News this Week

Science  09 Jan 1998:
Vol. 279, Issue 5348, pp. 166
1. WORLD HEALTH ORGANIZATION

Healer Needed for World Health Body

1. Michael Balter

As the World Health Organization (WHO) prepares to choose a new leader, public health experts are hoping for somebody who will bring a new vision to an agency that many think has lost its way

GENEVA—On 19 January, the executive board of the World Health Organization (WHO) will convene in this lakeside city for what may be the most important meeting in the agency's 50-year history. The 32-member board, made up of representatives from WHO's 191 member countries, will nominate a new director-general to carry the organization into the 21st century. The new leader will replace Hiroshi Nakajima of Japan, whose 10-year stewardship of WHO comes to an end in July.

The election comes at a critical turning point for WHO. The world's health landscape has changed over the past decade, and yet many believe the agency has not changed with it. Its narrow, disease-based approach is sometimes seen as too simplistic; its support is not always going to the countries that need it the most; and while member nations are attempting to interfere in its workings and some are arbitrarily withholding funds, other agencies not usually connected with health are muscling in on its territory. Such problems have mounted in recent years, and health experts both within WHO and outside it believe that the new director-general will need to create a new vision for the organization to get it back on track.

When WHO was established in 1948 as the United Nations (U.N.) agency chiefly responsible for safeguarding the world's health, it had two primary missions: to create and disseminate international health regulations and guidelines, and to provide expert technical assistance and emergency relief to its member countries. In addition to these advisory roles, the organization has coordinated international research efforts in a number of health-related areas, such as contraception methods, AIDS, toxic chemicals, and the health effects of radiation from Chernobyl and other nuclear accidents.

For many years, this straightforward biomedical approach worked well and led to some of WHO's greatest triumphs—particularly the much-heralded eradication of smallpox in the late 1970s. But more recently, international health issues have become increasingly complex, as economic and political factors—including the ravages of wars, particularly in Africa, that have wiped out entire health care infrastructures—have led many to question WHO's traditional approach. Many critics believe that WHO must be a greater advocate against poverty and the social conditions that contribute to poor health, especially in developing countries.

“We have been presiding over increasing health inequities, and in many cases worsening health situations, particularly linked to poverty,” says John Martin, a senior official in a WHO division established in 1990 to help concentrate more of the organization's multidisciplinary talents on the poorest nations. While WHO's public health experts and others outside the agency do not always agree on what WHO's priorities should be, there is widespread agreement that the agency's credibility has been compromised in recent years. “There was a huge increase in access to primary health care in the 1980s, much of which was due to WHO efforts,” says Gill Walt, a health policy analyst at the London School of Hygiene and Tropical Medicine. “But as recession hit and public spending began shrinking, the agency was still looking at technical issues in health and disease, and didn't take on the question of how to finance increasingly stretched health infrastructures.”

This task, Walt and others say, fell by default to other agencies not traditionally concerned with health, such as the World Bank, which have stepped in to fill the gap. While WHO itself does not have the funds to provide such financing, some observers believe that the organization has ceded much of its leadership role in defining what the health priorities should be. “Many people are worried that WHO has lost its lead role in many areas,” says Wilfried Kreisel, the agency's executive director for health and environment. James Sherry, a health analyst with the U.N. Children's Fund currently serving as an adviser to UNAIDS, the multiagency U.N. body responsible for coordinating the worldwide fight against AIDS, adds that “in the absence of sharp leadership at the top, WHO has reverted to what it draws the most comfort from—printing out guidelines in the headquarters basement and sending them out to 150 countries.”

After Nakajima

For most of WHO's staff, as well as public health experts and other observers outside the agency, restoring the organization's credibility will be one of the highest priorities for the new director-general. “It's tough right now to keep moving forward,” says Susan Holck, director of WHO's reproductive health division. “There's nothing holding us together except our commitment to the organization and its work.” WHO staff members are therefore anxiously waiting to see who their new leader will be. This month's executive board meeting will pick a sole nominee from among seven candidates vying for the position (see sidebar on p. 167). That person will almost certainly be elected when all of WHO's member states meet for the World Health Assembly next May, and will take office on 21 July.

As the suspense mounts, there is a palpable sense of relief that the Nakajima era is coming to an end. While some feel that the outgoing director-general has often been unfairly criticized, the last decade has been marked by accusations of financial irregularities and questionable awards of contracts by top officials, and many say that Nakajima's bureaucratic management style has compromised WHO's ability to respond to pressing health problems around the world. For example, one of WHO's most important programs—its new division of emerging and communicable diseases, created in late 1995 and devoted to controlling frightening new viral diseases such as Ebola and Lassa as well as more well-established killers like cholera—came into existence only after overcoming considerable bureaucratic resistance. “It took 3 years for WHO to respond to this new and important area,” says Jonathan Mann, dean of the Allegheny University School of Public Health in Philadelphia. “Nakajima had to be dragged into it.”

Mann, who in 1990 resigned as director of WHO's Global Program on AIDS, the forerunner to UNAIDS, in protest at what he saw as Nakajima's lack of commitment to the fight against the disease, says that Nakajima made “conformism and loyalty the highest value” within WHO: “What mattered most was fealty to the leader and not to the organization.” Indeed, a key reason for the creation of the multiagency UNAIDS program was the widespread perception that WHO's approach to the disease was unimaginative and narrowly focused (Science, 25 November 1994, p. 1312). However, some commentators told Science that the focus on Nakajima's perceived weaknesses has oversimplified the issues facing WHO. “I think that history will treat Dr. Nakajima's stewardship much more kindly than most people do now,” says George Alleyne, director of the Washington-based Pan American Health Organization and one of the candidates to succeed Nakajima. Sherry adds that “Nakajima didn't elect himself. This is not basically a failure of internal leadership, but of governance” by the member states that make up WHO.

Meddling in management

The often ambivalent attitude of WHO's member countries toward the organization may help explain many of the agency's problems. “The member states have the paradoxical tendency to micromanage parts of the organization, while at the same time abdicating their responsibilities for difficult issues that are vital for the organization as a whole,” says Peter Piot, executive director of UNAIDS. One WHO program director, who asked not to be identified, says that “the way some member state representatives behave leaves a lot to be desired. They pass resolutions in the World Health Assembly saying people should be hired on merit, and then during the coffee break they try to push program directors to hire people from their countries.”

At the same time, the member countries have kept WHO closely reined in by freezing its core budget for the past 15 years. Thus, the organization's regular budget for 1998–99—which comes from mandatory member contributions—will be only $843 million, roughly equal to the operating expenses of a medium-sized teaching hospital in an industrialized country. And this modest pie must be divvied up among some 15 major WHO programs, ranging from nutrition and food safety to communicable disease control. To make ends meet, most WHO programs cover part, or sometimes most, of their costs by seeking so-called extrabudgetary funds, from individual donor countries or other agencies. These extra contributions will make up an additional$958 million in 1998–99, or 53% of WHO's total spending. “The current proportion of the budget earmarked for specific programs is way too high,” says Jaime Sepulveda, director-general of the National Institute of Public Health in Cuernavaca, Mexico.

