News this Week

Science  20 Apr 2001:
Vol. 292, Issue 5516, pp. 410
  1. EPIDEMIOLOGY

    Intensified Battle Against Foot and Mouth Appears to Pay Off

    1. Martin Enserink

    In late March, three teams of epidemiologists took their latest computer model results on foot-and-mouth disease (FMD) to the British Ministry of Agriculture, Fisheries, and Food and the country's chief science adviser, David King. Their numbers held a grim message: Britain's attempts to control the disease weren't working, the epidemic was still growing exponentially, and, if nothing changed, would spiral out of control.

    In response, the government adopted a more aggressive campaign to stamp out the catastrophic outbreak—a strategy that seems to be paying off. Last week, the daily number of newly infected farms was dropping, and some researchers were predicting that the epidemic may be past its peak. The studies “certainly had more of an immediate impact than any previous mathematical model of an infectious disease,” says Neil Ferguson of Imperial College in London, one of the researchers. Meanwhile, as data on the economic costs of the outbreak emerge, FMD experts in other countries are reassessing whether the no-vaccination policy adopted by the European Union (E.U.) still makes sense.

    At the outset of the United Kingdom's FMD crisis, as many as 3 or 4 days typically elapsed between the identification of an infected farm and the slaughter and destruction of its herd. That delay, said the modeling teams, one made up of ministry scientists, one led by Ferguson, and the third by Mark Woolhouse of the University of Edinburgh, enabled the fiercely infectious FMD to spread. (Science published the Ferguson group's results online last week at www.sciencexpress.org.) At a joint meeting of the ministry and the Food Standards Agency on 21 March, the researchers also argued that “ring culling” at farms adjacent to each infected farm was necessary to halt the outbreak. Now, with the help of the army, most infected herds are culled within 24 hours—more than 1.1 million livestock have been destroyed—and ring culling has become standard.

    The models proved especially persuasive, says Woolhouse, because they showed essentially the same results, as did yet another simulation by the University of Cambridge. “That has helped the government believe them.” Woolhouse cautions, however, that it's still too early to be certain that the current decline really marks a turning point in the epidemic. An aggressive ring-culling policy would always reduce the number of new cases, he says, because some of those farms undoubtedly housed animals that were infected though asymptomatic.

    At the same time, the current outbreak is rekindling the debate over an old question: whether to vaccinate. Until 1991, farmers in most European countries had their cattle vaccinated yearly to prevent FMD outbreaks. That year, however, the E.U. banned the use of vaccines and switched to its current policy of stamping out outbreaks to enable E.U. countries to export to the United States and Japan. Both countries, which are FMD-free, refuse to import meat or animals from countries that allow vaccination because vaccinated animals could be silent carriers of the disease (Science, 23 March, p. 2298).

    The Dutch government, which faces its own small outbreak—25 cases, so far—is arguing that once this epidemic is over, the E.U. should reconsider its ban on preventive vaccination. Surprisingly little research has been done on the ban's costs and benefits, says Paul Berentsen, an agricultural economist at Wageningen University in the Netherlands. When Berentsen and his colleagues undertook such a study in 1989, they concluded that not vaccinating made economic sense. But the government is currently waging a much more aggressive and costly campaign than the researchers estimated, says Berentsen. In addition, other European countries appear to be more averse to importing animal products from the Netherlands than expected. Those two factors alone could tip the economic balance back toward vaccination, he says. He adds, however, that a reversal of the vaccination policy would have to be agreed upon by the entire E.U.—which by definition means nothing will change anytime soon.

    To cope with the current outbreak, the E.U. is permitting “emergency vaccination” of animals in the most affected area in the Netherlands. The goal is not to save the animals but to stop the spread of the disease quickly while allowing more time for disposal of the carcasses. All the vaccinated animals will eventually be killed. Although the British models conclude that such emergency vaccination is a less effective way to prevent the spread of the disease, virologist Aldo Dekker of the Dutch Institute for Animal Science and Health in Lelystad says it avoids a potential risk associated with culling: The teams and heavy equipment moving about the countryside to slaughter animals may themselves contribute to the spread of the virus. Vaccinating a herd is a much simpler and less risky task, he says.

    The emergency vaccination strategy may also minimize public resistance to the control measures. Already, fierce protests from small groups of farmers against the destruction of apparently healthy herds has delayed culling efforts in the Netherlands. By avoiding the grisly funeral pyres now commonplace in the United Kingdom, the Dutch government hopes to prevent a further escalation of the current protests and to stamp out the disease more effectively.

  2. UNIVERSITY OF ROCHESTER

    Researcher Sues After School Spent His Grant

    1. Constance Holden

    Robert Ader, a prominent neuropsychologist at the University of Rochester in New York, won a $200,000 research grant from Philip Morris Companies Inc. in 1989. He didn't need the money at the time, so he left it in an endowment fund for future use. But he later discovered that his department chair, without his knowledge, had spent the funds to renovate his lab. In January, after a long battle to get the money back, he sued. A judge rejected the suit last month on grounds that the statute of limitations on such complaints had run out, but Ader says he plans to appeal.

    The case is drawing national attention. Martin Snyder, an official at the American Association of University Professors, which is weighing whether to support Ader's legal campaign, calls it “a very, very curious situation. … I haven't encountered anything quite like this, and no one else has, either.”

    Ader, the George L. Engel professor of psychosocial medicine, has been at Rochester since 1957. He is known for his pioneering rodent experiments on the interaction between the nervous and immune systems that spawned the field of psychoneuroimmunology.

    His work was already well funded by public and private agencies when the money from Philip Morris—a general grant to support his research, with no strings attached and no reporting requirements—came in. So he left it untouched in his department's endowment account. For several years, he received regular interest statements indicating a growing balance, according to his lawyer, Alexander Geiger.

    Missing money.

    Robert Ader hopes to get back research money used to renovate his University of Rochester lab.

    CREDIT: COURTESY OF ROBERT ADER/UNIVERSITY OF ROCHESTER MEDICAL CENTER.

    But the money in fact wasn't there. When a new department chair arrived in 1996 and began going through the books, Ader was told that the money had been spent to renovate his lab. He says university administrators had promised to refurbish his lab when he was named head of the Division of Behavioral and Psychosocial Medicine in 1982, but he was never told his own research funds would pay for the work.

    After 4 years of memos and meetings with the then-dean of the School of Medicine and Dentistry, Ader says he was finally told his complaints were groundless because the $200,000 had been used for his research program, as Philip Morris intended. Ader won the backing of the University Committee on Tenure and Privileges, but the university president decided that the committee had no jurisdiction over the matter. After further futile appeals, Ader went to court asking the university to turn over $600,000—the grant award plus accrued interest—for his research.

    University spokesperson Teri d'Agostino says that using the grant money to pay for Ader's lab was appropriate because “the funding source had placed no restriction on the use of these funds,” and they “were used exclusively for Dr. Ader's program.” She says that the school has no explanation for the financial statements, and that only the former chair, now deceased, knew what they were. However, she agrees that Ader should have been kept better informed about what was going on.

    In court, the university did not argue the merits of the case but convinced the judge that Ader's complaint was invalidated by a 4-month statute of limitations on review of disputed grievances with government bodies. Geiger says the court has misinterpreted the law, because the last letter from university officials was sent in October, only 3 months before the suit was filed.

    Ader is keeping up the attack. “It's disheartening to find, after 40 years in academia, that there are university officials who will resort to patently deceptive practices,” he says. Nicholas Cohen, a longtime collaborator and a member of the Committee on Tenure and Privileges, says the group “argued [in vain] that it was indeed faculty privilege not to have money taken from them.” The committee plans to recommend the establishment of some channel to handle grievances against the administration, he adds, such as the appointment of a mediator.

  3. X-RAY CRYSTALLOGRAPHY

    Transcription Enzyme Structure Solved

    1. Jean Marx

    If any enzyme does the cell's heavy lifting, it's RNA polymerase II. Its job: getting the synthesis of all the proteins in higher cells under way by copying their genes into RNAs, and doing it at just the right time and in just the right amounts. As such, pol II, as the enzyme is called, is the heart of the machinery that controls everything that cells do—from differentiating into all the tissues of a developing embryo to responding to everyday stresses. Now, cell biologists can get their best look yet at just how the pol II enzyme of yeast and, by implication, of other higher organisms performs its critical role.

    In two papers published online today by Science (www.sciencexpress.org), Roger Kornberg's group at Stanford University School of Medicine describes the atomic structure of the yeast enzyme; a slightly lower resolution structure captures yeast pol II in the act of transcribing a piece of DNA into RNA. Cell biologist E. Peter Geiduschek of the University of California, San Diego, describes the achievement as “extraordinary.” Not only does it give cell biologists their first clear view of yeast pol II in action, but it also opens the door to seeing exactly how the enzyme interacts with the many other proteins that regulate its activity. And that, adds Geiduschek, will “transform the analysis of transcription and transcription mechanisms in a fundamental way.”

    Kornberg and his colleagues have been on the path to the pol II structure for nearly 20 years. The first 10, he recalls, were devoted to isolating the myriad proteins involved in gene transcription. During that time, his team and others found that the pol II machinery of higher organisms is very large. The enzyme alone contains 12 different proteins bound together in a complex that has a molecular weight of about 500,000.

    That, combined with the fact that the enzyme is present in cells in very low concentrations, meant that determining the enzyme's three-dimensional structure by x-ray crystallography would be extremely difficult. But by early last year, the Kornberg team, including postdocs Patrick Cramer and Averell Gnatt, the lead authors on the current papers, had determined the structure of a complex containing 10 of the enzyme's 12 proteins to a resolution of about 3.5 angstroms—good enough to see the backbones of the protein chains but not of the side chains of the individual amino acids (Science, 28 April 2000, p. 640). (The other two proteins, which aren't needed for RNA elongation, kept pol II from crystallizing.)

    In the current work, the team has solved the pol II structure to a resolution of 2.8 angstroms. Now, Cramer says, “we can see where every amino acid goes.” The new structure largely confirms what the earlier one had suggested. For example, the enzyme has a pair of “jaws” that enable it to attach to the DNA to be copied. And because the growing RNA chain is enclosed within pol II's active site, the bottom of the enzyme has a large pore through which the nucleotide building blocks of RNA can enter.

    Jaws of life.

    This ribbon image of pol II shows the opening to the enzyme's active site. The colors mark the different protein subunits of pol II.

    CREDIT: P. CRAMER ET AL.

