locked into a cycle in which it spits out a regular stream of light pulses tens of femtoseconds long and separated by nanoseconds. The spacing of those pulses is constant to a few parts in a million billion. Hänsch had the idea for the frequency comb 25 years ago, Lea says, but Hall's achievements were essential to making it work. Einstein's quantum hypothesis may be a century old, but the field of quantum optics is young and growing, Scully says. The likelihood of new applications, he adds, augurs well for more Nobels in the next 100 years. 10. ENDANGERED SPECIES # Ban on Beluga Caviar Points to Sturgeon's Worldwide Decline 1. Christopher Pala 1. Christopher Pala is a writer in Almaty, Kazakhstan ALMATY, KAZAKHSTAN—Seeking to protect one of the oldest species of fish on Earth, the United States on 30 September banned importing caviar from the king of sturgeon, the beluga. That's good news for the sturgeon, but a bit late. A comprehensive study published last month found that all 25 species of sturgeon and two related paddlefish have been depleted worldwide. “This is a case of the lessons not learned,” says Ellen Pikitch, director of the Pew Institute of Ocean Science in New York City, the lead author with Phaedra Doukakis of the study in Fish and Fisheries. “For the first time, we're looking not just at the possible disappearance of a species but of a whole order, … one of the oldest and most interesting ones in the world.” The study found local extinctions for 19 of 27 species. Belugas caught today usually weigh 150 kg—mere teenagers in a species that should include centenarians—and the study concluded that nearly all mature individuals, which can reach 6 meters in length, have been taken out. “It's no accident that the three species that are in the best shape are all in the States and are all completely protected,” Pikitch says. “We need to extend the same protection to the other species, particularly the beluga, before it's too late.” Since 1997, the United Nations has tried to limit exports of the three commercially harvested species—the beluga, the Russian/Persian, and the stellate—through its regulatory body, the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). But this hasn't prevented widespread poaching. Three U.S. environmental organizations 5 years ago petitioned the U.S. Fish and Wildlife Service (FWS) to place the beluga on its threatened list and urged consumers to boycott beluga caviar (Science, 16 September, p. 1799). As a result, the United States became the second nation, after Australia, to ban the importation of beluga. FWS Assistant Director for International Affairs Ken Stansell said in a telephone press conference that he hoped the U.S. measure would “encourage other nations to take a closer look at their imports.” Stansell, the U.S. representative to CITES, said the 143 member states next meet in June 2007, the earliest date they could consider a proposal to ban the trade. But no such measure has yet been proffered. In late July, Russia proposed a moratorium on fishing all three commercial species at a meeting of the Caspian Bioresources Commission, composed of the Caspian countries. The commission, which sets each country's yearly caviar export quotas, will take up the proposition at its next meeting, in November. If these countries adopt the moratorium, international trade will stop without CITES's intervention. What a worldwide ban on the wild caviar trade would achieve is unclear, as illicit harvesting would likely continue. “Most of the poached caviar is consumed in the former Soviet Union,” says Sabri Zain of Traffic International, an organization that tracks trade in endangered species. “As long as the producer countries don't control their domestic market, stopping exports will have very little effect.” 11. ASTROPHYSICS # Short Gamma Ray Bursts: Mystery Solved Bursts: Mystery Solved 1. Govert Schilling 1. Govert Schilling is an astronomy writer in Amersfoort, the Netherlands. The incredibly bright and extremely brief flashes of energy known as short gamma ray bursts have taunted astronomers for more than 3 decades, but it looks as if researchers have nailed their origin at last. According to a series of papers in this week's issue of Nature, these hugely powerful cosmic explosions that flood space with high-energy gamma rays are produced by merging neutron stars or black holes. Four international teams of astronomers reached that conclusion after observing two short gamma ray bursts earlier this year (Science, 13 May, p. 939). Detailed studies of three other short bursts support the merger scenario. Gamma ray bursts were first detected by spy satellites in the 1960s. No one knew their source or even how distant they were until 1997, when the Italian-Dutch BeppoSAX satellite first detected a burst's afterglow, enabling researchers to determine its distance and prodigious energy output. Since then, a wealth of new observations has convinced astrophysicists that the longer bursts—which last more than 2 seconds or so—are the death cries of rapidly rotating massive stars that explode as brilliant hypernovas while their cores collapse into black holes. However, a large and distinct population of very short bursts, lasting 0.3 seconds on average, remained mysterious. Now, follow-up observations of the afterglows of two short bursts on 9 May and 9 July, detected by the Swift and HETE-II satellites, respectively, have settled the issue. The bursts, which occurred in relatively nearby galaxies, showed no hint of an underlying stellar explosion. Given their distances, they appear to have less than 1/100th the power of their long-lasting cousins. These observations agree perfectly with the merger model, in which two orbiting neutron stars—themselves compact remains of exploded giant stars—slowly spiral toward each other and coalesce into a black hole, releasing huge amounts of energy. Unpublished results from three more short gamma ray bursts support the conclusions, says Jochen Greiner of the Max Planck Institute for Extraterrestrial Physics in Garching, Germany. “The general feeling in the gamma ray burst community is that the issue has been settled,” he says. “I am not aware of any remaining viable alternative explanations.” Some riddles remain: Astronomers still wonder why the x-ray afterglows of short bursts appear so faint, and they still can't tell whether the merger involved two neutron stars or a neutron star and a black hole. As one team notes in its paper: “The stage is now set for detailed studies of these exotic cosmic explosions.” 