To make matters worse, some member countries have recently expressed their displeasure with WHO's management by withholding funds from programs generally regarded as worthy of support. “We have lost considerable contributions,” says Paul Van Look, associate director of a special program on human reproduction research—some from countries known to be sympathetic to the program's goals. For example, Sweden, formerly one of the biggest contributors to the program, has drastically cut its donation, and Denmark—another major donor—has cut its subsidy entirely. An official of the Danish foreign ministry told Science that Denmark would not increase its donations to WHO programs until a new director-general was elected.

WHO resources have been further stretched by the failure of many rich Western countries to pay their membership dues on time, while some of the poorest countries in the world, including Rwanda, have managed to do so. Thus, the United States, the single biggest contributor, was nearly a year late paying its 1997 allotment of $107 million and still owes money from 1996. (A few countries, including Costa Rica and Bhutan, paid their 1998 dues months in advance.) But perhaps of greater ultimate concern are inequities in the way WHO resources are distributed around the world. “There is definitely less money going to countries with the greatest need,” says Walt. A recent study of 12 countries by a team of public health experts including Walt—which was commissioned by Australia, Canada, Italy, Norway, Sweden, and the United Kingdom—found that some of the nations most desperately in need of help from WHO were receiving significantly less aid than others in a better position to help themselves. For example, Mozambique, which is recovering from a 16-year-long civil war that essentially destroyed its health infrastructure, was found to be receiving only about half the assistance given to Ecuador, which has a relatively well-developed health system and only one-tenth the population. Physician Carlos Tiny, head of WHO's office in Maputo, Mozambique's capital, told Science that the office has a technical staff of only five people, including himself. Yet, since last August, Mozambique has been ravaged by a cholera epidemic that has racked up 7000 cases and more than 200 deaths—and this in a country that has only 400 doctors for its 15 million inhabitants. Fortunately, much of the gap is being filled by numerous other aid agencies also working in the country. “The WHO is a technical cooperation agency and not a funding agency,” Tiny says. “But if we had more staff, we could be more instrumental in coordinating donor input. We will never receive all the funds we need, but there is room for improvement.” Indeed, some critics of WHO believe the organization has stretched itself too thin and should concentrate its resources on the neediest countries. “The WHO has tried to be all things to all people,” says immunologist Barry Bloom of the Albert Einstein College of Medicine in New York City. “But it doesn't have the funds to control every disease in every country in the world. Most countries don't need the WHO in there to vaccinate their kids. The WHO should really focus on upgrading health care in the poorest countries, because no one else is going to do it.” Some go so far as to argue that the headquarters should move entirely out of Geneva, a city with one of the highest costs of living in the world. “The WHO should become an organization that spends far fewer resources bringing people to Geneva to discuss policy and more resources getting people to build real programs in communities in the developing world,” says Joseph McCormick, a former virus hunter with the U.S. Centers for Disease Control and Prevention in Atlanta and now at the Pasteur Institute in Paris. “Perhaps moving to Abidjan or Lagos or Karachi or Calcutta might reduce the bureaucracy and increase the amount of genuine commitment.” Such a dramatic step seems unlikely, at least at this juncture. But whoever is chosen as the organization's new director-general will clearly have to lead WHO in new directions if it is to retain its relevance into the next century. Says WHO's Holck: “To get us going along the right path at this crossroads, we need someone with guts and determination. And that person won't be easy to find.” 2. WORLD HEALTH ORGANIZATION Who Will Lead WHO? 1. Michael Balter GENEVA—Ask public health experts what qualities they would like to see in the next director-general of the World Health Organization (WHO), and one answer almost always comes up first: charisma. After 10 years of what is widely perceived as lackluster leadership from current chief Hiroshi Nakajima, whose tenure expires on 20 July, the international public health community is eager to see a visionary take his place. Yet, there is an undercurrent of fear that when the WHO's 32-member executive board meets later this month, the regional rivalries and horse trading that often mark United Nations (U.N.) politics will play a hand in the selection of the WHO's new leader. While seven candidates are vying for the job, observers within and outside the WHO say that four are clear front-runners: Gro Harlem Brundtland The former prime minister of Norway, Brundtland is an energetic campaigner on environmental and economic development issues. She is also favored by most of WHO's staff, chiefly because she hails from outside the U.N. system. One handicap: Although she is a physician, Brundtland has little public health experience. In an interview with Science, Brundtland stressed the relation between health and development issues: “Not only does poverty breed ill health, but ill health breeds poverty. Investing in health increases productivity and economic output.” Nafis Sadik A former obstetrician from Pakistan, Sadik has been executive director of the United Nations Population Fund since 1987. She is an outspoken advocate for women's reproductive rights and played a leading role at the Cairo conference on population and development in 1994. Chief handicap: She has already spent 10 years as head of a U.N. agency. But Sadik does not see that as a minus: “I have been working in public health all my life. It takes years to understand the U.N. system.” Ebrahim Malick Samba WHO's regional director for Africa since 1995, Samba, a physician from The Gambia, is noted for leading a highly successful campaign against onchocerciasis (river blindness) in Africa during the 1980s and '90s. Samba, who has the solid backing of the nations of sub-Saharan Africa, would be WHO's first director-general from the developing world. “WHO's budget is not distributed according to greatest need, but according to a formula no one seems to understand,” he says. If chosen, Samba promises to set up a commission to rectify this. George Alleyne A physician from Barbados, Alleyne is director of the Pan American Health Organization, which doubles as the WHO regional office for the Americas. Alleyne scores a lower charisma rating than his three chief competitors, but is well respected for his integrity and management skills. “Anyone who goes into an organization saying he's going to change everything is a fool,” Alleyne says. “But we are dealing with the perception that WHO has lost some of its credibility, and we must change that perception.” The remaining three candidates—Fernando Antezana of Bolivia, WHO's deputy director-general in Geneva; Arif Batayneh, former health minister of Jordan; and Uton Muchtar Rafei of Indonesia, head of WHO's regional office for Southeast Asia—are considered long shots by virtually all commentators who spoke to Science. But some observers expressed concern about what they call the “nightmare scenario”: The executive board, which is made up of representatives roughly split between developed and developing nations, might pick a compromise candidate of lower stature. “It would be absolutely naïve to think that geopolitics will not play an important role in the election of the new director-general,” says Jaime Sepulveda, director-general of the National Institute of Public Health in Cuernavaca, Mexico. And immunologist Barry Bloom of the Albert Einstein College of Medicine in New York City admonishes: “If they pick a candidate for reasons that have nothing to do with health, that would be shameful.” 3. WORLD HEALTH ORGANIZATION Hunting Down the Last of the Poliovirus 1. Lisa Schlein 1. Lisa Schlein is a journalist in Geneva. GENEVA—One early morning last month, millions of people across India, from the snow-peaked Himalayas to the deserts of Radjastan, set off by foot, camel, bike, car, or helicopter to run polio vaccination posts in 650,000 Indian villages. By the time this army of volunteers arrived home at the end of the day, 127 million children under the age of 5 had been immunized against this crippling disease. “Everybody said it just couldn't happen. And, yet it does,” says Harry Hull, chief of the World Health Organization's (WHO's) Polio Eradication Program. Indeed, while WHO's headquarters is preoccupied with the coming vote for a new director-general (see main text), initiatives such as the Polio Eradication Program show that WHO's foot soldiers can make a huge difference to the majority of the world's population without adequate health care. Since 1988, when the World Health Assembly declared its aim to eradicate polio globally by 2000, the number of cases has been slashed by 90%, from an estimated 350,000 cases to about 35,000 today. But with just 3 years of the initiative left to run, the job will get increasingly tough as health workers track down remaining pockets of the virus in some of the most remote, poor, and war-torn corners of the globe. “This is one we can win,” says Steve Cochi, director of polio eradication activities at the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta. He says the Polio Eradication Program “can make people who work in public health feel like they can do something meaningful.” At first, the campaign to rid the world of a disease that has left some 10 million to 20 million people paralyzed did not seem to be making an impact. But in 1995, WHO and its partner, the United Nations Children's Fund (UNICEF), adopted the new strategy of blitzing the entire child population of a country in a single day. In 1996, such National Immunization Days vaccinated more than 420 million children—almost two-thirds of the world's children under five—against polio. These dramatic campaigns captured the imagination of the world and have even persuaded hardened fighters in war-torn countries such as Afghanistan, Sudan, and Sri Lanka to stop fighting for a day so that their children can be immunized. In these campaigns, which are coordinated by WHO, the other main partners have different but complementary functions. UNICEF provides the oral polio vaccine, the CDC offers technical expertise, and the charity Rotary International, which has contributed$400 million to date, mobilizes millions of volunteers to carry out the mass immunization campaigns.