    These features are quite similar to those seen in the only other multisubunit RNA polymerase whose structure has been determined, the enzyme from the bacterium Thermus aquaticus. Seth Darst, a former Kornberg postdoc now at New York City's Rockefeller University, and his colleagues solved that structure. And even though the bacterial enzyme is less complicated than yeast pol II, having just five subunits rather than 12, Darst says, “the central cores of the structures are identical. … These enzymes are highly conserved.” However, they vary around the periphery, which carries important contact points for regulatory proteins. Researchers will now be able to see those of the yeast enzyme clearly.

    And the structure of human pol II should be very similar. Kornberg notes that 53% of the amino acids in the yeast and human enzymes are the same and that the identical amino acids are distributed similarly throughout the proteins of the two enzymes. “To all intents and purposes, the structures are the same,” Kornberg says.

    Once they had nailed down pol II itself, Kornberg's team was able to take the next step: solving the structure of the enzyme in a complex with DNA and an elongating piece of RNA. The researchers couldn't have done that with last year's lower resolution structure, Cramer says. But with the new one, “the elongation complex [structure] just pops out.”

    In the loop.

    The pol II “clamp” (orange) holds onto the DNA while it's being transcribed into RNA (red).

    CREDIT: A. L. GNATT ET AL.

    Among other things, that structure provides an answer to a long-standing puzzle in gene transcription. When pol II transcribes a gene, it has to latch onto the DNA and then move long distances—sometimes millions of nucleotides—without falling off. But when it reaches the end of the gene, it needs to let go. What this second structure shows, Kornberg says, is that one segment of the enzyme forms a “clamp,” which is open in the free enzyme but swings shut once RNA synthesis begins and the active site contains a DNA-RNA hybrid. RNA synthesis stops at the gene's termination site, however, and with no hybrid there, the clamp swings open, releasing the enzyme.

    Although researchers are thrilled by the new work, Geiduschek and others point out that “this is really more of a beginning, rather than an end, to the story.” The next big step is solving the structure of pol II complexed to the many transcription factors and other proteins that regulate gene transcription. Then, “people can really begin to understand how those factors interact with the polymerase. That will have a huge impact on the field,” says Robert Landick of the University of Wisconsin, Madison.

    The structural work may have practical implications as well. If researchers can find differences between the way human pol II and its bacterial and fungal counterparts interact with either DNA or associated proteins, they may be able to find antibiotics that work by specifically inhibiting pathogen polymerases. Another possibility is to look for drugs that prevent transcription factors involved in stimulating cell growth from binding to pol II, as these may be potential targets for cancer therapy.

    Meanwhile, the members of Kornberg's team can pride themselves on a feat that was judged impossible just a few years ago. “Until a relatively short time ago,” Geiduschek says, “pol II was regarded as beyond contemporary reach.”

  4. ECOLOGY

    Birds Weigh Risk Before Protecting Their Young

    1. Elizabeth Pennisi

    As every parent knows, what's best for the children may not always be best for the parents, be it a movie choice or where to spend hard-earned money. Feathered parents can face an even starker decision: whether to trade their progeny's survival for their own.

    And cold-hearted though it may seem, birds are sometimes willing to sacrifice their young to save themselves so they can breed again. New work, reported on page 494, clearly shows that breeding birds factor in both the number of their young and their own likelihood of surviving when deciding whether to risk delivering food to the nest in the presence of a predator. This behavior even varies according to what type of threat a specific predator poses. “Birds have the cognitive ability to react [differently] to certain kinds of predators,” says Jeffrey Brawn, a population ecologist with the Illinois Natural History Survey in Champaign.

    The work, by Cameron Ghalambor, now at the University of California, Riverside, and his colleague Thomas Martin at the U.S. Geological Survey in Missoula, Montana, probed a long-suspected difference between birds in the Northern Hemisphere and their counterparts in the tropics and the Southern Hemisphere: Northern birds tend to lay more eggs than do similar species in the South.

    For these studies, Ghalambor and Martin first analyzed preexisting data on number of young and adult survival of some 182 species, comparing birds from Europe and North America with those from New Zealand, Australia, and South Africa. They also probed these characteristics in more detail in two bird populations on opposite sides of the Equator, in Arizona and in Argentina. “I've never seen comparisons over such a broad geographic area,” comments Amy Krist, an evolutionary biologist at the University of Hawaii, Hilo.

    Both the preexisting data and those from the Argentina and Arizona sites confirmed the disparity in the number of eggs laid per season between northern and southern populations. Ghalambor argues that the difference may be explained by the fact that northern birds sometimes live just one season, so they “invest more in reproduction” by laying more eggs the one chance they have.

    Ghalambor and Martin then tested whether that investment also results in differences in the risks northern and southern populations run to protect either themselves or their young. They looked at the parents' willingness to return to the nest to feed their chicks when confronted with a predator. The researchers compared five Argentinian species—a flycatcher, a thrush, a wren, a sparrow, and a warbler—to their closest relatives in Arizona.

    For each species, they tested the parents' reactions to recordings of calls from a hawk, which attacks adults; a jay, which attacks chicks; or a nonthreatening stuffed tanager. They attempted to test each bird call on each set of parents and observed them for 90 minutes both before and after. All told, they made 175 presentations to 61 nests.

    As expected, birds from both hemispheres reduced their food deliveries when they heard and saw either the hawk or the jay. “It's been known for a while that birds avoid going to nests when they know they are being watched,” says Robert Ricklefs, an ecologist at the University of Missouri, St. Louis. But there were some intriguing differences.

    Take the house wren. The wrens in Arizona averaged 5.8 chicks per nest, while their southern counterparts averaged just 3.7. The jay, which attacks chicks, spooked the Arizona wrens more than those in Argentina, inciting a greater reduction in feeding. In contrast, the Argentinian birds were less concerned about leading the jay to their nests but were more leery of the hawk, very quickly abandoning feeding their chicks to protect themselves.

    “There is a trade-off between survival and reproduction,” explains Ghalambor, in which the northern birds that are unlikely to survive the winter have put all their eggs in one nest, so to speak, and do everything they can to care for those eggs. Southern birds hedge their reproductive potential, producing fewer eggs at one time but breeding more than once. Hence, they value their own survival more than that of their chicks.

    Biologists have long thought that some traits evolve to compensate for other traits that might compromise an organism's reproductive potential, says Brawn. Yet demonstrating how characteristics such as nest size and risk-taking behavior vary in different environments to contribute to the species' survival has been tough. Ghalambor and Martin, says Brawn, have corroborated “one of the central principles of life history theory.”

  5. MICROARRAYS

    Data Standards on the Horizon

    1. R. John Davenport

    Microarrays offer researchers a tantalizing way to reap the bounty of genome sequencing—if the torrent of data they generate can be managed properly. In an effort to tame the flood, a group of scientists is almost ready to propose standards for describing and sharing microarray data. Even so, researchers and journal editors are not very far along in figuring out how to enforce them.

    Microarray data won't reach their potential until researchers can compare their own results with those of experiments in other labs. But right now there is no standard format for transferring microarray data between scientists and no rules for how a microarray experiment should be described in a publication. In 1999 a group of bioinformaticists and biologists met in Cambridge, U.K., and formed five working groups to tackle the problem. Last month, at the third such meeting,* two of those groups announced that they are close to submitting recommendations on defining what data should be recorded and the format for transferring and archiving them. “It now has a momentum of its own,” says Alvis Brazma of the European Bioinformatics Institute, who convened the first meeting and has seen attendance more than triple, to 300 participants.

    The Minimal Information About a Microarray Experiment (MIAME) working group presented a final draft of a document that defines how to describe not only the gene expression data, but also the sample and experimental conditions under which the data were collected. The working group hopes to submit the MIAME document for publication in the next 2 to 3 months in what Brazma calls “MIAME version 1.0.”

    Seeing spots.

    Standards would help scientists share and interpret microarray data.

    CREDIT: NIH

    A second challenge involves creating a tagged-text computer format for transferring and archiving microarray data. One proposal comes from a working group led by Paul Spellman of the University of California, Berkeley. Two biotech firms have also individually crafted proposals for a software standard: microarray developer Rosetta Inpharmatics Inc. of Kirkland, Washington, and NetGenics Inc., a bioinformatics software company in Cleveland, Ohio. The three have agreed to submit a revised consensus proposal to a software standards organization by 18 June. “People are putting aside their egos” in the quest for a single standard, says Doug Bassett, senior director of biosoftware products and services for Rosetta.

    It will then be up to journal editors to enforce the standards. Brazma hopes that eventually authors will be required to deposit data in a public database—but not until it's clear to everyone that the standards capture the right information and don't present a burden to researchers submitting the data, he and others say. Establishing standards is “something everyone realizes needs to happen,” says Mike Cherry of Stanford University, who organized this year's meeting, “There'll be a lot of complaints if it's not done well.”

    • * The Third International Meeting on Microarray Data Standards, Annotations, Ontologies, and Databases, 29–31 March, Stanford University, Palo Alto, California (www.mged.org).

  6. STEM CELLS

    NIH Pulls Plug on Ethics Review

    1. Gretchen Vogel

    Advocates for research with human embryonic stem (ES) cells are worried by the latest twist in the cells' political story. Last week the National Institutes of Health cancelled its planned meeting of the panel that is supposed to determine whether a given stem cell line complies with NIH's ethical guidelines (Science, 6 April, p. 27). Because the NIH can't fund projects until their cell lines have been approved by the panel, the cancellation delays indefinitely federal funding of human ES cell research.

    ES cells have the potential to develop into any cell type in the body, and many scientists would like to discover how to use them to treat intractable diseases such as diabetes or Parkinson's. However, the work is controversial because the cells are derived from week-old human embryos. Although a clause in the law that funds NIH prevents the agency from funding research that would harm or destroy an embryo, a lawyer at the Department of Health and Human Services (HHS) ruled in 1999 that because ES cells—which can grow ad infinitum in culture—are not themselves embryos, the NIH could fund work with cells that were derived by privately funded researchers or researchers overseas. The Bush Administration is reviewing that ruling.

    Meanwhile, the Human Pluripotent Stem Cell Review Group was to meet on 25 April to review at least one cell line, derived with private funds by Australian researchers Martin Pera and Alan Trounson and their colleagues. However, NIH said last week that the meeting had been cancelled. “The [HHS] department told us inasmuch as they're conducting a review, it was premature for the review group to meet to assess compliance” with the guidelines, said NIH spokesperson Anne Thomas.