12. DRUG REGULATION # Plan B: A Collision of Science and Politics 1. Jennifer Couzin Studies of the emergency contraceptive in thousands of women have failed to assuage the concerns of abortion opponents and top drug regulators in the United States. Researchers see ideology trumping sound science The U.S. Food and Drug Administration (FDA) promised a decision on the emergency contraceptive Plan B early last summer. But on 26 August, after more than 2 years of deliberation, leaked memos, and a contentious advisory committee meeting, FDA ducked, putting off indefinitely a ruling on the application from Barr Laboratories in Woodcliff Lake, New Jersey, to move Plan B over the counter (OTC). The problem, agency officials said, was a dearth of information on whether the drug, approved for prescription use in 1999 and widely available in European pharmacies, would negatively influence the sexual behavior or health of adolescents. FDA was unsure how to restrict the drug's OTC status to older age groups. That announcement, say critics of the nondecision, highlighted Plan B as the latest scientific issue—after climate change and evolution—to be taken ideological hostage by the Bush Administration. In late August, the head of FDA's Office of Women's Health, Susan Wood, resigned and publicly stated her disagreement with the Plan B decision. On 22 September, a New England Journal of Medicine editorial written by the journal's editor and two members of the two FDA advisory committees that voted in favor of the shift, citing the drug's safety, proclaimed that FDA's recent actions “have made a mockery of the process of evaluating scientific evidence.” Considered dead after the August announcement by then-FDA commissioner Lester Crawford, Plan B may yet rise again. Senators Hillary Clinton (D-NY) and Patty Murray (D-WA) had voted to confirm Crawford in July only after he promised a quick decision on Plan B. Crawford failed to deliver. Two weeks ago, he resigned suddenly, and National Cancer Institute Director Andrew von Eschenbach was named FDA acting director (Science, 30 September, p. 2142). But a spokesperson for Murray says she would consider blocking the nomination of a new FDA head until the agency rules definitively on Plan B. Clinton, says a spokesperson, continues to press for a decision. The furor stands in sharp contrast to how the issue has been handled in the rest of the world. Emergency contraception is available OTC or from a pharmacist in 39 countries. In France, it's provided by school nurses in every senior and junior high school, says James Trussell, director of the office of population research at Princeton University in New Jersey. U.S. contraceptive researchers say the delay is inexplicable because of studies, some done years ago, that answered questions now being raised by Plan B opponents. Those studies involved thousands of young women from Scotland to San Francisco who were offered easy or more burdensome access to emergency contraception; it must be taken within 72 to 120 hours of intercourse to prevent pregnancy. They had been tested for sexually transmitted diseases and pregnancies. They'd been quizzed to determine whether keeping shrink-wrapped packs of Plan B in their nightstands made them likelier to engage in unprotected sex. The results were unambiguous: Teenagers appeared to have no trouble understanding how to use Plan B, and its availability didn't change their behavior. Those results contributed to the near-unanimity among FDA scientists and the scientific community that the drug ought to move from prescription-only status to OTC. Plan B, or levonorgestrel, is a progestin-only pill that interferes with ovulation and perhaps with fertilization, explains Margaret Blythe, a pediatrician at Indiana University Medical Center in Indianapolis. Its effectiveness declines with time, which argues for making it rapidly available, say OTC supporters. Blythe spent 18 months reviewing studies of Plan B and helping write a statement for the American Academy of Pediatrics in support of OTC use. In her experience, politicians and the public often don't distinguish between Plan B and RU-486, a drug that chemically induces an abortion in the early weeks of pregnancy. Still, the difference between the two is often insufficient to appease opponents of abortion, including doctors. “We've had some physicians in the academy … who are very, very upset” with its Plan B position, she says. Two FDA advisory committees—on Reproductive Health Drugs and Nonprescription Drugs—together considered Barr's application in December 2003. Most members agreed that it met the OTC criteria. First, says Alastair Wood, an associate dean at Vanderbilt University in Nashville, Tennessee, and an advisory committee member who voted in favor of Barr's application, the drug is designed for an event (unprotected intercourse) that a patient can easily diagnose. Second, Plan B doesn't come with undue monitoring requirements, such as regular blood tests. And finally, side effects are few and can normally be managed without help from a doctor. The advisory committees voted unanimously that the drug was safe for OTC use. This view is bolstered by a general belief among physicians that reproductive drugs work similarly in teenagers and adults. In the 1990s, oral contraceptive makers inquired at FDA about receiving “pediatric exclusivity”: patent extensions on their products as a reward for conducting trials in a pediatric population. FDA turned down the request, says Lisa Rarick, who spent 15 years at the agency, including as head of its reproductive drugs division, before leaving in 2003. “Reproductive-age women are reproductive-age women,” says Rarick. “The contraceptive drugs work the same in a 14-year-old [as in] a 20-year-old.” But now, with Plan B, she says, FDA is “saying kids are different.” Opponents, including advisory committee members David Hager, an obstetrician-gynecologist at the University of Kentucky in Lexington, and Louis Cantilena, a clinical pharmacologist at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, worry about how the drug might affect a teenager's behavior. Will easier access to Plan B make teenagers more likely to engage in risky sexual behavior, and will they use the drug properly? Hager worries too about the safety of repeated use. “What happens when a young woman uses a medication three to four times a month for several months?” asks Hager of Plan B. “We just don't know how it will affect her.” It's true that such repetitive-use data are lacking, mainly because young women in virtually all the studies chose not to take emergency contraception very often, even if supplied it in advance. Cynthia Harper, a demographer at the University of California, San Francisco (UCSF), had some of the same questions. So in the late 1990s, she teamed up with UCSF ob-gyn Tina Raine, who runs a young women's reproductive health clinic in San Francisco's gritty Mission district, to follow up on a 1998 Scottish study of Plan B. That study of 1083 women (248 of them under age 20) found no difference in behavior among those offered easy access to emergency contraceptives and those who had to visit a doctor to get it. But Raine's patients were poorer than those in the Scottish study, and at much higher risk of pregnancy. Would the results be the same? The answer seems to be yes. In 2001, Raine and Harper began recruiting 2117 women aged 15 to 24 to follow up on a smaller pilot study they'd published in 2000. The large study, published last January in the Journal of the American Medical Association (JAMA), assigned the young women to one of three groups: “advance provision” (receiving Plan B to keep at home), access to Plan B through a pharmacist, or access through a clinic. The team found no differences in contraceptive use among the three. A similar outcome has been reported in other studies, including one of 15- to 20-year-olds in Pittsburgh, Pennsylvania. After 6 months, more than a third of women in the advance-provision group had used Plan B at least once, compared to a fifth of the controls. All three had similar rates of unprotected intercourse and sexually transmitted diseases. Oddly, however, despite more frequent use of Plan B among the advance-provision group, all three had similar pregnancy rates. The comparable pregnancy figures—precisely what Plan B is designed to prevent—troubled some physicians. “Promoting easier access because it increases the use of a medication without any improvement in its desired outcome seems counterintuitive,” wrote family physician Stephen Wilson of the University of Pittsburgh Medical Center