Only a small number of diseases are suitable for such an eradication program. Polio is a perfect candidate because the virus infects only humans, is carried in the body for a short period of time, and has an effective intervention. “We have great vaccines against polio,” says Hull. The WHO-led campaign uses the live, attenuated oral polio vaccine developed by Albert Sabin in 1961, rather than Jonas Salk's 1955 inactivated injectable vaccine, because it is cheap—8 cents a dose—can be easily administered by mouth by an untrained volunteer, and produces high levels of intestinal immunity which blocks the replication of the disease. Its disadvantage is that in approximately one in 3 million cases the vaccine will produce the disease it is designed to prevent. The Salk vaccine, while it protects a child from paralysis, is less effective in preventing the transmission of the wild virus. “We do not think that, in the world as we know it today, eradication of wild poliovirus is possible with the Salk vaccine,” says Hull.

As the possibility of eradication nears, the campaign's partners know that failing to wipe out the virus would make all their efforts thus far futile. If not treated, the last pockets of the virus could quickly spread again. “The poliovirus is one day's journey from any spot on the globe,” says Hull. “So, countries that have been free of polio for years must continue immunization until the entire world is free of polio.” The United States, for example, spends $230 million annually immunizing children for a disease it has been free of for 20 years. Eradicating polio will save an estimated$1.5 billion in immunization, treatment, and rehabilitation around the globe every year. WHO estimates that between $600 million and$800 million will be needed to complete the job of eradicating polio by the turn of the century.

Buoyed by their anticipated success, WHO and its collaborators have started planning a new campaign to eliminate measles, one of the world's five major child killers. Such a campaign will be much more difficult than eradicating polio, because an injectable vaccine will have to be used. But the team is convinced that, with determination and strong, committed leadership from WHO's new director-general, WHO could begin the new millennium with another remarkable public health achievement in sight.

4. HIGH-ENERGY PHYSICS

Physicists Dream of a Muon Shot

1. Alexander Hellemans
1. Alexander Hellemans is a science writer in Naples, Italy.

When you plan to accelerate subatomic particles to astronomical energies and collide them to spawn new forms of matter, your choice of a projectile is critical. Hadrons—protons, for instance—shatter on impact into smaller pieces such as quarks and gluons, making their collisions messy and hard to interpret. Electrons are indivisible and yield cleaner collisions, but they emit energy-wasting synchrotron radiation when they are accelerated in circular machines. At a meeting last month in San Francisco, a group of physicists considering the next great collider—a hoped-for successor to the Large Hadron Collider (LHC) now being built at CERN in Geneva—pinned their hopes on the electron's chubby brother, the muon.

Pointlike, negatively charged particles 207 times more massive than the electron, muons generally have a fleeting existence in the debris resulting from particle collisions. Partly for this reason, they have never before been used as accelerator projectiles. But they and their positively charged antiparticles have some compelling advantages, promising the clean collisions of electrons without their wasteful synchrotron radiation. Although some researchers favor a hadron or electron collider as a successor to the LHC, the group that met at the 4th International Conference on Muon Colliders “is becoming more and more enthusiastic about muon colliders,” says Andrew Sessler of Brookhaven National Laboratory (BNL) in Upton, New York.

Indeed, Sessler and his colleagues are now proposing a large-scale test of muon collider technology to see if they can generate and marshal these ephemeral particles into a coherent beam. “This is becoming more and more a real thing,” he says. “And we expect that we can do it for less money.”

The $5 billion LHC, which will begin colliding protons and antiprotons at an energy of 14 trillion electron volts (14 TeV) in 2005, may well offer a glimpse of the Higgs boson, a hypothetical particle that would help explain the varied masses of other particles. The machine may also reveal supersymmetric particles, heavier partners to known particles, which are predicted by a theory called supersymmetry. But to follow up on these clues, researchers will need a new machine that can produce Higgs and supersymmetric particles en masse and precisely measure their properties. Proton-antiproton collisions are ill suited to making these precision measurements, says Howie Baer of Florida State University in Tallahassee: “You get lots of extra quarks and gluons, making the events very ‘messy.’” And because electrons give off copious synchrotron radiation when a magnet bends their paths, a next-generation electron collider would probably take the form of a linear accelerator, or linac, tens of kilometers long. Muons might offer the advantages of an electron collider without the expense of a huge linac. Because of their larger mass, they lose much less energy in the form of synchrotron radiation, so they can be accelerated in relatively small circular machines. “You don't have to build full-energy linacs,” says Sessler. A 1-TeV muon collider “can fit on an existing laboratory site and use some of the existing infrastructure, and that is a tremendous advantage,” adds William Marciano of BNL. What's more, because of muons' mass, their collisions spark physical processes that should generate Higgs particles far more efficiently than electrons can. “We can build a Higgs factory,” says Sessler. But producing and handling muons are still largely terra incognita, says Alvin Tollestrup of the Fermi National Accelerator Laboratory near Chicago, one of the proponents of the muon-collider idea. Muons are scarce in nature because they survive for only a few microseconds before decaying into electrons and neutrinos. In current designs, the first step toward making them is to collide an intense proton beam with a liquid metal target, producing quark-antiquark pairs called pions. The pions then decay into muons. In what Tollestrup calls “the critical part of that sequence,” these muons have to be “cooled”—marshaled into a beam in which they all move at the same velocity. Only then can they be accelerated to nearly the speed of light, which extends their lifetime through Einstein's time dilation. Sessler and his colleagues are now hoping to test muon-cooling schemes, which would rely on arrays of magnets and energy-absorbing materials. “We are proposing a$30 million experiment to be put in Fermilab,” says Sessler. They expect to complete the final proposal early this year and hope to win funding in the fiscal year 2000 science budget.