    That worries stem cell advocates. “I'm traditionally an optimist, but I don't take this as a very good sign,” says Tim Leshan of the American Society for Cell Biology, which has been lobbying in favor of the research.

    Meanwhile, Senators Arlen Specter (R-PA) and Tom Harkin (D-IA) introduced a bill on 5 April that would authorize NIH to fund derivation of and research on human ES cells. Two antiabortion senators are co-sponsors, Senator Strom Thurmond (R-SC) and Senator Gordon Smith (R-OR).

  7. JAPAN

    Women Academics Propose Steps to Equity

    1. Dennis Normile

    TOKYO—The campaign has begun. On 30 March, 35 Japanese women scientists met here to draw up a list of obstacles they face in obtaining grants and plot a lobbying effort to create a better working environment. But initial reaction suggests that some of those barriers—while they pale in comparison to more serious forms of discrimination—are rooted in the country's culture or its economic woes.

    “Women scientists [in Japan] face a mountain of troubles,” says Mariko Kato, an astrophysicist at Keio University's Hiyoshi campus in Yokohama and one of the conference organizers. “We have to start with those problems that have easily identifiable solutions.”

    Under fire.

    The government's Kenji Sakuma, right, discusses gender issues with faculty members (from left) Hiroko Hara, Michiyo Nakane, and Mariko Kato.

    CREDIT: D. NORMILE

    As is true elsewhere, women hold a disproportionately small share of senior faculty positions in Japan's universities (Science, 2 February, p. 817). Although participants suspect that discrimination and harassment play a major role in keeping them from achieving equity, they also point to a slew of seemingly innocuous policies that, in practice, put them at a disadvantage in competing for grants.

    One such policy is the automatic termination of grant funding if the recipient goes on leave for more than 6 months. It clashes with the rule allowing women at national universities, and some private universities, a full year of leave after childbirth. The policy forces women returning from maternity leave to reassemble their labs and restart their research careers, say symposium participants, who also complained about a rule that restricts most grants for new investigators to those age 37 or younger. With more women wanting to resume their research careers after starting a family, they say, a ceiling based on years in the field rather than age would be more equitable.

    An even bigger problem may be a rise in the number of part-time and nonpermanent university faculty and staff positions at private nonprofit institutes, a trend fueled by the sagging economy. “No one ever expected that so many researchers would be stuck in temporary positions,” said Michiyo Nakane, a science historian now working as a part-time lecturer at Rikkyo University in Tokyo. Although the squeeze on tenured positions applies to both men and women, men are more likely to be appointed to permanent posts when they are offered.

    Another source of irritation for women and confusion for reviewers is a rule requiring grant applicants to use the name entered in Japan's family registry. By law, married couples must register under one name, and most choose the husband's name. Although many women still use their family name on the job, some faculty members have been pressured by their superiors to use their registered name.

    Gamely defending the government's current policies was Kenji Sakuma, director of planning in the Scientific Research Aid Division of the Ministry of Education, Science, Technology, Sports, and Culture (Monbukagakusho), which is the primary source of grants for researchers. Sakuma brought good news on some issues, including the fact that grant applicants will soon be able to choose which name they prefer to use. He also said that the ministry would like to find a way to make grants compatible with child-care duties. But those rays of light were more than overshadowed by his defense of the status quo on other topics.

    Grants need to be terminated if researchers are on leave for extended periods, he explained. “The intent of research grants is to support world-class, leading-edge research,” said Sakuma, adding that a hot idea can grow cold if put on hold for a year. And extending grants to nonpermanent employees, who are typically on 1-year contracts and often lack laboratory space, “would be very difficult.”

    The symposium participants took heart from what they see as a growing awareness of the issue. Hiroko Hara, a cultural anthropologist at the University of the Air in Chiba, noted that the Association of National Universities and the Science Council of Japan, the country's largest grouping of researchers, have recently issued statements in support of more women professors and researchers. “There is a lot of power behind these requests,” she said.

    Some noted that the meeting itself was a sign of progress. “A decade ago we were just trying to get women into research. Now we're getting to the point of addressing specific problems [that hold women back],” said Mitsuko Asakura, a professor of labor law at Tokyo Metropolitan University. Participants hope that, over time, such incremental changes in the grants process may ultimately achieve their goal of parity.

  8. WORKFORCE DIVERSITY

    NSF Makes the BEST of a Good Idea

    1. Jeffrey Mervis

    Every PI should have it so easy. On 8 January, John Yochelson submitted a proposal to the National Science Foundation (NSF) to create a $10 million, industry-led organization to promote diversity in the U.S. scientific workforce. Barely 6 weeks later, Yochelson learned that eight federal agencies had agreed to give him $2.3 million, an award that was officially announced earlier this month at the national innovation summit of the Council on Competitiveness, a Washington, D.C.-based nonprofit. Its speedy success is testament to two government officials who decided not to let yet another federal report on the problem gather dust.

    Yochelson heads the council, which will serve as midwife for a new entity called Building Engineering and Scientific Talent. BEST hopes to become a national clearinghouse on diversity in science and engineering, studying what works and publicizing its findings. The council has also pledged to raise an additional $7 million or more from corporations and foundations to get BEST off the ground.

    The council's proposal dovetailed with a recommendation of the Commission on the Advancement of Women and Minorities in Science, Engineering, and Technology, known informally as the Morella Commission after Representative Constance Morella (R-MD), its chief legislative sponsor. Last July, the commission recommended that an ongoing public-private body be established to help clear away barriers to underrepresented groups in science and engineering (www.nsf.gov/od/cawmset).

    Although the Morella panel made recommendations similar to those in a 1989 report by another congressionally mandated panel, this time there will be a visible follow-up. NSF director Rita Colwell, whose agency staffed both panels, spent the next few months cajoling the other federal agencies that had worked with the commission to chip in money for the proposed organization—an entity that didn't exist, not even on paper. And Morella urged her on. “It is extremely important,” Morella wrote in a 30 November 2000 letter to Colwell, “that each agency steps forward and provides contributions to seed this collaborative entity.”

    BEST man.

    John Yochelson's Council on Competitiveness has a new grant to boost the number of women and minority scientists.

    CREDIT: KAREN MCCOMB

    In the end, eight of the nine agencies agreed. “NSF was pushing us hard,” recalls Jane Coulter, deputy administrator for the Cooperative State Research, Education, and Extension Service within the Agriculture Department, one of two agencies to scrape together $50,000. NSF and five others each put up $367,000. The only agency to opt out was the Department of Education.

    With the groundwork laid, the council jumped at a suggestion by NSF officials to submit a proposal. “We've been doing benchmarking for quite some time, especially in terms of regional development,” says Yochelson about an organization formed in 1986 to combat the perception of Japanese technological dominance. “And the idea of looking at what works, and how communities have put together partnerships to increase diversity, seemed to resonate well with everybody we talked to.”

    There was no formal competition, and no other proposals were submitted. Representatives from the sponsoring agencies were asked to review the proposal, and NSF made the award official on 21 February.

    A senior NSF official, Wanda Ward, will work with the council to help put BEST together. The council has already lined up a $1 million corporate donation, and it hopes to have a small staff assembled by summer. BEST will also draw advice from a public-private National Leadership Council, co-chaired by Morella and Representative Eddie Bernice Johnson (R-TX).

  9. BEHAVIORAL ECOLOGY

    Elephant Matriarchs Tell Friend From Foe

    1. Elizabeth Pennisi

    Elephants have good reason to love their mothers. New research reported on page 491 shows that the lifetime experience of a matriarch helps her group discriminate friend from foe and contributes in many other important ways to the well-being of her companions.

    Not only is the work “a neat demonstration,” but “it probably applies to a wide range of animals,” says Timothy Clutton-Brock, a behavioral ecologist at Cambridge University in the United Kingdom. Furthermore, according to animal behaviorist Richard Connor of the University of Massachusetts, Dartmouth, “the conservation implications are really profound: If that older individual is killed, it could have a very negative impact on the group.”

    For this work, Karen McComb of the University of Sussex in Brighton, U.K., and Sarah Durant of the Institute of Zoology in London teamed up with Cynthia Moss and her colleagues, who have tracked some 1700 elephants for the past 28 years as part of the Amboseli Elephant Research Project in Kenya. The elephants McComb studied live in about 20 small family groups, typically containing several females and their calves. Each group moves independently, sometimes encountering other groups or individuals as it forages for food.

    McComb and her colleagues played back recordings of elephant calls and watched the elephants' responses. Calls from complete strangers prompted the mothers to cluster around their young, whereas familiar calls were ignored. But the groups “differed in how good they were” at discriminating friend from foe, says McComb: Some groups bunched up even at the sound of familiar calls, while others were better at picking out the strangers.

    Grandma knows best.

    By having a keen nose for strangers, the matriarchs in elephant clans help their families prosper.

    CREDIT: COUNCIL ON COMPETITIVENESS

    A group's ability to tell acquaintances from strangers correlated strongly with the age of the oldest female. Other factors, such as the number of calves, number of females, or even the mean age of the females, were not important. “You have this older individual who has this great storehouse of knowledge,” Connor notes.

    That storehouse of knowledge also contributes to the group's reproductive success. When McComb combined her 7 years of audio playback data with Moss's 3 decades of observations, she found that groups with older matriarchs at the helm produced more young per female once factors such as age were taken into account. “In evolutionary terms, you can see why intelligence was selected for,” McComb notes. The matriarch's ability to spot the riskiest encounters makes life easier for her companions.

    “People who've studied elephants for a long time have always felt there are strong cultural attachments [within groups], but they're really hard to quantify,” notes Andrew Dobson, an ecologist at Princeton University. McComb's approach provides “a way of actually showing how behavior and experience accrued over a long lifetime translates into benefits for the whole group,” he says.

    For that reason, the work sends a strong message to conservationists. “When you poach an animal, you are not just taking one life away; you're taking away the influence of that animal on other animals,” says Hal Whitehead, a marine biologist at Dalhousie University in Halifax, Canada. That loss could be particularly great if the individual is an elder statesman of the group.

    Sperm whales could be a case in point, notes Whitehead. They have a social structure similar to that of elephants, with small groups of females that communally look after and defend their young, wander many kilometers in search of food, and have chance encounters with other sperm whales. Given McComb's new data, Whitehead wonders whether the low birthrates recorded in sperm whales off the coasts of Peru, Chile, Japan, and even northwestern Europe—compared to whales in the Caribbean—are a vestige of whaling practiced until some 18 years ago. If whalers consistently took the larger, older individuals, he suggests, the groups may have “lost their social knowledge and may be less successful.”