St. Margaret Hospital and his former colleague Allen Last in a letter to JAMA. The problem, Raine suspects, is that the drug was underused. “Only half the women who said they had unprotected sex” used Plan B in the JAMA study, she says. “Everyone's worried that people are going to abuse it. The problem to me is that people don't understand how easy it is to get pregnant.” Other emergency contraceptive studies have consistently found similar pregnancy rates regardless of the ease of Plan B access. Why this is so is unclear, says Anna Glasier, an ob-gyn at the University of Edinburgh, U.K., who conducted the 1998 study as well as another on 18,000 women published last fall. She agrees that many women may not realize they're at risk for pregnancy. Another possibility, she says, is that even at its best the drug works less well than thought, reducing the risk of pregnancy by perhaps 50% instead of 80% or more, as many believe. Still, says Glasier, who supports easy access to Plan B, “even if something is only 50% effective, it's 100% better than doing nothing.” David Grimes, an ob-gyn at Family Health International in Research Triangle Park, North Carolina, distinguishes between the population effect seen in these studies and an individual woman's need for Plan B access—“for example, a rape victim, or a woman who's had sex with a man she does not wish to father a child with,” he says. By 2004, the American Academy of Pediatrics, the Society for Adolescent Medicine, and the American College of Obstetricians and Gynecologists had all expressed their support for making Plan B available OTC. But at FDA, which had been reviewing data sometimes even before it was published, the effort to switch Plan B to OTC status “fell apart for nonscientific reasons,” says Grimes. “Everybody's on board with this,” he says. “Everybody but the FDA.” It's unclear who made the decision to indefinitely postpone a ruling on Plan B. An internal memo in April 2004, from John Jenkins, head of FDA's Office of New Drugs, notes that “both [FDA] divisions and offices responsible for this application have recommended approval.” Jenkins concurred with that assessment and added his own support for Barr's application. Although FDA occasionally overrules its advisory committees—which in this case voted 23-4 in favor of OTC status—former FDA officials and those familiar with the agency say it almost never rejects the consensus of its own staff. The FDA official who signed off on the delay—Steven Galson, head of the Center for Drug Evaluation and Research—declined through the press office to be interviewed. Susan Wood, who quit over Plan B last month, says she spoke with people below and above Galson prior to the August announcement, and “no one seemed to know what the answer was going to be. … The scientific staff were shut out of this decision,” including members of the commissioner's office and the reviewing staff. Hager says that he was encouraged by someone at FDA to “write a minority opinion” on Plan B, which was submitted to the commissioner's office. He declines to reveal who made the suggestion. “I have never seen anything like this happen before,” says Rarick, now a consultant, who oversaw approval of both Plan B and RU-486 for prescription use. At the time, she says, FDA scientists were shielded from the politics of drug approval. “You had a buffer zone,” she says, which has since disappeared. Now the question may be whether von Eschenbach will make a decision. “This will be [his] first test,” says Wood, “as to whether he can be independent and … can ensure that science drives the decision.” 13. CONSERVATION BIOLOGY # Premier Latin American Institute Loses Grants, Ponders Future 1. Erik Stokstad Layoffs hit Costa Rica's INBio, underscoring the difficulties of funding taxonomists International biologists rejoiced when the National Biodiversity Institute (INBio) of Costa Rica was founded in 1989. Although the fledgling institute was modest—its first building was an idle warehouse for farm equipment—its vision was enormous: to inventory each and every species in Costa Rica, a country renowned for its biodiversity, and find sustainable ways to both preserve and use it. “We all thought: 'There is an opportunity, there is hope'” for conservation in the tropics, says Arturo Gómez-Pompa, a botanist at the University of California, Riverside. The cornerstone of INBio has been its pioneering species inventory. In a novel approach, the nonprofit institute trained dozens of parataxonomists from local communities to collect specimens across the country. Soon INBio had amassed major collections, and from that core it started new ventures in bioprospecting, publishing, and ecotourism that were designed to provide revenues that could be invested in conservation. “It takes your breath away to see what they're doing there,” says Elizabeth Losos, a forest ecologist who heads the Organization for Tropical Studies. But now, that flagship project is in serious trouble. Last month, INBio officials began the process of laying off a third of the 50 taxonomic staff. The proximate cause is that two major grants, which have funded most of the inventory work at INBio for the past 7 years, are running out. INBio officials play down the implications, saying that it's just a temporary funding squeeze. But some outsiders worry that the problem extends beyond next year's budget. They fear a depleted staff may curtail the organization's critical survey work and compromise INBio's broader goal of fostering biodiversity conservation. INBio's shortfall also underscores the difficulty of raising money for taxonomy, they say, and the need to pursue more innovative funding mechanisms. INBio led the way in showing scientists and policymakers that it makes economic sense to preserve biodiversity. “They were the first out of the gate in terms of trying to sell the idea of biodiversity,” says Losos. The institute negotiated savvy deals with pharmaceutical companies to search for new molecules (Science, 22 May 1992, p. 1142), and the idea of nurturing native scientific talent in a developing country garnered broad appeal within the research community. Although taxonomy was always a hard sell, international donors became more willing to open their wallets after the 1992 Convention on Biological Diversity. INBio won start-up grants to launch new operations that capitalized on biodiversity, such as tourism and education. Many projects now cover much of their own costs. A nongovernmental institution, INBio earns half its budget from revenue-producing activities including royalties from bioprospecting work and relies on grants for the other half. Because grants for taxonomy are difficult to get, especially as donor interests have shifted, INBio has occasionally trimmed its inventory staff and scaled back the ambitious plans to survey absolutely everything. Last year, INBio decided to jettison its collections of mollusks and nematodes, which were shipped to Costa Rican universities, to focus on insects and plants. “It's been really a struggle over the past decade to fund taxonomic inventories,” says Anne Larigauderie, head of Diversitas, a biodiversity network based in Paris. Some 90% of the inventory program's$900,000 budget has come from two 7-year awards, one from the World Bank's Global Environment Facility (GEF) and the other from the Dutch government. But both grants will have expired by the end of the year. “They're against the wall,” says Daniel Janzen, an ecologist at the University of Pennsylvania in Philadelphia and co-founder of INBio, who's now an unofficial adviser.