Still, any push for a muon collider will encounter plenty of skepticism. Alvaro de Rújula, a theoretical physicist at CERN, acknowledges that the “clean physics” of a muon collider would be attractive. But he thinks the technical problems with these machines are daunting. “There are two types of machines of the future: the hadronic machine, where the experiments are extremely difficult, and the muon machine, where the machine is difficult.”

5. ASTRONOMY

Far-Off Planet Makes a Comeback

1. James Glanz

“It looks like we're back to an ugly old planet,” says David Gray. Nearly a year ago, the University of Western Ontario astronomer had issued a serious challenge to the case for an extrasolar planet—the first to be discovered around a sunlike star. He presented evidence that slow jitters in the spectrum of the parent star, thought to result from a planet's periodic tug, were actually due to a pulsation of the star's gases (Nature, 27 February 1997). The ensuing debate was at times less than civil. But harmony has been restored: Gray and at least three other groups say they have been unable to reproduce his earlier results. What looked like a planet killer may have been just a chance alignment of noisy data points.

One group, led by Artie Hatzes of the University of Texas, Austin, published its results in yesterday's issue of Nature alongside Gray's concession. A paper by another group, led by Timothy Brown at the High Altitude Observatory in Boulder, Colorado, has been accepted at Astrophysical Journal Letters. And a third group, at the University of Paris, is still finishing its analysis but also sees “no indication” of pulsations of the star, 51 Pegasi, says team member Jean Schneider. “The only reasonable explanation for the velocity wobble is [still] a planet,” concludes Didier Queloz, who made the discovery with Michel Mayor at the Geneva Observatory (Science, 20 October 1995, p. 375).

Mayor and Queloz, who is now at the Jet Propulsion Laboratory in Pasadena, California, had monitored hundreds of dark absorption spikes carved into 51 Peg's spectrum by elements in the star's atmosphere such as iron and calcium, which filter out specific frequencies of light. In light from a stationary star, the frequencies would remain fixed. But the observed frequencies shifted up and down by small amounts over a 4.23-day period. Mayor and Queloz inferred that a roughly Jupiter-size planet was whipping around 51 Peg in an orbit much closer than Mercury's around the sun, causing the entire star to wobble and shifting the spike frequencies by the Doppler or train-whistle effect.

Then came Gray's challenge. Using a spectrograph most astronomers describe as somewhat outmoded, he monitored a single absorption spike and found that asymmetries in its shape also changed over a 4.23-day period. A simple Doppler shift couldn't cause the distortion, but Gray believed that both the shape changes and the frequency shifts could be due to a bizarre type of “nonradial” oscillation never seen in a sunlike star: a slow sloshing of the star's surface gases. Because his 39 noisy data points were scattered over 7 years, however, Gray and others now emphasize that there was roughly a one-in-300 chance that a spurious 4.23-day signal might show up by chance.

That appears to be what happened. “I have to conclude that nature played a dirty trick on him,” says Brown. In the most conclusive of the new measurements, Hatzes and co-workers made about 120 measurements of several absorption lines at more than twice Gray's spectral resolution and saw no changes in the line shapes. Neither did Gray when he made further observations with his original apparatus. His earlier results, he says, were either a fluke or a transient phenomenon that has since stopped.

But as the technical disagreement fades, the dispute has thrown light on the underside of a high-stakes field where new claims are followed like sports scores by the wider public. Astronomers grumbled privately about the attacks on Gray's work that appeared on an elaborate Web site—complete with links to corporate sponsors—maintained by the planet searcher Geoff Marcy of San Francisco State University. Gray responded in kind on his own Web site, calling some objections “arguments of ignorance.” Tempers have since cooled, but Hatzes says: “I didn't like to see that. It should have been a more civilized debate.”

6. GERMAN RESEARCH

Gene-War Veteran Seeks New Roles for Granting Agency

1. Robert Koenig
1. Robert Koenig is a writer in Bern.

MUNICH—The presidency of Germany's basic-research granting agency—the Deutsche Forschungsgemeinschaft (DFG)—is hardly the comfortable administrative chair it once was. These days, German universities are in turmoil over budget cutbacks, prominent scientists grumble about stingy support for research, and the country's science community is still reeling from last year's scandal over falsifications in research (Science, 15 August 1997, p. 894, and 19 December 1997, p. 2049). But biochemist Ernst-Ludwig Winnacker, who took over as the DFG's president on 1 January from literature professor Wolfgang Frühwald, is tackling his new position with the confidence of a working scientist who is by all accounts well equipped with the political savvy, communication skills, and management acumen needed for the job.

Describing the 3-year-long DFG post as “quite a challenge,” Winnacker told Science in an interview that he looks forward to the opportunity “to think on another level, to see the whole picture,” and to help lead German science into the new century. A Munich University professor and founder of its Gene Center, Winnacker is an ardent Europeanist who wants to make German research more visible internationally. He is also an advocate of interdisciplinary research who wants to link scientists from different universities and countries, and an educational innovator who wants to foster a “postdoc culture” in Germany by giving bright young researchers more funding and independence.

As DFG president, Winnacker will oversee a $1.1 billion annual budget for research projects at universities and institutes. He will also face new challenges, such as countering the political trend of shifting resources from basic to applied research and helping restore public confidence in the DFG in the wake of the scandal involving two professors accused of falsifying data in biomedical research—one of whom was formerly a member of a DFG advisory panel. “Fraud can never be excluded from any system, but we have to make the system as transparent as possible” to prevent it, he says. Colleagues say they are confident that Winnacker is up to the job. Biologist Hubert Markl, a former DFG president who now heads the Max Planck Society, told Science that Winnacker “is not only an excellent scientist, but he thinks a lot about how science affects society. I've found him to be a clear and deep thinker on such issues, with the courage to take positions.” Fifteen years ago, when genetic research was a hot issue in German politics, Winnacker led the effort to create a Gene Center in Munich. Starting with a loose association of junior researchers and university institutes, the Genzentrum is now one of Germany's leading centers for gene research, with its own new building, 130 scientists, and a$15 million budget. And Winnacker, who was placed on the “hit list” of an extremist antigenetics group in the mid-1980s, is now more likely to be targeted for advice on advancing German biotech research and industry. “Our windows were made bulletproof back then, but now it's ridiculous. There has been a remarkable turnaround,” he says.

Winnacker's advocacy of genetic research has made him enemies in Germany's Green Party, however, and other critics complain that, as a former member of the supervisory board of the chemical giant Bayer AG, he is too close to Germany's powerful chemical industry. But Winnacker says his contacts may prove helpful to German research. He is a firm believer in setting up centers where a “critical mass of good science” can help create new business ventures, as it has in U.S. biotech meccas such as Boston and San Francisco. Such symbiosis was once rare in Germany, but now Munich has emerged as such a center, with new science faculty buildings and biotech businesses springing up around the Genzentrum building on the city's outskirts. Winnacker himself co-founded a biotech firm, MediGene, in 1994 and remains chair of its board. “Seven companies have been founded out of [the Genzentrum] building already, and they are all based around here,” says Winnacker.