  10. QUANTUM COMPUTING

    Souped-Up Software Gets a Virtual Test

    1. Mark K. Anderson*
    1. Mark K. Anderson is a writer in Northampton, Massachusetts.

    Amazing things, quantum computers. On paper, they can outpace conventional computers a billionfold, bringing new worlds of computation within human reach. The only hitch is that no one has built one that does that yet. That raises a practical problem for designers of quantum software: How do you test a potential “killer app” for a machine that doesn't exist?

    If you have time, you can run it on machines that do exist. That's how researchers led by Edward Farhi and Jeffrey Goldstone of the Massachusetts Institute of Technology in Cambridge and Sam Gutmann of Northeastern University in Boston pitted a quantum algorithm against one of the toughest problems in computer science. In preliminary tests, described on page 472 of this issue, the algorithm racked up an encouraging virtual track record that left some scientists hankering for more.

    “If it is truly powerful, then it is very broadly applicable,” says John Preskill, a theorist at the California Institute of Technology in Pasadena. Although the algorithm's prospects remain “highly speculative,” Preskill says, “the incentive to press forward with the daunting task of building large-scale quantum computers will be greatly strengthened if quantum computers are really as powerful as the work of Farhi et al. suggests.”

    The dream machines get their potential power from storing information in objects that obey quantum laws, such as electrons, atomic nuclei, or molecules. Whereas each bit stored in a classical computer can take on only one of two values—0 or 1—the “qubits” in a quantum computer can also exist in a strange state called superposition, in which, in a sense, they possess every possible value at once. That gives quantum computers an amazing knack for parallel processing, raising hopes that they might conquer problems that ordinary classical computers can't handle.

    The Mount Everest of computer science is a class of problems known as NP-complete. Algorithms designed to solve NP-complete problems mushroom exponentially into impossibly long calculations as the size of the input increases. One famous example is to find the most efficient route for a traveling salesman who must visit every city on his map once and only once. As the number of cities increases, the problem quickly becomes so complex that, in general, conventional computer algorithms can't solve it for more than a few thousand cities. (The current world record is 3038.)

    Where next?

    Problems such as finding the best route through many cities can stump ordinary computers but may yield to quantum ones.

    SOURCES: (TOP TO BOTTOM) APPLEGATE, BIXBY, CHVATAL, AND COOK (1998); GEORGE DANTZIG, RAY FULKERSON, AND SELMER JOHNSON (1954)

    To tame that exponential monster, computer scientists are hunting for a problem-solving algorithm whose run-time grows more slowly, with some power of the size of the input. One such “polynomial time” algorithm is all they need, because mathematicians have proved that any algorithm that solves one NP-complete problem in polynomial time will crack every other NP-complete problem, too. Last year the Clay Mathematics Institute in Cambridge, Massachusetts, offered a $1 million bounty to anyone who either writes such an algorithm or proves that it can't be done (Science, 26 May 2000, p. 1328).

    An NP-complete problem, Farhi and his colleagues decided, was just the thing for road-testing a virtual quantum computer. A year earlier, they had devised a way to program a quantum computer to solve an NP-complete problem called Exact Cover. Exact Cover is like Twenty Questions played with bits: Given a series of rules describing a string of ones and zeroes, the player must decide whether the string exists. The quantum algorithm “isn't clever,” Farhi says, but it always gets a solution sooner or later. “The question is how long is long enough.”

    To find out, the scientists programmed a cluster of workstations to simulate a quantum computer running the algorithm, by running in sequence the operations that a quantum machine would perform simultaneously. Then they fed it various combinations of rules and waited for it to crank out the answers. Although the problems weren't difficult (a nonquantum desktop PC could have solved each one in a fraction of a second, Farhi says), the simulation took days to find each solution. The quantum run-time, it turned out, grew in proportion to the length of the bit string, squared. That put the algorithm solidly within polynomial time—the realm of practical solvability.

    Time to alert the Clay Institute? Unfortunately not, Farhi says. Even if quantum algorithms qualify for the prize, a few promising results are a far cry from a mathematical proof, he points out. Besides, the simple problems in the simulation represented only a small patch of Exact Cover's infinite terrain. Harder ones might have made the algorithm stumble.

    Some computer scientists think that's exactly what is in the cards. “I don't expect any quantum approach to give a speedup of NP-complete problems in polynomial time,” says Charles Bennett, a quantum-computing researcher at IBM's Thomas J. Watson Research Center in Yorktown Heights, New York. To do that, he thinks, an algorithm would have to target some still-unknown Achilles' heel in the problems themselves—a feat he considers unlikely.

    Preskill, however, is guardedly optimistic about the algorithm. Although the evidence is still “far from conclusive,” he says, “I think it is a promising idea that ought to be pursued aggressively.” Farhi says that's just what he has in mind.

  11. NUCLEAR RADIATION

    Living in the Shadow of Chornobyl

    1. Richard Stone

    Fifteen years after the world's worst nuclear accident, the entire population of Belarus is involuntarily taking part in a decades-long experiment on how radiation affects human health

    MINSK, BELARUS, AND KYIV, UKRAINE—Early on a warm, sunny morning on 26 April 1986, Valeriy and Natasha Glygalo went to buy groceries at the open-air market of Pripyat, a Ukrainian town near the Belarusan border. Despite the splendid weather, Natasha began to feel strange: She had an odd, bitter taste in her mouth. Valeriy, a nuclear physicist and safety officer at the Chornobyl Nuclear Power Plant, missed that early clue to the unfolding disaster. “I was smoking and didn't taste anything,” he says. Moments later, however, a babushka told them that an explosion had rocked the power station just a few kilometers south of Pripyat. With mounting dread, Valeriy rushed to the edge of town, where from the top of a bridge he could see clearly the gigantic duplex housing the plant's third and fourth reactors. Unit four lay in ruins, as if it had been bombed. Glygalo remembers staring numbly as flames, fed by the graphite rods that had moderated the fission reaction in the uranium fuel assembly, licked above the ruins and smoke poured into the sky. “We never conceived of something like this happening,” he says. The fumes swept toward Pripyat and its 50,000 residents, who were inhaling the invisible radioactive particles that coated the town.

    The world's worst nuclear accident had begun at 1:23 that morning, when Chornobyl's unit four exploded and sent a plume of radioactive particles 2 kilometers into the air. As the cloud raced northwest, it rained radioactive particles on a swath across Belarus, Poland, the Baltic nations, and into Scandinavia. Over the next 10 days, the reactor pit belched a staggering 100 million to 200 million curies of fission products, about 100 times the amount of radiation released by the atomic bombs dropped on Hiroshima and Nagasaki. Much of it settled on northern Ukraine, southern Belarus, and Russia's Bryansk region, defiling millions of hectares of land. The Chornobyl catastrophe, as it's called in Russian, triggered political unrest in Belarus and Ukraine and halted nuclear power projects, sparking an energy crisis that may well have applied the coup de grâce to a dying Soviet Union.

    Chornobyl took a substantial human toll as well. Two plant personnel were killed instantly by the blast, while 28 firefighters and plant workers died horribly days later from radiation poisoning. In Belarus, more than 700 children under the age of 14 have been treated for thyroid cancer—a disease that occurs spontaneously in only one in a million children. “These are incredible numbers,” says Japanese thyroid disease specialist Akira Sugenoya, whose 5-year stint working in Belarus has helped convince Western experts that the numbers are real and attributable to a massive exposure to radioactive iodine (see p. 425). Although the disease has one of the highest cure rates of any cancer, four Belarusan children are known to have died after their tumors spread to other organs. What's more, thyroid cancer cases among adolescents in Belarus are still on the rise.

    Radioactive fallout.

    Deposition of cesium-137 in Belarus (above) and around the Chornobyl power plant. (Activity levels as of May 1986; Cs137 has a half-life of 30 years.

    CREDITS: MODIFIED FROM EC/IGCE, ROSHYDROMET (RUSSIA)/MINCHERNOBYL (UKRAINE)/BELHYDROMET (BELARUS),1998)

    Fifteen years after the Chornobyl explosion, some scientists fear that the worst is yet to come. Compared to the general population, rates of some noncancer diseases— endocrine disorders and stroke, for instance—appear to be rising disproportionately among the roughly 600,000 “liquidators” who cleaned up the heaviest contamination in the plant's vicinity and entombed unit four's lethal remnants in a concrete sarcophagus. Whether people living in the shadow of Chornobyl remain at risk for health problems is a subject now under intense scrutiny. And at Chornobyl's epicenter, an international effort is about to embark on an unprecedented engineering project that aims to prevent further release of radionuclides from the sarcophagus (see p. 422).

    Chornobyl still haunts the people of Belarus and Ukraine. “The psychological effects are devastating,” says physicist Mikhail Malko of the Institute of Physical and Chemical Radiation Problems in Minsk. “Many women feel they will give birth to unhealthy babies or babies with no future. Many people feel they will die from Chornobyl.”

    Putting a lid on it

    On a warm, cloudless day earlier this month, a German shepherd basks in the sun near the bridge leading from Pripyat to the Chornobyl Nuclear Power Plant. Other than the two Ukrainian soldiers guarding a post next to a red-and-white-striped gate that blocks unauthorized access to the town, the lazy dog is the only sign of life in this urban wasteland. The people are gone.

    Within hours after Natasha Glygalo got a mouthful of bitter air 15 years ago, she, her son Roman, and nearly all other residents of Pripyat were whisked away by train to nearby Chernihiv or bused to other cities across Ukraine where they had relatives. Some 800 Chornobyl personnel, including Valeriy Glygalo, stayed behind to take stock and deal with the accident. Glygalo was not the only scientist who struggled to come to grips with the enormity of what had occurred. “It was impossible to imagine that a reactor simply couldn't exist,” says nuclear physicist Konstyantyn Rudya, who was working in Chornobyl's unit two reactor building at the time of the blast.

    Although radiation monitors in Finland and Sweden had alerted the world to the explosion, Soviet authorities cast a shroud of secrecy over the cleanup and the subsequent studies carried out inside the evacuated “exclusion zone,” roughly 30 kilometers in radius, around the power station. Running the show was the Soviet military and the country's premier nuclear research laboratory, the Kurchatov Institute in Moscow. Helicopters dumped sand and boron on the seething remnants of the reactor core to quench the fire—a strategy that backfired, because it raised the temperature so high that the nuclear fuel melted and released even more radionuclides into the environment. Thousands of soldiers dispatched to the zone performed tasks ranging from the mundane—bulldozing more than 1 million cubic meters of contaminated topsoil for disposal as nuclear waste—to the surreally brave: timed dashes onto the roof of the unit three building to shovel chunks of unit four's core into the maw of the destroyed reactor.