Randall García, INBio's associate director of conservation, says that about a year ago INBio was discouraged from reapplying for one of the grants because the Dutch are shifting their grant money from Costa Rica. Mario Ramos, GEF's biodiversity program manager, says his organization's grant was a one-time infusion to strengthen INBio's capacity for the inventory of bees, wasps, beetles, vertebrate parasites, and fungi. “The idea is that the GEF is catalytic,” Ramos says. “We expect the follow-up won't be by us.”

Critics inside and outside of INBio feel that managers weren't very aggressive in seeking other sources of support. “The current leadership is not all that interested in inventory,” says Paul Hanson, an entomologist at the University of Costa Rica in San José, whose curator wife was given a pink slip. Not so, says García, who points to some $250,000 the institute has raised in the last year from the Spanish government, the Nature Conservancy, and Conservation International. But those grants don't cover current inventory costs. So last month, 13 parataxonomists, curators, and technicians cleaned out their desks; about five more will be let go in December. The layoffs have been concentrated in entomology, the department that had received the lion's share of support from the big grants. “It's the best insect collection” in Latin America, says Hanson. “This is sending tremors through the taxonomic community.” INBio also shut down an ecological mapping division. The layoffs will mean an end to field collecting, including the work of a team of five parataxonomists who provide information to the Costa Rican government for decisions on how to protect its lands. García hopes that INBio can rehire staff by 2007 if it can nail down more funding. But Janzen worries that well-trained staff members may not come back, taking with them their extensive knowledge of the collection. Even so, Janzen and others agree that INBio had no better alternatives. Administrators say they are pursuing new grants from conservation organizations and other governments, as well as trying to spin grant applications toward donor interests such as poverty alleviation. Longer term, they hope to further build INBio's revenue-generating operations, such as bioprospecting, and invest profits back into inventory. Some observers are skeptical that INBio will ever be able to cover its own inventory costs. Gómez-Pompa thinks that winning support from the Costa Rican government will be vital: “It's a dream to think that they will be able to survive for a long time without government support.” To Janzen, however, government support is a mixed blessing because of its unreliability. A major endowment—INBio's García mentions$21 million as a target for inventory—is the only permanent solution, he says. To that end, Janzen has agreed to help INBio pursue major donors. Despite the crowded playing field, Janzen is optimistic: “INBio is a first-class product.”