All the while, the 56-year-old Winnacker has remained an active researcher, spending about half his time in Genzentrum labs until recently. In a recent paper published in Nature Medicine, a team led by Winnacker identified a receptor that may allow the malformed prion proteins thought to cause Creutzfeldt-Jakob disease and other conditions to enter brain cells. And in addition to authoring scientific papers, he also writes popular science books, most recently The Genome (1996).

Winnacker believes that the DFG, as the basic-science granting agency for universities, can play a greater role in both informing the general public about science and promoting improvements in higher education. “One very important emphasis is to support young, independent scientists,” he says. Winnacker, who benefited from postdoc work at both the University of California, Berkeley, and at Stockholm's Karolinska Institute, complains that Germany has no real postdoc culture, because universities do not have a tradition of independent assistant professors. He wants the DFG to help foster such a culture by creating positions and supplying more grants to postdocs.

But Winnacker's DFG will have to contend with a depressed university system. Recent cutbacks in federal support have sparked demonstrations by tens of thousands of students, and Germany's education and research ministry is pushing for changes that it argues are needed to make the overcrowded universities more flexible and competitive in education and research. While Winnacker believes that “German universities are much better than their reputation,” he adds that “they could be more efficient and flexible in a number of ways.” He also would like to make German science “more visible on an international level. … Why not fund projects that extend into other countries?”

Another major problem is scarce funding for basic research. Germany's research ministry had promised that both the DFG and Max Planck budgets would increase by 5% each year, but the parliament reduced this year's increase to 3.9%. Winnacker calls that cut “an indicator in the wrong direction. … In basic science, you need continuity and predictability of funding.”

Despite the tight budgets, Winnacker is optimistic about the future of German science, especially in fields such as molecular biology. While the United States and some European nations maintain a wide lead in “classical recombinant-DNA research,” he thinks that “the emergence of genome research has changed the picture. … When that happened, we all had the chance for a new beginning.”

7. PAPUA NEW GUINEA

Management Dispute Shutters Tropical Research Institute

1. Jeffrey Mervis

Situated in one of the world's most biologically diverse regions, with a spectacular coral reef sitting just offshore, the Christensen Research Institute (CRI) in Madang, Papua New Guinea, has provided researchers from many fields with a temporary home away from home. Last month, with little notice, the lodge and laboratory complex closed, the victim of a festering management dispute between its major benefactor and its former director. The conflict also has derailed a promising collaboration with a major research university that could have made the 12-year-old institute self-supporting.

The sudden closure of CRI has dealt a sharp, short-term blow to researchers like Bill Fenical of Scripps Institution of Oceanography in La Jolla, California, who had already shipped $40,000 worth of equipment to the tropical island north of Australia in anticipation of conducting a 5-year research project there. “It's a tragedy,” says Fenical, who spent several weeks at CRI in 1996 and who had planned to study the reefs' chemical defenses against predators. “Not only is this the most biodiverse and species-rich place on Earth, but CRI was such an active, vibrant research environment, with scientists from many different fields interacting with one another. And for most residents of Papua New Guinea, it was also their sole exposure to modern scientific inquiry.” CRI was founded through the efforts of Diane Christensen, a specialist in African art who lived in Papua New Guinea (PNG) in the 1980s while her husband managed a Belgian research station on the island. The daughter of a U.S.-born mining engineer and art collector, Christensen tapped into a family foundation to set up a research station with modern scientific amenities, including wet and dry labs and a 24-hour source of electricity. “We wanted to provide a venue for scientists to identify what existed in this incredibly rich environment,” she explains from the Palo Alto, California, offices of the Christensen Fund (CF). Christensen also served as CRI's first administrator before handing over the reins in 1987 to British plant taxonomist Matthew Jebb, a freshly minted Ph.D. from Oxford University who had done fieldwork on the island. Jebb hewed to CRI's mission as a research station for marine and terrestrial activities. In addition to renting out space to foreign scientists, it helped to fund graduate training for a handful of promising local residents and gave younger students their first look at modern laboratory science. “I had set up research plots in the forests near Madang, and I was sleeping in the bush because I didn't have any money for lodging,” recalls one recipient, PNG forester Philip Siaguru. “Matthew found out and told me to apply for a fellowship, which helped me get through my Ph.D.,” says Siaguru, now an associate professor at the University of Technology in Lau. But CRI's role began to change after Jebb returned home in late 1993. (He now directs the National Botanic Gardens in Dublin.) His hand-picked successor, University of California, Berkeley-trained entomologist Larry Orsak, had done extensive fieldwork on the island and had spent the past few years at the Wau Ecology Institute, an independent, PNG-run facility founded in 1961 by the Bishop Museum in Honolulu. At Wau, Orsak had tried to link conservation efforts with economic development by setting up a farm that raised butterflies for sale, using school dropouts to collect and classify the insects. Orsak brought that activist philosophy to CRI. “I believed that CRI should become increasingly relevant to PNG, which mandated that we go further into training, education, and community conservation,” he says. To support that broader vision, Orsak enlarged CRI's annual budget from roughly$150,000, supplied chiefly by CF, to more than $350,000, thanks to grants from the PNG government, the U.S. National Science Foundation (NSF), the MacArthur Foundation, and various international bodies. Christensen and Jebb, who with Orsak constituted CRI's board until early last year, agree that such activities are important but say that CRI was too small to serve both scientists and the local community. Moreover, they accuse Orsak of pursuing his agenda behind their backs, and in a way that obscured how the money was being spent. “We were misled. Maybe it was his idealism, but he should have come to us first for permission,” says Christensen. Orsak left CRI in July (Christensen and Jebb say he was dismissed) and now works for the World Wildlife Fund in Moro, PNG. In September, he was replaced by Keyt Fisher, a Harvard-trained naturalist who had spent several years at CRI. She was recruited, in her words, “to get the place sorted out.” But the problems apparently proved intractable. The final blow, says Christensen, was the auditor's inability to close the books on 1995 and 1996, which made it impossible for organizations like her own to contribute to CRI without jeopardizing their tax-exempt status. “The mismanagement has crippled CRI's ability to receive funds,” she says, “and so closing it was the only option. … Larry didn't realize that he was killing the goose that laid the golden egg.” In November, the board told the 14-person staff, all locals, that CRI would close on 19 December. Orsak, however, believes that CRI's financial situation was a side issue and that a more fundamental problem was the board's reluctance to take on PNG-based members and to grant local leaders a bigger role in managing CRI. Orsak believes the board chose to “pull the plug” to avoid dealing with the matter. “Had CRI been populated by a PNG-majority board, and had CF behaved like any other CRI donor, the organization would have survived,” he says. That analysis makes sense to Alan Allison of the Bishop Museum, part of an NSF-funded team using CRI to study how the habits of plant-feeding tropical insects affect biodiversity. “I think that governance is the source of [CRI's] problems,” says Allison, who helped the Wau Ecological Institute wean itself from the museum in the early 1980s and become a PNG-run organization. Christensen says the foundation will continue to support activities in PNG, and the PNG University of Technology is negotiating with CRI and the managers of a nearby hotel and diving resort to take over some of the institute's research and education functions. But in the meantime, researchers may be on their own. Fisher plans to leave CRI later this month on a fellowship to study tool use among orangutans in Sumatra, and scientists on other CRI-based projects are scrambling to find other locales for their work. The decision to close CRI also may have shut the door on a potential new benefactor. The University of California, Santa Cruz (UCSC), has some two dozen faculty members who have used or would like to use the facility in fields ranging from anthropology to plate tectonics, says Dave Kliger, dean of natural sciences, and the university was interested in meeting that need. Although the school wasn't interested in directly managing the station, Kliger says, it had planned to create an endowment sufficient to support CRI operations and allow CF to play a smaller role. “We were hoping to raise$5 [million] to $10 million,” says Kliger, who was one of two UCSC officials added to the CRI board early last year. The plans are now on hold, he adds. Fenical says there are other countries where he and his students can do similar work. But he's still shaken by the events of the last few months. “It should be clear what an enormous loss this is to science and to PNG,” he says. “It was a unique place and a tremendous asset.” 8. AGRICULTURAL RESEARCH Bill Offers Abundant Harvest for USDA 1. Jocelyn Kaiser Soon after members of Congress return to Washington later this month, they will consider the fate of a proposed$780 million, 5-year fund that could more than double what the U.S. Department of Agriculture (USDA) spends on competitive research grants each year. The proposal, part of a bill approved by the Senate last fall, could infuse dozens of plant and animal science labs with the latest molecular biology techniques and pricey new instruments. The bill is also likely to bring more rigorous peer review to USDA's in-house research programs.