    Abandoned.

    “No entry” sign near Gomel (above); Bartolomeevka's lonely cemetery, former supermarket, and World War II statue (bottom photos).

    CREDITS: R. STONE

    Besides putting a lid on reactor four, Communist Party officials studiously maintained a news blackout. But from the start, odd occurrences began to tip people off to what had happened. For example, researchers at the Institute of Genetics and Cytology (IGC) in Minsk had left some unexposed film on a lab bench the night before the accident. The next day, they found their film spotted. “We couldn't understand what happened until we found out about the accident a few days later,” when researchers began to whisper about a nuclear explosion, says IGC director Nikolai Kartel. “For a long time we just heard rumors.”

    A few days after muted celebrations to mark 1 May, recalls IGC geneticist Rose Goncharova, the institute's former director Lubov Khotylyova gathered her senior scientists and explained that the accident had been much worse than the government was letting on. While several institutes started investigating the harm inflicted on the Belarusan population, Khotylyova asked her staff to prepare a major research program on Chornobyl's effect on wildlife. By August, Goncharova and her colleagues were out collecting bank voles and other animals in central and southern Belarus (see p. 421).

    Some institutes closer to the blast found themselves thrust into a scary new role. Located only 30 kilometers north of the exclusion zone, “our institute had a very bad fate,” says Vladimir Baginsky, director of the Institute of Forestry in Gomel. A few days after the accident, a five-person team led by Ivan Bulavik hurriedly set up experimental plots near the zone and took plant and soil samples. The land was already becoming contaminated, but they would have something resembling baseline data when more fallout rained down in subsequent days. They risked their lives, says Baginsky: “Graphite was falling on them,” he says, “but Bulavik would be too modest to admit this.”

    That May, Bulavik met with his Ukrainian and Russian counterparts to sketch out a research program on how the forests were affected by the huge doses of radioactivity. In the coming months, they discovered that the forests had concentrated far more radionuclides than had the surrounding farmlands, which were more readily cleansed by rain. “The forest played the role of a vacuum cleaner,” Baginsky says. And contradicting models based on nuclear accidents in the Ural Mountains, the Gomel modelers predicted that radionuclide accumulation in the forests would worsen over time. By the mid-1990s, “we observed that the forest began to be contaminated more and more,” as trees continued to soak up more radionuclides from the soil, says Victor Ipatyev, the former director of the forestry institute who 2 months ago was appointed president of the National Academy of Sciences of Belarus. He estimates that nearly 2 million hectares of forest are contaminated. Depending on prevailing winds, forest fires could spread the radionuclides far from contaminated areas.

    Rehabilitating the forests seemed out of the question until a few years ago, when institute researchers found that certain forest undergrowth plants—such as raspberry and hazel—preferentially remove radionuclides from the soil, which in turn reduces contamination in the trees. These preliminary findings have not been put into practice yet.

    Early on, such studies were kept under tight wraps by Soviet officials, who hammered home the message that only a few villages in northern Ukraine had been affected by the accident. Indeed, for nearly 3 years, it was forbidden in Belarus to even speak publicly about Chornobyl. The situation dramatically changed on 20 March 1989, when all the republic's newspapers simultaneously published maps depicting cesium contamination in Belarus, setting off a firestorm of anger and demonstrations against the party.

    Unforeseen consequences

    In a pine grove near the village of Bartolomeevka lies a peaceful cemetery, each gravesite surrounded by meter-high wrought-iron fences. No new graves will be dug here for some time, because all the residents of this tiny village 50 kilometers northeast of Gomel—like those of 400 other villages in Belarus—were resettled in less contaminated areas around 1990. But for the former residents of Bartolomeevka and other villages and towns downwind from Chornobyl, help came too late: They received heavy doses of radiation before they were moved out.

    Perhaps the biggest surprise in the first few years after the explosion was that a spate of leukemia cases, predicted from Japanese atom bomb survivor studies, never materialized. “This was completely different from our expectations,” says Vladimir Ostapenko, director of the Research and Clinical Institute of Radiation Medicine and Endocrinology in Minsk. “We were preparing not only scientifically but medically for leukemia.” Most scientists now believe that the amount of cesium-137 absorbed by the general population was not high enough to trigger leukemia, says endocrinologist Shunichi Yamashita of the University of Nagasaki in Japan, an expert with the Chornobyl Sasakawa Project. And although Russian scientists have found a higher risk for leukemia among the liquidators, some of whom received cumulative doses of up to 5 sieverts—10 times the radiation dose needed to suppress the immune system and blood cell production—many researchers say that better screening could account for these elevated numbers. “It occurred to us that judging what would happen based on pre-Chornobyl experiences was useless,” Ostapenko says.

    But there were unhappier surprises revealed by robust medical record keeping. Before the Chornobyl explosion, of the 15 former Soviet republics only one had a population registry of birth defects: Belarus. Since 1979, Gennady Lazjuk's Institute for Hereditary Diseases in Minsk has run the registry and thus had a good baseline for drawing comparisons between lightly contaminated regions such as Minsk (less than 1 curie per square kilometer), moderately contaminated regions (1 to 15 curies per km2), and heavily contaminated regions (more than 15 curies per km2). In all three areas, birth defects skyrocketed after Chornobyl: about a 50% increase in both the lightly and moderately contaminated regions, and 83% in the heavily contaminated regions. These birth defects include polydactyly—extra fingers or toes—and shortened limbs.

    Western critics have pointed out that much of this rise in birth defects could be due to more assiduous screening after the accident, or from exposures to chemical pollutants. Lazjuk, along with collaborators in Japan and Europe, acknowledges that better screening undoubtedly pumped up the figures, and he doubts that any increases in birth defects seen in lightly and moderately contaminated regions were due to Chornobyl. But with Soviet industrial output falling off after the breakup of the Union in 1991, he dismisses the notion that chemical exposures played a role in the sharper rise in the most contaminated areas, which persisted until 1995. After eliminating confounding factors, Lazjuk's group concluded that radiation exposure accounted for a 12% increase in birth defects in the heavily contaminated areas. Western scientists had predicted rises of anywhere from 1.5% to 7%.

    “Lazjuk's data are beautiful,” says Goncharova, who notes that a major shortcoming is the dearth of data on how much radiation the parents absorbed. That makes it impossible to say with certainty that radiation was responsible. Nor is the picture likely to get any clearer: This year, the Belarus government did not come up with funds to support birth defects surveillance and research.

    The thyroid mystery

    The government waited more than a week to hand out iodine pills to people in the affected regions in an attempt to saturate the thyroid and prevent it from taking up radioactive iodine. By then, it was too late. Even so, “we didn't expect much of an increase in thyroid cancer,” says Sir Dillwyn Williams, a thyroid cancer expert at the University of Cambridge in the United Kingdom. Radioactive iodine had been used extensively to treat Graves' disease, and studies showed no increased risk of thyroid cancer. And studies of Japanese atom bomb survivors and Marshall Islanders exposed to fallout from an atom bomb test suggested that a few additional cases of thyroid cancer might be seen about 10 years after the accident, which would fall off within a few years. Instead, the number of childhood thyroid cancer cases began rising within a year after the accident.

    Puzzling numbers.

    Unexpected rise in childhood thyroid cancer is now showing up in adolescents, as exposed children turn 15.

    SOURCE: THYROID CANCER CENTRE, RESEARCH AND CLINICAL INSTITUTE OF RADIATION MEDICINE AND ENDOCRINOLOGY, INSTITUTE OF PHYSIOLOGY, MINSK

    This was so surprising, says Williams, that “there was a general reluctance in the West to believe the data.” Some scientists attributed the rise to better screening, others to the misdiagnosis of benign nodules. Many Belarusan scientists are still unhappy with how the West viewed their data in those days. “People who thought that the increase in thyroid cancer was due to better screening were crazy,” says Malko.

    Few now doubt the trends. “We learned a lesson,” says one Western expert. Although childhood thyroid cancer cases peaked in 1995, the incidence among adolescents has more than doubled since 1996. Because children are classified as adolescents when they turn 15, this group now includes all the children exposed to the radioactive iodine. There's fresh hope that the childhood and adolescent thyroid cancer wave is cresting. Yamashita and his colleagues studied 20,000 Belarusan children who were born in the 3 years before the explosion, were in the womb during the explosion, or were born 3 years afterward. Their findings, which will be presented at a Chornobyl anniversary conference in Moscow next month, show that thyroid cancer appears only in those born before the explosion.

    The unusual dynamics of the thyroid cancer incidence are prompting a flurry of research. “The mechanism of this cancer has not been unveiled yet,” Sugenoya says. To speed studies, Williams and Cambridge colleague Gerry Thomas, in collaboration with the governments of Belarus, Russia, and Ukraine, have set up a thyroid tumor tissue bank in each of the three countries. The tissue bank—sponsored by several heavyweights including the U.S. National Cancer Institute (NCI), the European Commission, the World Health Organization, and the Sasakawa Memorial Health Foundation—now holds DNA and RNA from more than 280 thyroid tumors from patients younger than 19 at the time of the explosion. “This will allow us to look for a specific signature of radiation-induced cancer,” says Yamashita.

    “All of our projects are addressing this mystery,” says Ostapenko, whose institute is collaborating with NCI and various European centers to study thyroid cancer. “We have a sad joke,” he says. “Why should people look for test animals for radiation research when there is a natural laboratory here·” Indeed, he and others are bracing for a Chornobyl-driven rise in breast and prostate cancer down the road.

    In Belarus, this natural experiment is becoming harder to sustain, scientists say. Government funding for Chornobyl research is drying up, and earlier this month, as Belarus and Russia celebrated their 5-year anniversary as a union, researchers with the National Academy of Sciences learned that they would be receiving a 20% pay cut, to about $60 per month—endangering their ability to stay in science at all. They are reluctant to air their concerns publicly, fearing reprisals from the government of President Alyaksandr Lukashenka—so loathed by many researchers that rather than utter his name, they refer to him as “the top person in our government.”