14. RUSSIAN SCIENCE

# Academy Agrees to Post-Soviet Crash Diet

1. Bryon MacWilliams*
1. Bryon MacWilliams is a writer in Moscow.

Faced with an aging membership and deteriorating infrastructure, the Russian Academy of Sciences accedes to government calls for reform

MOSCOW—It would turn out to be the most tumultuous meeting of the Russian Academy of Sciences (RAS) that anyone could remember. Many of the best scientific minds in Russia quietly seethed last May as science minister Andrei Fursenko told them how things were going to be different. The government would spend more on the sciences in return for a massive reorganization that would mean layoffs and many fewer research institutes.

But before Fursenko could finish, a shrill, stifling whistle pierced the air. Mathematician Yuri Osipov, the academy's president, immediately rose from his chair and said, “I demand that whoever whistled leave the hall.” An elderly man with a thick, gray beard—a well-known specialist in artificial intelligence—stood and left. “The minister made my blood boil … to such a degree that my fingers wound up in my mouth and a whistle came out,” Vladimir Arlazarov later told the newspaper Izvestia.

Arlazarov wasn't alone in his outrage. But, in the end, RAS agreed to meet the government halfway in reconciling the scientific legacy of the Soviet Union with the realities of modern Russia. RAS plans by 2008 to close or reorganize dozens of its 452 research institutes and withhold funding from as much as 20% of its staff. Half of that workforce, some 56,000, are researchers. In return, the government has promised a 150% rise in state financing of the sciences, from $1.6 billion to$3.9 billion. That influx of cash would boost the average researcher's monthly salary from $240 to$1050, and annual per capita spending on labs and equipment would soar from $3200 to$26,000.

The academy comprises only 6% of Russia's state scientific workforce, but its roster of Nobel laureates and its commitment to basic research traditionally have made it the star of the country's scientific firmament. Russia inherited the best institutes and infrastructure when the Soviet Union split up. Since then, however, the fortunes of its scientists have withered as government financing plummeted, and RAS members refused to countenance any downgrading of fundamental research. Yet many institutes can no longer afford to do any science and lease their premises to businesses. Many of those researchers who have remained at their posts hold second or third jobs.

Last year, government officials began to argue that a country as poor as Russia could not afford a system of 2670 scientific organizations with few ties to Russian businesses. The Ministry of Education and Science drew up a secret plan to reform and modernize the sciences that would have all but abolished the academy, triggering protests nationwide by trade unions. Nobel laureate Zhores Alferov pronounced RAS akin to the Russian Orthodox Church: It neither could be, nor should be, reformed.