Agricultural research “hasn't had that kind of funding boost in decades,” says Mike Phillips, director of the National Research Council's agriculture board. The House, however, has approved a companion bill that doesn't include the research fund. So agricultural scientists will be watching anxiously to see if it survives in the final version of the bill that is expected to be hammered out in the coming weeks.

Going nowhere.

NRI's budget has never come close to expectations.

View this table:

Like a hot-air balloon with a slight tear, the premier program for funding competitive ag research—the USDA's National Research Initiative (NRI)—has struggled to stay aloft. Since its launch in 1991, the $100-million-a-year initiative has supported everything from biosensors for detecting Salmonella in tainted food to cottonwoods engineered to yield more paper. But because of flat USDA research budgets of late and a tradition in Congress of earmarking ag funds for pet projects, the NRI has never approached the budgetary stratum—$500 million a year—that its congressional founders staked out for it (see table). Miserly funding for competitive research, experts say, is dissuading many young scientists from an agricultural career. Says National Academy of Sciences (NAS) President Bruce Alberts: “There's really no opportunity for their new ideas in the way that there is for biomedicine.”

A kindred spirit on this issue is Senator Richard Lugar (R-IN), who chairs the Agriculture Committee. He argues that a big boost in ag research funding is needed to keep food production apace with a predicted doubling of the world's population in the coming decades. Last summer, Lugar introduced a bill that would overhaul the legal framework for ag research for the first time in 20 years. The bill proposes a research, extension, and education fund for competitive grants amounting to $100 million in 1998, followed by$170 million a year from 1999 to 2002. The bill stipulates that the new program would be endowed mainly by raiding a pot of roughly $1.25 billion a year that states must give back to the federal government for having claimed too much money from the food stamp program. Unlike most other federal accounts, excess food stamp money does not require a separate appropriations law in order to be spent. Rather than beef up NRI's budget, the bill orders USDA to set up an independent program to target a narrower range of projects in areas such as food safety, human nutrition, agricultural biotech, natural resources management, and a National Food Genome Strategy (Science, 15 August 1997, p. 889). The fund would exist separately from NRI because, in part, it's “supposed to be more multidisciplinary” and fund more applied projects than NRI does, says USDA competitive grants administrator Sally Rockey. Although the Senate passed the bill unanimously in October, “a whole series of obstacles has to be overcome” before it becomes law, says Mike Stephens, a consultant for the Federation of American Societies for Experimental Biology (FASEB). The biggest hurdle is persuading the House to go along with the funding provisions. Last November, some House Democrats blocked a conference to hammer out a joint bill in part because they want the extra food stamp cash to get funneled back into welfare programs. The research fund is doubly uncertain, because the food stamp surplus could shrink next month if the Congressional Budget Office revises its estimates for that account. One possible outcome, observers say, is that lawmakers could compromise by agreeing to divvy up the funds between research and welfare. “The science community needs to be doing all it can to support” the bill, says American Society of Plant Physiologists spokesperson Brian Hyps. The House and Senate bills are in agreement on one measure, however: Both order the agency to strengthen its review of department research. For example, the Senate bill calls for program areas in USDA's$700 million Agricultural Research Service to be reviewed at least every 5 years by panels composed mainly of non-ARS scientists. ARS programs already get reviewed, but a law might make the process “a bit more rigorous and a bit more visible to the public,” says ARS associate administrator Ed Knipling. The Senate bill also calls for NAS to review USDA's research and delineate “the role and mission” of federally funded agricultural science.

“We're very supportive” of more peer review in ag research, says John Suttie, a nutritional biochemist at the University of Wisconsin, Madison, who pushed for such changes last year as FASEB president. But Suttie and others are far more excited about the prospect of a windfall for competitive agricultural research. Legislators are expected to lock horns again over the research fund as early as next month.

9. NEURODEGENERATIVE DISEASES

Possible New Cause of Alzheimer's Disease Found

1. Gretchen Vogel

Scientists usually blame errors in protein structure on mistakes in the DNA—the genes that are passed on from one generation to the next and provide the blueprints for proteins. But as any manufacturer knows, mistakes can arise not only in the blueprint, but also on the production line. A team of Dutch scientists reports on page 242 that aging cells seem to be plagued by mistakes in protein assembly, possibly contributing to the brain degeneration characteristic of Alzheimer's disease (AD).

Fred van Leeuwen and his colleagues at the Netherlands Institute for Brain Research in Amsterdam have found a new kind of faulty protein in the abnormal plaques and tangles that are hallmarks of Alzheimer's brain pathology. While 40% of Alzheimer's cases apparently arise from specific gene mutations, there seems to be nothing wrong with the DNA blueprints for these proteins. The scientists theorize that the mistakes arose during protein synthesis—and that such mistakes may help cause Alzheimer's in the majority of patients.

Some researchers caution that the results are preliminary and are based on tests that could be misleading. But others, including Zaven Khachaturian, who is a scientific adviser for the Alzheimer's Association, say that if it is right, the work could help explain why age is the greatest risk factor for developing AD—because the protein errors would presumably increase with time.

And the findings may have even wider importance. Similar mistakes could take place in thousands of proteins, says Rudolph Tanzi of Harvard University, contributing not only to other age-associated diseases, but also to aging in general. If so, he says, the finding would have “profound implications beyond the genes that they're looking at.”

The team first found evidence for such protein-synthesis mistakes more than 10 years ago in an unusual breed of rat, which carries a mutation in a gene that helps regulate urine production. As expected, those rats produced none of the normal protein at birth, but surprisingly, as the animals aged, more and more of the normal protein showed up in their brain cells.