    Researchers in Ukraine, meanwhile, have been more fortunate. With the country's economy booming, their salaries were doubled this year to $120 per month. And their government has aggressively courted Western support for Chornobyl research. In 1998, these efforts paid off with the creation of a radioecology laboratory in the exclusion zone and surrounding territories. Now Ukraine's Cabinet of Ministers is negotiating with China and Japan to launch a research center to study the population of Slavutych, a town built after the Chornobyl accident to accommodate the power plant's workers.

    The center will probe the long-term health of residents, many of whom lived in Pripyat until the accident and received high radiation doses immediately after the explosion. Of particular interest to scientists are the 7000 or so Chornobyl engineers and scientists who work in and around the sarcophagus each day, and the 6000 to 7000 liquidators now living in Slavutych. “My dream is to have a research agreement ready by the end of this year,” says Valeriy Glygalo, the one-time liquidator who is now director of the Cabinet of Ministers' International Chornobyl Center for Nuclear Safety, Radioactive Waste, and Radioecology in Kyiv. The residents of Pripyat are gone, but they are clearly not forgotten.

  12. NUCLEAR RADIATION

    Genetic Studies of Wildlife in the Hot Zone Reach Different Conclusions

    1. Richard Stone

    SLAVUTYCH, UKRAINE—For several months in 1986, Sergei Gashchak was a “liquidator,” participating in the hellish work of decontaminating helicopters and trucks used to put out the burning Chornobyl reactor and clean up the aftermath. Since then, he says, “many people who worked with me in the zone [have become] sick.” Yet 4 years after the accident, Gashchak, trained as a biologist, returned to the hot zone to study how to reduce exposures of livestock to radioactivity.

    Now he's part of a new U.S.-Ukraine laboratory studying wild animals in the exclusion zone. In the 15 years since most people were evacuated from the zone, it has become a refuge for wildlife: Moose, wild boars, endangered black storks, and other species less abundant in other parts of Ukraine are thriving here. “The zone is an excellent place for conservation,” Gashchak says. “In the future we may even be able to create an area for wildlife sightseeing.” According to radioecologist Ron Chesser of Texas Tech University in Lubbock, “Only the clicks and whistles of our electronic equipment indicate that the habitat is contaminated with radioactivity.”

    But the zone's vibrant wildlife masks a debate over the genetic health of animals exposed to lingering contamination from Chornobyl. In the early 1990s, a team led by Rose Goncharova and Nadezhda Ryabokon of the Institute of Genetics and Cytology in Minsk found that the chromosomes of bank voles living in contaminated areas were riddled with breaks and rearrangements; the amount of damage roughly correlated with the measured absorbed dose. Even bank voles in control regions near Minsk had DNA damage, although on a lesser scale. “When we began to find an increased level of mutations in control regions, we were shocked,” says Ryabokon. Further studies revealed that maps of cesium contamination in Belarus published at the time were flawed: The so-called clean regions, the researchers found, were contaminated, too. Although many scientists believe that low-level exposures are not harmful, the DNA damage, Ryabokon says, suggests that “we have real evidence of biological effects of very low doses of chronic exposure.”

    Early studies by a team led by Chesser and Texas Tech colleague Robert Baker also indicated genetic damage in animals exposed to high levels of radioactivity. In a 1996 Nature paper, they reported mutations in the cytochrome b gene among bank voles in the exclusion zone. However, the team—which is supported by the U.S. Department of Energy—retracted the paper when it was unable to substantiate any increased mutation rate among animals in the zone using improved techniques. Chesser is dubious of the Belarusan team's findings. “If the dose rates near Minsk created chromosome damage to the extent they reported, then the risks due to radiation should be enormous,” he says.

    Goncharova and Ryabokon suggest that voles in the zone, exposed to intense radiation over 30 generations since the accident, have become “radioresistant”: a genetic selection for mechanisms that not only enable individuals to survive in the hot zone but to suffer minimal chromosomal damage. But Chesser and his colleagues tested that theory by bringing in unexposed animals from clean parts of Ukraine and keeping them in cages in the exclusion zone for 30 days. They found no evidence of chromosomal damage or genetic mutations in the imported animals, indicating that they are no more susceptible to radiation than the local animals.

    Damage assessment.

    Ron Chesser in the exclusion zone, roughly a 30-km radius around the plant.

    CREDIT: ROBERT BAKER

    Some high-tech gadgetry is now being brought to bear on the study of wildlife in the zone. In July 1998, the Ukrainian and U.S. governments unveiled an International Radioecology Laboratory in Slavutych. In subsequent months they outfitted it with millions of dollars' worth of brand-new instruments: everything from drying ovens and liquid nitrogen sample containers to a liquid scintillation analyzer for measuring radioactive strontium. But the United States did not kick in operating money for the lab, so for now it's underutilized: The only team that can pay its own way to come to the lab this summer is the Texas Tech group. Goncharova and Ryabokon, meanwhile, don't even have enough funding to continue their experiments, let alone upgrade their only pieces of equipment: two microscopes made in the 1960s in the German Democratic Republic.

  13. NUCLEAR RADIATION

    Dealing With a Slumbering Hulk

    1. Richard Stone

    CHORNOBYL—The black concrete sarcophagus that covers the wreckage of Chornobyl's unit four reactor looks like a fitting mausoleum for the estimated 190 tons of nuclear fuel still in its bowels. But it was never meant to be an eternal resting place. Although designed to last a century, the structure, thrown up in 6 months after the April 1986 explosion, is eroding faster than expected. “The sarcophagus is unstable,” says Viktor Baryakhtar, director of the Institute of Magnetism in Kyiv. Even if the sarcophagus does not collapse under its own weight, scientists envision dozens of freak scenarios—ranging from monster snowfalls to earthquakes—that could bring the structure tumbling down. Such a disaster would spread clouds of radioactive dust into the environment and spark an international outcry. “The public response could be even bigger than the response was to the explosion,” says Baryakhtar.

    Now, after years of false starts and political and scientific wrangling, the Ukrainian government has settled on a permanent solution. A commission headed by Ukrainian Prime Minister Viktor Yuschenko decided earlier this month to erect an arched structure, as big as a baseball stadium, to cover the sarcophagus. “Nothing like this has ever been done before,” says Baryakhtar. Indeed, “building it will be a formidable challenge,” says Mike Durst, a nuclear engineer with the Pacific Northwest National Laboratory in Richland, Washington. But some Ukrainian experts are unhappy with the decision, arguing that it does not address their government's long-term goal of removing the fuel from inside the belly of the beast and storing it in sealed containers.

    The sarcophagus, and the estimated 20 million curies of radioactivity it harbors, is a bizarre physics laboratory that has provided disturbing insights into the behavior of molten uranium fuel. “We have all the elements from the periodic table inside the shelter,” says Myroslav Holovko of the Institute for Condensed Matter Physics in Lviv, Ukraine. Working over the past decade out of a former kindergarten in Chornobyl, more than 100 scientists with the Interdisciplinary Scientific and Technical Center (ISTC) “Shelter” have risked their lives to probe the warren of rooms beneath the reactor, tracing where the molten uranium fuel flowed after the reactor exploded. At first they believed that up to 50 tons of fuel had gone missing, perhaps dispersed in the environment. But recent studies have reduced that uncertainty to a few tons.

    Crumbling sarcophagus.

    Engineers plan to replace the concrete shell because of concerns about its stability.

    CREDITS: R. STONE

    One of the team's more urgent tasks has been to assess the risk that the fuel-containing masses (FCMs)—formed when the lavalike fuel mixed with concrete and other building materials before solidifying—might achieve criticality and explode. This risk increases when water, which speeds up fission reactions, seeps into the sarcophagus. Indeed, following heavy spring rains, detectors in the sarcophagus often register sharp increases in neutron flux. “We observe this phenomenon every year,” says ISTC Shelter's Viktor Krasnov. “But these are deeply subcritical reactions,” he adds. Nevertheless, Shelter scientists take no chances: They have set up pumps that spray a neutron-quenching solution of gadolinium nitrate at the neutron sources. So far at least, that has quelled the reactions.

    Over the past few years, studies of the FCMs have suggested that fears of a full-blown explosion are overblown. “It's possible, in principle, to achieve criticality,” although the odds are vanishingly low, says Alexander Zhidkov, director of the materials science division at ISTC Shelter. Such a chain reaction would threaten only personnel inside the sarcophagus, he adds. Concern has instead shifted to the dust in the sarcophagus, which is on the rise. “The destruction of the lava is much faster than we believed 10 years ago,” says Baryakhtar.

    About 95% of the dose to sarcophagus personnel comes from submicrometer-sized FCM particles, which are “almost impossible to filter,” says Zhidkov. He and his colleagues have found that these particles may be escaping into the atmosphere through the 1000 square meters of holes in the sarcophagus. “This is a global problem,” he asserts. “These particles can be disseminated around the world.”

    Hot property.

    Abandoned house in Chornobyl.

    CREDIT: R. STONE

    To deal with this and other threats, the Ukrainian government held a design competition for a second-generation sarcophagus in 1992 but was dissatisfied with the proposals it received. The government then assembled a consortium, dubbed Alliance, to design a structure that would not only isolate the remains of unit four but also allow the sarcophagus to be dismantled and the FCMs to be safely buried. Many Western and Ukrainian experts approved the $2 billion design that Alliance came up with in 1995. However, the project was sidetracked when the European Bank of Reconstruction and Development (EBRD), which was considering Ukrainian demands for hundreds of millions of dollars to close two other Chornobyl reactors still in operation, refused to sink billions more into a new shelter.

    So Ukraine and the EBRD went back to the drawing board, soliciting cheaper designs from several new consortia. When Chornobyl was finally closed a few months ago, the Ukrainian prime minister's commission selected the arch as its favored design. To minimize workers' radiation exposure, the 260-meter-long, 140-meter-tall arch will be built next to the sarcophagus, then slid along rails over the top of it—not an easy task. “Difficult engineering problems must be solved,” says Durst, the project manager for the Chornobyl Shelter Implementation Plan—run by the Battelle Memorial Institute, Bechtel Group Inc., Electricité de France, and the Chornobyl Nuclear Power Plant. EBRD has agreed to pay the estimated $800 million cost of the structure and has begun soliciting bids for a contract to design and build it by 2007.

    But some experts disparage the arch. “It's a Hollywood production by the West to say, ‘We're helping Ukraine,'” charges Kostyantyn Rudya, scientific director of the International Chornobyl Center of the Cabinet of Ministers of Ukraine. “But this is not a final solution. There will be no money left for fuel removal.” Anatoly Nosovsky, director of the Slavutych Laboratory of International Research and Technology, favors scrapping the arch and spending the EBRD money to remove and bury the contents of the sarcophagus. But he doubts that will happen: “The shelter is more a political issue than a scientific one.” That view is echoed by ISTC Shelter director-general Oleksandr Klyutchnykov, who claims that “the main purpose from the West's point of view is to insulate the sarcophagus from the environment and forget about it for the next 200 years.”