But hostility toward the plan began to soften as researchers realized that time was not on their side. With 69 as the average age of RAS members and only 5% under 35, “everyone came to the conclusion that reform is necessary and urgent, because any other way science will simply cease to exist,” says RAS spokesperson Irina Presnyakova. Osipov and Fursenko began to talk seriously.

The final compromise preserves both the academy and basic science. But the brunt of the cuts will be borne by thousands of other scientific organizations—those engaged almost exclusively in applied research—largely under the control of state industries and various government ministries. Last month, Fursenko announced that, by 2010, the number of such organizations would be slashed to 1600. “Right now, the government is trying to restore control,” says Aleksei Ananchenko, press secretary of the ministry's Federal Agency for Science and Innovation, who expects legislation spelling out the changes to be presented early next year in the State Duma, the lower house of Parliament.

The bulk of the institutes still left standing by 2010 will be compelled to compete for funds in seven priority areas including information technology, ecology, and research in security and counterterrorism. Ananchenko says that directors of these institutes would have to retire at 55, and heads of labs and departments at 60. Researchers would not be subject to age limits but would undergo annual reviews for the first 3 years beginning in 2006 instead of once every 5 years, as they do now. There will be special incentives for researchers between 30 and 35 years old, and inducements to return for those now working abroad.

After more than a decade spent defending their status and livelihood, the old warhorses of RAS are finally resigned to the inevitability of change. “Without science,” says Presnyakova, “we'll become a Third World country with missiles.”

15. NEURODEGENERATION

# Huntington's Research Points to Possible New Therapies

1. Jean Marx

By studying the mutant protein made by the Huntington's gene, researchers have identified several candidate drugs that are starting clinical trials

The discovery of the gene that causes a life-threatening disease always sparks a wave of hope that it will lead to a cure. That certainly occurred in 1993 when researchers bagged the gene at fault in Huntington's disease, an inevitably fatal neurodegenerative condition that afflicts about 30,000 people in the United States alone. The gene hasn't so far provided a cure for Huntington's disease, let alone a therapy. But in the past few years, researchers have learned a great deal about how its product, a protein known as huntingtin (Htt), malfunctions and kills neurons when mutated—information that is suggesting therapeutic strategies.

Cell and animal studies have revealed that mutant Htt disrupts nerve cell function in several ways, all of which can contribute to neuronal death. Its actions range from disrupting normal gene activity patterns to interfering with the transport of proteins needed for nerve cell maintenance to overwhelming the cell with toxic amounts of calcium ions. “Talk to a dozen people, and you'll get a dozen different ideas” about what happens in Huntington's disease, says Christopher Ross of Johns Hopkins University School of Medicine in Baltimore, Maryland.

At present, no one knows whether any particular neuronal insult is primary, with the rest following as consequences, or whether they operate independently. “Some people believe there is a priming event you must find and address [for therapy], others that mutant Htt causes multiple problems,” says Marian DiFiglia of Harvard's Massachusetts General Hospital in Boston.

Despite that uncertainty, researchers have already identified potential drugs that counteract some of the neuronal problems caused by mutant Htt and are beginning to move them into clinical trials. “It's an exciting time in this field. The pace is picking up, and things look brighter than they did,” says Steven Finkbeiner of the University of California, San Francisco.

## Getting started

One of the first clues to how mutant Htt causes the brain degeneration of Huntington's disease came when researchers created a mouse model of the disease a few years after the responsible gene was discovered. The mutations causing the disease occur near the beginning of the gene, in a segment that codes for a repeating string of the amino acid glutamine. In the normal version of Htt, that string contains anywhere from six to 35 glutamines, but in Huntington's patients, the repeat contains 36 or more, with higher numbers producing earlier disease onset.

Over the years, researchers have identified such polyglutamine expansions in the proteins encoded by about nine genes. In all cases, the gene mutations cause neurodegenerative diseases, none of which are completely understood.

Back in 1997, while trying to find out how glutamine expansions in Htt lead to the nerve cell death of Huntington's disease, Gillian Bates of King's College London and her colleagues introduced into mice the first (or N-terminal) coding segment of the human Htt gene bearing glutamine stretches of various lengths. Rodents with the longer expansions developed a fatal neurological disease with symptoms, such as abnormal movement coordination, similar to those of human Huntington's disease, the researchers reported.

They also saw abnormal deposits of the mutant Htt fragments, along with other proteins, in the animals' neurons, and these so-called inclusion bodies were present before symptoms developed. Subsequently, the Bates team and others studied brain tissue taken during autopsies of Huntington's patients and found similar clumps in both the cell bodies of neurons and the long axonal projections through which they contact their target cells.

These findings suggested that Htt fragments containing extra glutamines cause at least some of the nerve damage of Huntington's disease and that their abnormal clumping contributes to this toxicity. Bolstering the idea that the fragments are toxic, researchers found that introducing them into cultured nerve cells leads both to clump formation and to the cells' death and that putting them in fruit flies produces a Huntington-like neurodegeneration in the small creatures.