A closer look at both the DNA of the gene and the messenger RNA (mRNA) transcribed from it, which tells the cell to make the corresponding protein, provided an explanation. The scientists found that the mutation itself—a loss of a single base pair that shifts the genetic code by one, totally garbling the instructions for making the protein—was still present. But some of the mRNA had acquired a compensating mistake: In decoding the RNA, the cell had misread a “GAGAG” sequence, shortening it by two bases to “GAG.” Because three bases code for one amino acid—the actual building blocks of proteins—the loss of two more bases restored the proper reading frame and produced a functioning protein.

In subsequent work, the team found evidence for the same type of GA deletions in mRNAs in the brains of normal aging rats and humans. Because GAGAG, the sequence that is prone to being misread, shows up in mRNAs coding for hundreds of different proteins, van Leeuwen and his colleagues decided to search for other proteins affected by frameshift errors. They looked at two proteins involved in Alzheimer's disease: β amyloid precursor protein (βAPP) and ubiquitin. No one knows exactly what the βAPP does normally, but it can be cleaved to produce a smaller protein—β amyloid—that is abundant in Alzheimer's plaques. Ubiquitin is a garbage-disposal protein, marking faulty proteins for degradation and disposal in the cell. It, too, is common in Alzheimer's plaques and also in tangles.

To see if mutant proteins were present in AD brains, the scientists synthesized the theoretical proteins that would result from GA deletions and injected them separately into rabbits, which produced antibodies to the proteins. The scientists then applied the antibodies to brain samples from Alzheimer's patients and people with Down syndrome, who develop early symptoms of AD. The antibodies reacted with their target proteins in almost all the Alzheimer's and Down samples, and in elderly nondemented controls with early signs of plaques and tangles. Samples from young controls showed no reactivity.

The researchers then took a closer look at the proteins stained by the antibodies. In mixtures of proteins from Down and AD patients' brains, the team's antibody stained a 38-kilodalton protein—the size expected of the βAPP mutant, because the frameshift produces an early stop signal that makes the mutant roughly half as big as the normal protein. In addition, analysis of mRNAs turned up examples of GA deletions in all of the AD and Down syndrome patients studied.

The scientists speculate that as cells age, the protein assembly line becomes more error-prone, causing mutated proteins to build up and somehow damage cells. For example, the loss of normal ubiquitin could allow the cell to choke on faulty or unneeded proteins. “It's like when the garbage can is not emptied,” says van Leeuwen. “It causes big problems for the cell.”

How a shortened βAPP could contribute to the disease is harder to explain. Indeed, a shortened protein might even interfere with a mechanism most Alzheimer's researchers favor: They believe that abnormal cleavage of βAPP produces a longer than normal form of β amyloid, which tends to form toxic deposits that eventually kill brain cells. But the shortened version of βAPP might not be able to produce β amyloid at all, says John Hardy of the Mayo Clinic in Jacksonville, Florida.

Indeed, Hardy isn't convinced that altered βAPP and ubiquitin are present in diseased brains. The brain cells affected by Alzheimer's are so damaged, he says, that the antibodies could be staining many things besides the mutant βAPP and ubiquitin. And even if the mutant proteins are present, he says, “they are much more likely to be an effect than a cause” of AD brain damage. While van Leeuwen concedes that it's unclear how the GA deletion in βAPP might lead to AD, he says there are several possibilities. For example, the mutant protein might disrupt the processing of the normal protein so that it produces the longer form of β amyloid.

The current evidence is already enough to intrigue Khachaturian. The work “puts [AD] in a different frame of reference.” he says, and provides a plausible connection between AD and aging. Caleb Finch of the University of Southern California in Los Angeles adds that he, for one, will pay close attention to errors in protein synthesis. The finding raises “many perplexing mysteries,” he says, “but their resolution will be the basis for a whole new set of hypotheses” about how the disease causes its devastation.

10. PLANETARY SCIENCE

Pathfinder Tells a Geologic Tale With One Starring Role

1. Richard A. Kerr

SAN FRANCISCO—From the moment Mars Pathfinder bounced to a stop on the rolling, rock-littered surface of Mars, the lander and its wheeled companion, Sojourner, wowed scientists with their maneuvers—and with the torrent of data they sent back to Earth. The deluge continued for almost 3 months and delivered 3 gigabits' worth of data, including 16,000 images and 20 chemical analyses, before the craft finally fell silent in early October. Now, team geologists have had time to weave this wealth of information into a single story about the patch of martian surface that Pathfinder explored, and they have found that the landing site was not what they had expected.

Pathfinder researchers had hoped that the landing site would reveal a grab bag of different rock types deposited by great ancient floods, and initial results supported that idea. But, at the fall meeting of the American Geophysical Union here last month, many Pathfinder researchers suggested that a single rock type lies behind the varied shapes, colors, and textures that Pathfinder observed. The same volcanic rock acquired diverse guises by being tumbled in flood waters, shattered by a nearby impact, gouged by the wind, and coated by varying amounts of martian dust, these researchers argued.

“That is not what we expected in selecting this landing site,” says team member Harry McSween of the University of Tennessee, Knoxville. But the identification of a single rock type may allow geologists to understand the history of an alien landscape in unprecedented detail—an exercise essential to future Mars missions designed to return martian rocks to Earth.

The growing evidence that Barnacle Bill, Yogi, Bamm-Bamm, and the rest of the gang are chips off the same rock comes from both Sojourner's direct measurements of the rocks' compositions and the lander's imager, which recorded subtle color variations in the rocks. At the meeting, team members Thanasis Economou of the University of Chicago, Heinrich Wänke of the Max Planck Institute for Chemistry in Mainz, Germany, and their Pathfinder colleagues reported that the Sojourner rover did indeed measure a range of compositions when it set its alpha proton x-ray spectrometer against the surface of five different rocks. But many of the measurements showed high levels of the element sulfur—much more than any crystalline rock could incorporate into its structure. Separate measurements showed that the reddish soil at the site is enriched in sulfur, too. When the amount of sulfur in the rocks is taken as a measure of the amount of dust on their surfaces, the compositions of all five rocks converge. “I don't believe there are different types of rocks at the landing site,” said Wanke. “All … are almost identical in composition, but what varies is the dust cover.”

Pathfinder team members studying rocks through the lander's camera see the same underlying uniformity. Judging by brightness and subtle differences in “redness,” Scott Murchie of the Applied Physics Laboratory in Laurel, Maryland, and his Pathfinder colleagues divided surface rocks into two classes: darker, less red rocks such as Barnacle Bill, which tend to be smaller and more angular, and brighter, redder ones like Yogi, which are larger and more rounded. The color variations mimic the palette seen in dark rocks dusted in the laboratory with varying amounts of a bright red powder of oxidized iron, says Murchie. And the side of at least one very red rock scoured by wind-driven sand appears darker and less red, he says. All this suggests that the redness is only a coating. “I think we can explain most of the elemental and spectral variations as just due to varying amounts of dust on the rock,” says Murchie. The “rusty,” sulfur-laden dust seems ubiquitous on the martian surface, but where it came from is still a mystery.