    Baryakhtar defends the arch as “the best proposition.” And Durst says that removing the dangerous fuel was never part of the deal, although the arch will permit this to be done in the future. Still, many experts maintain that this crucial step must be carried out sooner rather than later. Says physicist Ihor Yukhnovs'kiy, head of the Ukrainian parliament's science committee: “We have to diffuse this big bomb.”

  14. NUCLEAR RADIATION

    Ordeals of a Dissenter

    1. Richard Stone

    GOMEL, BELARUS—Yuri Bandazhevsky slumps in an armchair in his apartment. He looks haggard, having recently spent half a year in jail awaiting trial. “It is very difficult,” he says. “I have been isolated from people and from work.”

    For several years, Bandazhevsky, a pathologist and the former rector of the Gomel Medical Institute, a research and teaching center, has argued that the cesium-137 accumulating in the Belarus population poses a serious health threat, particularly to children. He claims that he and other researchers at his institute have found evidence that the cesium damages heart muscle and suppresses the immune system. And the threat will persist, he says: With a half-life of 30 years, it will take more than a century for most of the cesium to decay. When his team published its findings in 1995, the former minister of health wrote a laudatory preface to their monograph.

    Prisoner of conscience?

    After Yuri Bandazhevsky challenged government cleanup policy, he was arrested and jailed on bribery charges. He is now on trial.

    CREDIT: R. STONE

    That collegial relationship soon changed. When the government over the next few years failed to take steps to reduce exposure to cesium by decontaminating inhabited areas—an unnecessary step, the government maintained, as Chornobyl experts had rejected the Gomel team's findings—Bandazhevsky began to speak out. In spring 1999, he questioned the Ministry of Health's spending on Chornobyl and argued that more funding should go to Gomel, the most contaminated region. In July 1999 he was arrested, accused of taking bribes from students seeking admission to his institute, imprisoned, and stripped of his post.

    Most Belarusan Chornobyl experts will not comment publicly on Bandazhevsky's case for fear of retribution. However, after a few Western scientists sounded the alarm, Amnesty International designated Bandazhevsky a prisoner of conscience, and the American Association for the Advancement of Science (publisher of Science) last fall issued a human rights alert questioning whether the Belarusan authorities “have any evidence to support [the bribery] charge.”

    Bandazhevsky's trial is now under way, despite a blow to the prosecution last year when a key witness recanted his testimony. If convicted, Bandazhevsky could face 5 to 15 years in prison. Meanwhile, the jury is out on his scientific findings. “If cesium were so potent, I wouldn't be speaking with you now,” insists physicist Mikhail Malko of the Institute of Physical and Chemical Radiation Problems in Minsk. Nonetheless, he says, Bandazhevsky's work merits further scrutiny.

  15. NUCLEAR RADIATION

    Rewards of a Volunteer

    1. Richard Stone

    MOZYR, BELARUS—A dozen sweaty teenagers practice a choreographed folk dance around a painted wooden set depicting an old-fashioned stove, or pechka—the center of any Eastern European village home. They are preparing for an exhibition this summer that will take several members of their 200-person ensemble to Japan, far from this town some 100 kilometers northwest of Chornobyl.

    Akira Sugenoya watches the performance with a big grin. An expert on autoimmune diseases of the thyroid, Sugenoya is helping to organize their trip. Sugenoya first came to Belarus in 1991 and has spent most of the last 5 years here—a record no thyroid expert from outside the former Soviet Union has matched.

    Sugenoya credits a midlife crisis for bringing him to Belarus. In the late 1980s, Sugenoya says he realized that he had spent too much time on research and too little with patients. But he had a good job at the Shinshu University School of Medicine—a job that, in the Japanese psyche, he couldn't just quit.

    Then in 1991 he saw a documentary on Chornobyl; 2 months later he was in Minsk. What he saw there disturbed him. In 20 years in Japan, he had seen five cases of thyroid cancer in children. In Belarus he was confronted with dozens of cases, and the few good doctors in the country “couldn't deal with it,” he says.

    After several trips to Belarus, Sugenoya retired from the university in 1995, guessing that his pension would last 5 years in his temporary home. He set up shop at the Minsk Thyroid Oncology Center before moving to the Gomel State Cancer Center, where he helped train doctors in surgical techniques. He soon developed a reputation throughout the country and last fall became the third foreigner awarded the top medal in Belarus, the Skorina Prize.

    Sugenoya says the Mozyr dance troupe has helped transform his attitude about Chornobyl. Several years ago, before Sugenoya became involved with the ensemble, the troupe was flown to Japan for a charity show. “The attitude was to invite sad, miserable victims of Chornobyl,” Sugenoya says. And Belarus officials exploited this, instructing the ensemble's adult leader to implore the children “to not look so lively so that it would be easier to raise money,” says Sugenoya. But when he met them, he felt the teenagers offered an uplifting message. Intent on nurturing that feeling, his Chernobyl Medical Fund has helped arrange this summer's exhibition in Japan. “He has helped give these children hope for the future,” says Shunichi Yamashita of the University of Nagasaki.

    Man on a mission.

    Akira Sugenoya has spent the past 5 years treating thyroid cancer cases in Belarus.

    CREDIT: MUTSUMI STONE

    With his pension nearly finished, Sugenoya plans to return to Japan in June. He knows that thousands more people in Belarus— including some of the children in the Mozyr ensemble—could develop thyroid cancer and that the last chapter of the terrible accident is far from written. But Sugenoya feels he has made a difference.

  16. CELL BIOLOGY

    Do Centrosome Abnormalities Lead to Cancer?

    1. Jean Marx

    Evidence suggests that at least some cancers arise because centrosome malfunction causes chromosome damage and missorting

    It may be small and inconspicuous, but the structure called the centrosome plays a big role in the cell. One key duty: helping to organize the mitotic spindle—the collection of protein filaments that pull the duplicated chromosomes apart during cell division, thereby ensuring that the two daughter cells each get a complete set. Without the centrosome, normal division of human cells could not occur. But accumulating evidence hints that this structure has a dark side as well. When the centrosome malfunctions, cancer may result.

    Researchers have known for decades that cancer cells are rife with chromosomal abnormalities. Some cells lack one or more chromosomes, for example, while having extra copies of others. “Virtually every cancer cell has an abnormal chromosome complement, whereas virtually every normal cell has the [normal] diploid number,” says cancer researcher Bert Vogelstein of Johns Hopkins University School of Medicine. The conventional wisdom has been that this aneuploidy, as it's called, is a late event in cancer development—the result of all the other disruptions in cancer cells. But now, “more and more it's coming out that [aneuploidy] is an early change and may be driving malignancy,” says Vogelstein, whose own work has been pointing in that direction.

    Contributing to this new view of aneuploidy is the realization that many types of cancer cells have abnormalities in their centrosomes—in particular, the cells often have extra copies. The supposition now is that the extra centrosomes lead to chromosome missorting and damage, thus causing the aneuploidy. Aneuploidy, in turn, may result in the loss of tumor suppressor genes or the gain or activation of cancer-causing oncogenes. “Once you have multiple centrosomes, that could increase the error rate [in chromosome replication and sorting], and those errors could be very dangerous,” says centrosome researcher Greenfield Sluder of the University of Massachusetts Medical School in Worcester.

    Researchers caution that the progression from centrosome derangements to aneuploidy to cancer isn't yet firmly established. Moreover, centrosome abnormalities likely aren't the only route to aneuploidy. For example, problems with the telomeres—the protective structures capping the ends of the chromosomes—have been implicated in the aneuploidy seen in some cancer cells. And two reports in the April issue of Nature Cell Biology suggest that mutations in a gene called APC, which are known to predispose to colon cancer, contribute to the chromosomal instability associated with that malignancy. But if centrosome abnormalities underlie at least some of the aneuploidy seen in cancer, they might be useful as diagnostic or prognostic indicators to help clinicians distinguish highly malignant cancers from those that are less dangerous. They might also point to possible new therapeutic strategies aimed at restoring normal centrosome function.

    Centrosomal chaos.

    The mouse mammary cancer cell (top) has multiple centrosomes (red) and has generated four sets of spindle microtubules (green), which will lead to abnormal partition of the chromosomes (blue) in the daughter cells. At right is a normal dividing mammary epithelial cell.

    CREDIT. W. BRINKLEY AND T. GOEPFERT

    Hints of centrosome involvement

    Early in the 20th century, a prescient microscopist named Theodor Boveri suggested that centrosome malfunction might lead to cancer. But the idea was more or less forgotten until about 5 years ago. At that time, Kenji Fukasawa, then in George Vande Woude's lab at the Frederick Cancer Research and Development Center in Frederick, Maryland, and colleagues found that cells lacking a critical tumor suppressor gene, known as p53, have multiple centrosomes instead of the normal one or two.

    In work described in the 22 March 1996 issue of Science (p. 1744), the researchers reported that in cell culture, this centrosome amplification apparently disturbs mitotic fidelity, causing the cells to end up with abnormal chromosome complements. Because p53's loss or inactivation is thought to contribute to the development of many human cancers, these findings suggested a new way that lack of a functional p53 gene might lead to cancer: by disturbing centrosome function and thereby generating aneuploidy.

    Two years later, a team led by Dennis Roop and William Brinkley of Baylor College of Medicine in Houston, Texas, produced evidence that this can in fact happen, at least in an animal cancer model. When the researchers blocked p53 activity in skin cells of living mice, those animals developed skin cancers when exposed to carcinogenic chemicals much more readily than controls did, and the centrosomes were amplified in the cells of 75% of the tumors. (The results appeared in the July 1998 issue of Oncogene.)

    At about the same time, Jeffrey Salisbury of the Mayo Clinic Foundation in Rochester, Minnesota, and his colleagues found centrosome abnormalities in the cells of human breast cancers, and Stephen Doxsey and German Pihan of the University of Massachusetts Medical School detected them in most of the common human cancers, including breast, prostate, lung, colon, and brain. In addition to extra centrosomes, the researchers saw oversized centrosomes and some that contained more than the normal amounts of phosphate groups. “When we first looked at breast tumors, it was striking how unusual the centrosomes were. They stuck out like a sore thumb,” Salisbury says.