Researchers have also found that numerous protein-splitting enzymes, including certain caspases, can cleave Htt and release N-terminal fragments. As shown in 1996 by Michael Hayden's team at the University of British Columbia in Vancouver, Canada, this cleavage occurs in the brains of both normal humans and Huntington's patients, although only the mutant fragment is toxic.

If the pathology of Huntington's disease indeed depends on Htt being cleaved, then inhibitors of the enzymes responsible offer a potential therapy. In fact, researchers have found that treatments that inhibit or inactivate caspase activity decrease the toxicity of mutant Htt in both cultured cells and Huntington's mice.

Although the idea that N-terminal fragments of mutant Htt are toxic has been gaining acceptance, the role of the aggregates remains controversial. Some evidence indicates that they contribute to Huntington's pathology, whereas other findings suggest that, far from causing harm, they serve to protect cells from mutant Htt's toxic effects. This debate mirrors a similar one in Alzheimer's disease in which researchers are wrestling to determine whether deposits of a protein fragment called β amyloid are toxic to brain neurons or are protective because they take the real culprit—soluble β amyloid—out of action.

The evidence that Htt aggregates are harmful includes demonstrations that inhibiting their formation reduces the toxicity of mutant Htt. For example, in the 18 January issue of the Proceedings of the National Academy of Sciences, a multi-institutional team led by Anne Young and Aleksey Kazantsev of Massachusetts General Hospital reported that feeding a compound, called C2-8, to fruit flies engineered to express mutant Htt prevents aggregate formation and reduces neurodegeneration in the insects' photoreceptor neurons.

David Rubinsztein of the Cambridge Institute for Medical Research in the United Kingdom and his colleagues have also found that the drug rapamycin suppresses Htt aggregate formation and decreases related toxicity in cultured neurons and in fruit fly and mouse models. The drug seems to work by enhancing a recycling process called autophagy that cells use to destroy excess or damaged proteins. The process involves moving the proteins into small membranous sacs called lysosomes, which are essentially the cell's garbage-disposal units. The lysosomes are packed with enzymes that break down proteins and other cellular constituents. In the past few years, researchers, including DiFiglia and Rubinsztein, have found that autophagy helps clear Htt from nerve cells, thereby decreasing aggregate formation in the cells.

But autophagy apparently can't keep mutant Htt in check forever. The Rubinsztein team found that when rapamycin treatment began 33 hours after introducing DNA encoding the mutant N-terminal fragment of Htt into cultured neurons, it had no affect on aggregation or cell death, whereas it worked just fine when introduced 15 hours after the gene transfer. “In the later stages [of Huntington's disease], autophagy might fail and allow the mutant protein to accumulate,” DiFiglia says. These results suggest that if drugs such as rapamycin ever reach the clinic, they will have to be given before such a stage is reached.

Not all the researchers who have looked at Htt aggregation have found it harmful, however. In work described last fall in Nature, Finkbeiner and his colleagues found in lab cultures that many mouse neurons die even though they lack Htt inclusions. Indeed, the neurons with the inclusions survived better than those without, whereas neurons with lots of diffuse Htt had very poor survival. More recently, the Hayden group has confirmed this in mice, showing that animals with massive inclusions show no signs of neurodegeneration.

Work by Ross with Michelle Poirier and other Hopkins colleagues has shown that the inclusions develop in a stepwise process, with small, soluble aggregates forming first. The Finkbeiner and Hayden teams' results suggest that this diffuse Htt is the toxic form and that sequestering it in insoluble aggregates actually helps protect neurons. “At the moment, it looks like earlier forms of certain kinds of aggregates cause the problems,” says Erich Wanker of the Max Delbruck Center for Molecular Medicine in Berlin, Germany, whose team has also looked at how the aggregates form.

## Into the nucleus

No matter which form of mutant Htt is toxic, there is no doubt that the extra glutamines in the protein cause a raft of problems for nerve cells, including disruption of gene activity. Normal Htt binds to various transcription factors, proteins that control gene expression, and is thus part of the cell's gene regulatory machinery. Researchers, including Ross, Leslie Thompson of the University of California (UC), Irvine, and Dimitri Krainc of Massachusetts General Hospital, have found that the mutant N-terminal fragment of Htt disrupts this machinery. In some cases, it does this by binding to transcription factors and taking them out of action. This prevents the factors from turning on needed genes such as those encoding certain nerve cell growth factors.

Mutant Htt also indirectly alters gene expression by binding to and inhibiting a histone acetylase, an enzyme that marks genes for activity by tagging their associated histone proteins with acetyl groups. This suggests another way of decreasing Htt's toxicity. “You can compensate for the decreased acetylation by using an inhibitor of the enzyme that removes the acetyl groups,” says Thompson, who is one of the researchers who made the histone acetylase connection.