    But could centrosomal defects such as these actually cause aneuploidy and thus possibly contribute to the development of the cancers? Some hints that they might came from Doxsey's work, which showed a strong correlation between centrosome abnormalities and chromosome instability, and from Thomas Ried and his colleagues at the National Cancer Institute in Bethesda, Maryland. As reported in the February 2000 issue of Genes, Chromosomes and Cancer, when the Ried team looked at cultured lines of human colorectal cancer cells, they detected aneuploidy only in those cell lines that also displayed centrosome abnormalities. Ried cautions, however, that this work simply shows a correlation between the centrosome and chromosome abnormalities: “Causality has not been established.”

    How centrosomes might go awry

    Whatever their role in cancer, if any, researchers want to know what causes the centrosomal abnormalities. They have unearthed several intriguing possibilities. Fukasawa's earlier findings pointed to loss or inactivation of the p53 tumor suppressor gene as one possibility. More recently, Fukasawa, who is now at the University of Cincinnati College of Medicine, has been working out just how that loss leads to centrosome amplification.

    As shown 2 years ago by Sluder and Massachusetts colleague Edward Hinchcliffe, and independently by Tim Stearn's team at Stanford University, the activity of a kinase enzyme called CDK2 is needed for centrosome replication (Science, 5 February 1999, pp. 770 and 851). Because CDK2 activity is also needed to drive cells through the division cycle, this helps ensure that the centrosome replicates only once and at the right time. The Fukasawa team now has evidence that CDK2 controls centrosome replication by tacking a phosphate group onto a centrosome protein called nucleophosmin, causing it to leave the centrosome. Nucleophosmin's departure then initiates centrosome duplication, Fukasawa says. The p53 gene comes into this picture because its protein product, working through another protein called Waf-1, inhibits CDK2. Thus, p53's absence allows the centrosome to replicate when it shouldn't and accumulate extra copies.

    Inappropriate activity of other kinases may also lead to the centrosome abnormalities seen in cancer cells. One of these is a so-called aurora kinase, discovered about 15 years ago in the fruit fly Drosophila melanogaster by David Glover of the University of Dundee, Scotland, and his colleagues. They found that when the gene encoding this kinase is mutated, mitosis is disrupted in fly cells, apparently because the kinase is needed to separate the duplicated centrosome before cell division.

    The first clue that an aurora kinase might be involved in human cancers came about 3 years ago. Two groups, one led by Brinkley and Subrata Sen of the University of Texas M. D. Anderson Cancer Center in Houston and the other by James Bischoff and Gregory Plowman of SUGEN Inc., in Redwood City, California, found an aurora kinase gene in a region of chromosome 20 that is amplified, or present in multiple copies, in many colon, breast, and other tumors. Presumably as a result of the amplification, the protein itself was present in the cancer cells in abnormally high concentrations.

    To see whether the elevated aurora kinase levels actually cause the centrosome defects, and possibly the cancers, the Texas team genetically engineered noncancerous cells that had the normal one or two centrosomes to overproduce the enzyme. As a result, Brinkley says, the cells “produced multiple centrosomes, became aneuploid, and [displayed] other characteristics of transformed [cancerous] cells.”

    Too much of a good thing?

    Centrosomes from cancer cells (bottom) nucleate the formation of many more microtubule fibers than do centrosomes from normal cells (top).

    CREDIT: W. L. LINGLE AND J. L. SALISBURY

    Abnormalities in the proteins that make up the centrosome structure have also been linked to cancer. For example, Doxsey and his team have found that concentrations of a centrosome protein called pericentrin are higher than normal in prostate and other cancers. And, similar to the situation with aurora kinase, when the researchers genetically engineered normal cells to overproduce pericentrin, the cells developed extra centrosomes. Says Doxsey: “We can create in vitro what's going on in tumor cells.”

    But questions remain …

    Many questions must still be answered to firm up the link between centrosome abnormalities and cancer development. For example, if the abnormalities are causative, one might expect to find mutations in the genes for centrosome structural or regulatory proteins in tumors. Aside from the amplification of the aurora kinase gene, none has been found so far, although Mark Winey, who studies centrosomes in yeast, thinks “it's just for want of looking.”

    Another question is how cells with centrosomal abnormalities manage to divide and survive at all. Normally, a variety of so-called checkpoints ensure that a cell doesn't divide if its DNA is damaged or abnormal. So “how does a cancer cell become a virtual dividing machine in the presence of all those centrosomes?” Brinkley asks.

    One possibility is that multiple centrosomes coalesce at the poles of a dividing cancer cell. That way, instead of having multiple spindle poles, the cell would have just two functional poles that partition the chromosomes equally. Brinkley, Salisbury, and others have detected such structures in some cancer cells.

    Perhaps the biggest question is when in cancer development the centrosomal abnormalities and aneuploidy arise. If they are driving cancer formation, as opposed to being a consequence of it, “they should be present not only in bad tumors, but in early ones,” Doxsey says. Although the case isn't airtight, the researchers do have some evidence that the abnormalities are present in early tumors.

    For example, in work that's not yet been published, Brinkley and his colleagues treated young mice with a carcinogen that induces breast cancer and then periodically examined samples of mammary gland cells to see when extra centrosomes appeared. That turned out to be just 90 days after the carcinogen treatment began, when the tissue showed precancerous changes but had not formed full-fledged tumors, Brinkley says.

    Salisbury has also detected centrosomal abnormalities in ductal carcinomas in situ—an early stage of human breast cancer. And Doxsey and his colleagues report in the March issue of Cancer Research that they have found the abnormalities in a variety of early cancers, including 15% to 20% of prostate cancers.

    Doxsey and his colleagues are now exploring whether centrosome abnormalities, or concentrations of the centrosome protein pericentrin, can be used to help clinicians assess the aggressiveness of prostate tumors. Most of the tumors that are detected early will grow so slowly that they won't be a danger to the patient, but right now they can't be distinguished from the fast-growing ones. As a result, many men may have their prostate glands removed unnecessarily.

    Doxsey notes that the percentage of early prostate tumors in which he found the centrosome abnormalities is about the same as the percentage of dangerous tumors. His team's work also shows a correlation between the degree of centrosome abnormality and cytological indicators of tumor seriousness. If those abnormalities can be used as a prognostic indicator, the tiny centrosome may prove a big help to patients with prostate and other cancers.

  17. DEVELOPMENTAL BIOLOGY

    The Hottest Stem Cells Are Also the Toughest

    1. Gretchen Vogel

    Although political uncertainty is rampant, researchers are making progress in the effort to tame human embryonic stem cells

    DURANGO, COLORADO—In the United States, public funding for work with embryonic stem cells looks ever more uncertain, as the National Institutes of Health has put on hold its process for approving cell lines that government-funded scientists can use (see p. 415). That move comes as the handful of privately funded labs already using the cells are reporting progress— albeit limited—in manipulating these temperamental cells.

    Although the cells were first derived more than 2 years ago, work has been frustratingly slow; indeed, only a few researchers have published any results with human embryonic stem (ES) cells. Not only are ES cells fussy about their growing conditions, but they also tend to differentiate spontaneously into a range of cell types other than the desired one, confounding research efforts. But at a recent Keystone meeting here,* researchers described new techniques to get around these obstacles.

    Several teams are tackling the “very labor-intensive” process of growing human ES cells, as James Thomson of the University of Wisconsin, Madison, described it. Most researchers grow the cells on a feeder layer of mouse cells to keep them from differentiating. But before these cells can be used to treat disease in humans, researchers need to come up with a culture free of mouse cells. Melissa Carpenter and her colleagues at Geron Corp. in Menlo Park, California, reported that they have managed to grow cells on Matrigel, a commercially available gel commonly used to culture cells. They bathe the cells in a serum-free medium that is first “conditioned” by incubating it with irradiated mouse cells. The scientists do not yet know what the mouse cells add to the medium; they are working to characterize its active components. If they succeed, they might be able to produce a synthetic medium that could keep the cells dividing but not differentiating.

    First step.

    Differentiating human embryonic stem cells express nestin (red), a marker for neural precursor cells. Cell nuclei are stained blue.

    CREDIT: SU-CHUN ZHANG/UNIVERSITY OF WISCONSIN

    Stem cell researchers eagerly await the day when they can grow an unlimited supply of human liver cells. Not only would they be extremely valuable for tests of drug toxicity, but they might also be useful for treating some liver diseases. Geron scientists have taken a first step, reported Carpenter, coaxing their ES cell lines to produce “hepatocyte-like” cells. They first exposed the cells to sodium butyrate, a chemical known to promote cell differentiation. Many of the cells died, Carpenter said, but when the team cultured the survivors in media designed for growing hepatocytes, many of them began to store glycogen and express proteins typical of liver cells. Although the results are promising, Thomson cautions that liverlike cell markers appear on other cell types as well: “If they're really hepatocytes, it would be good. It's not yet clear to me that they are.”

    Meanwhile, Thomson and his colleagues have found an efficient way to transform human ES cells into neural epithelial cells—precursors of more mature cell types in the brain. The team allowed the ES cells to cluster into balls of cells called embryoid bodies and then exposed them to media designed for neural cells. Next they isolated a partially differentiated cell type from the embryoid bodies and cultured those cells with basic fibroblast growth factor. Ninety-six percent of the resulting cells expressed neural markers, Su-Chun Zhang and Thomson reported. When transplanted into the brains of newborn mice, the cells migrated to several brain regions and showed signs of developing into mature neurons and glia, the neuronal supporting cells.

    Stem cell researchers would like to create immune-neutral stem cells that wouldn't trigger rejection when transplanted into a patient. But that would require genetically altering ES cells. So far, that has proved far trickier in human cells than in their mouse counterparts. At the meeting, Joseph Gold of Geron said that he and his colleagues have genetically altered cell lines to express green fluorescent protein (GFP)—making them easier to track in animal transplantation experiments. And in a paper now in press, Nissim Benvenisty of the Hebrew University in Jerusalem, Joseph Itskovitz-Eldor of Rambam Medical Center in Haifa, Israel, and their colleagues report that they have created cells that express GFP only when they are undifferentiated. This would enable the scientists to weed out cells that have already chosen a developmental path.

    Ultimately, researchers hope to devise a way to target genetic changes precisely. Several teams are working to adapt so-called homologous recombination—the technique that has made mouse ES cells such a valuable tool for geneticists—to human cells. So far none has reported success.

    • *“Pluripotent Stem Cells: Biology and Applications,” 6–11 February.

Log in to view full text