A few years ago, Thompson, working with Lawrence Marsh, also at UC Irvine, and colleagues, showed that this works in fruit fly models of Huntington's disease. Treating the animals with either sodium butyrate or a drug known as SAHA, both of which inhibit the enzyme that removes acetyl groups from histone, slowed down neurodegeneration in the flies. At about the same time, Bates and others obtained similar results with SAHA in Huntington's mice. Both of these deacetylation inhibitors are being explored for use in cancer therapy and are now also moving toward clinical trials for Huntington's disease.

Mutant Htt may also cause neuronal damage by increasing the activity of certain cell death-related genes, a new study suggests. Evidence has accumulated that the mitochondria, the small structures that produce most of the cell's energy, malfunction in animal Huntington's models and in human patients. In work reported in the 7 July issue of Neuron, Akira Sawa, working with Ross, Solomon Snyder, and colleagues at Johns Hopkins University School of Medicine, found that mutant Htt, but not the normal version, binds to a transcription factor called p53. Best known as one of the body's major tumor suppressors, p53 controls several genes, including some affecting mitochondria. Sawa's team found that the increase in p53 activity that occurs when it binds mutant Htt causes an abnormal flow of calcium ions across the mitochondrial membrane, thereby disrupting function of the organelles and leading to nerve cell death.

Sawa and his colleagues also showed that they could prevent the mitochondrial dysfunction by inactivating the p53 gene in cultured mouse brain neurons carrying a toxic Htt N-terminal fragment. Similar p53 inactivation suppresses neurodegeneration in Huntington's mice and flies, an indication that it might be another drug target. But Sawa cautions, “p53 is so important for our life that complete p53 suppression could be bad for us.” Instead, he suggests, scientists should look for molecules that either block the p53-mutant Htt interaction or inhibit the products of the mitochondrial genes activated as a result of that interaction.

A continuing mystery concerns the fact that the medium spiny neurons of the striatum of the brain are the first to degenerate in Huntington's disease. Hayden's team, working with that of Ilya Bezprozvanny at the University of Texas Southwestern Medical Center in Dallas and Lynn Raymond of the University of British Columbia, produced lab cultures of these neurons from mice carrying a full-length mutant Htt and compared the responses of those neurons to the excitatory neurotransmitter glutamate with those of neurons from normal mice. The modified medium spiny neurons experienced a much greater influx of calcium ions—and died—as a result, the researchers reported in the 15 February Proceedings of the National Academy of Sciences.

What's more, Hayden says, these changes occur very early. They were present in neurons studied just after the animals are born—well before disease symptoms develop. Hayden suggests that the receptors through which glutamate exerts its effects are possible targets for Huntington's therapies. In support of that idea, he and his colleagues found that drugs that block their activity suppressed the glutamate-induced death of cultured medium spiny neurons.

## Protective actions lost

Because the huntingtin mutation is dominant—causing disease if only one gene is inherited—researchers have focused mainly on the idea that the mutated protein has gained a toxic function. But recent work suggests that glutamine expansions can also contribute to neurodegeneration by reducing normal Htt's protective effects on neurons.

About a year ago, Frédéric Saudou of the Institut Curie in Paris and his colleagues found that normal Htt is part of the machinery that transports a nerve growth factor called brain-derived neurotrophic factor (BDNF) along their axons. Because of the structural changes caused by the additional glutamines, mutant Htt can't perform this transport function and in fact disrupts normal Htt interaction with the transport machinery.

As a result, the neurons lose part of their supply of BDNF, which the cells need to survive. Saudou speculates that this may be one reason that medium spiny neurons are hit first in Huntington's disease. They're especially dependent on BDNF produced by other brain cells and taken up by their axons.

Possibly making matters worse, Htt mutations may also lead to a decline in BDNF production by medium spiny neurons. Elena Cattaneo and her colleagues at the University of Milan, Italy, have found that normal Htt helps turn up the activity of genes encoding BDNF and other proteins needed for neuronal maintenance. As a result, the BDNF supply will be further reduced when Htt is mutated, producing a double whammy for the cells.

If any of these revelations about the causes of Huntington's pathology ever generate effective treatments, they may have to be started early in life. Recent brain imaging studies from Ross's team, including Sarah Reading and Elizabeth Aylward, show that the degeneration in the striatum of the Huntington's brain is visible at least 11 years before a person develops symptoms, usually in their 40s.

Ross notes that this means there is a long time to try to halt the decline before a person gets sick. “What I've found most gratifying is that we've gone from a single gene to multiple possible mechanisms,” he says. “Now we need to find which are most important and will lead to therapy.”