To explain how a single rock type could look so varied, Daniel Britt of the University of Arizona in Tucson and his lander imaging team colleagues have spun a tentative geologic tale. In this scenario, all the rocks originated in a single layer of volcanic bedrock hundreds of meters thick. At the landing site, the bedrock may lie tens of meters below flood debris. The catastrophic floods that swept the region from the south a billion years ago or more may have picked up chunks of this volcanic bedrock from areas tens of kilometers away and quickly dropped them at the site. These flood-borne rocks are large, rounded, and red, as expected of rock tumbled short distances in floods and then left exposed to the elements—including dust—for perhaps half the age of the solar system.

The same volcanic rock could also have reached the surface of the landing site by another route, giving it a very different appearance. Just 2.2 kilometers away lies Big Crater, a 1.5-kilometer scar left by an impact that would have flung out chunks of bedrock. Those chunks could explain the smaller and more angular rocks at the site. Because these rocks were ejected long after the last of the floods, their dust coats are thinner and they look darker. Adding to the site's diversity, winds have abraded some rocks and, in certain places, exposed a few centimeters of “rock” made of soil solidified by a sort of chemical cement, said Britt.

Not everyone on the Pathfinder science team is inclined toward the one-rock story. The rover team's Henry Moore of the U. S. Geological Survey in Menlo Park, California, has noted loose pebbles and rocks pocked by small holes, presumably left when pebbles fell out. To him, these rocks look like conglomerates, sedimentary amalgamations of sand and pebbles from many different sources (Science, 17 October 1997, p. 380). “I think you can make a fair case for [such] a variety of rocks,” agrees Pathfinder project scientist Matthew Golombek of the Jet Propulsion Laboratory in Pasadena, California. But Britt isn't convinced. “I'm a rock guy,” he says. “I look at a lot of [terrestrial] rocks. Every Pathfinder picture I've seen looks like either a fresh [volcanic] rock or a weathered [volcanic] rock. I have yet to see anything that looks like a sedimentary rock.”

“The bottom line,” says Golombek, “is that we have very crude tools to analyze these rocks.” Help is on the way, although it won't arrive anytime soon. In April 2001, NASA plans to launch the Mars Surveyor 2001 Lander-Rover Mission, which will deliver a bevy of remote-sensing instruments designed to see through the dust layers, as well as a rover-mounted drill to bore 5 centimeters into rocks and extract a core for possible later return to Earth. Promises Steven Squyres of Cornell University, who is leading the 2001 instrumentation effort: “By hook or by crook, we're going to get down below this stuff.”

11. CELL BIOLOGY

Structure of Key Cytoskeletal Protein Tubulin Revealed

1. Elizabeth Pennisi

Five years ago, Kenneth Downing and Eva Nogales set out to accomplish with an electron microscope what x-ray crystallographers had tried and failed to achieve for decades: solving the three-dimensional (3D) structure of the protein tubulin. Few people gave them much chance of succeeding with the tedious technique, called electron crystallography, that they brought to bear on this elusive molecule.

But at last month's annual meeting of the American Society for Cell Biology in Washington, D.C., Downing and Nogales, biophysicists from the Lawrence Berkeley National Laboratory in Berkeley, California, announced that their long pursuit has paid off. They dazzled their audience with the first detailed view of tubulin: a map of the protein's structure down to 3.7 angstroms, sufficient to see the precise arrangement of its amino acids.

Cell biologists had been waiting eagerly to get a good look at tubulin because it is the building block of one of the major components of the cell's internal skeleton—the microtubules. These structures play key roles in many cell functions: They shuttle proteins and other molecules through the cell, for example, and form the mitotic spindle that pulls the chromosomes to the two daughters when cells divide. Yet, despite years of biochemical and biophysical studies, researchers do not yet fully understand such critical aspects of microtubule function as how their tubulin subunits assemble and disassemble—information also needed to help understand how cell division is controlled.

The new structure, which the Berkeley Lab team also describes in the 8 January issue of Nature, should help resolve those issues, cell biologists say, because it reveals how the two subunits that make up tubulin interact with each other and with other molecules. Indeed, Harold Erickson, a cell biologist at Duke University in Durham, North Carolina, describes the structure as “a huge milestone in the cytoskeleton field.”

And it's not the only one: In a second paper in this week's Nature, Jan Löwe and Linda Amos at the Medical Research Council's lab in Cambridge, United Kingdom, report on the atomic structure of a bacterial protein called FtsZ that appears to be tubulin's ancestor. Its structure, “to an inexperienced eye, is indistinguishable” from tubulin's, says molecular biologist Löwe. This indicates, says Downing, “that bacteria have an evolutionary precursor of tubulin.”

The discoveries could also lead to biomedical advances, such as new cancer drugs and antibiotics that disrupt cell division by targeting the microtubules or FtsZ. For example, the anticancer drug taxol works by stabilizing microtubules, and now drug companies should have an easier time trying to improve it. “It's the first view of what amino acids [taxol] interacts with,” says Ted Salmon, a cell biologist at the University of North Carolina, Chapel Hill. “The work is seminal.”

Previous efforts to determine the 3D structure of tubulin by x-ray crystallography failed because researchers simply couldn't grow tubulin crystals of sufficiently good quality. So, Downing and Nogales turned to electron crystallography, a technique that researchers have only recently adapted for solving high-resolution structures. “It was their conviction, courage, and willingness to try a whole host of approaches that made it work,” says Erickson. “It wasn't obvious even 2 years ago that it was going to.”

First, Nogales explains, she and Downing had to work out procedures for growing and preserving large tubulin sheets one molecule thick. They mixed tubulin's two component proteins—called α-tubulin and β-tubulin—and then caused the sheet to form, adding taxol to stabilize it.

To avoid damaging the sample, the researchers used an extremely dim electron beam and recorded the diffraction patterns as the electrons scattered off the target. Special computer averaging techniques were needed to get rid of the noise that arises from using such a dim beam and to discern the repetitive patterns of electron density. To get a 3D perspective, the team tilted the specimen and repeated the process from many different angles. A set of computer programs then compiled all these data into the final structure.

But while electron crystallography is challenging, the approach has its advantages. The tubulin is imaged the way it exists in the cell—as part of a polymer. That would not have been the case had a crystal of isolated tubulin molecules been examined. “We have extra information that could not have been gained by x-ray crystallography,” says Nogales. They now know, for example, which amino acids link tubulins into thin strands called protofilaments, as well as which allow protofilaments to bundle together to form the final microtubules.

The structure also explains a long-confusing observation about the two tubulin subunits. Both α- and β-tubulin have binding sites for the high-energy molecule GTP, whose breakdown into GDP helps microtubules grow and shrink. But only the GTP in β-tubulin undergoes that breakdown. Downing and Nogales found that's because β-tubulin masks the GTP-binding site on α-tubulin, preventing access of water, the other molecule needed for the GTP reaction.

This new view of tubulin should give cell biologists plenty of such insights into how tubulin works. Together with the structure of the bacterial protein FtsZ, it should also provide clues to the molecule's evolutionary role. Cell biologists long wanted a better look at FtsZ's structure because its amino acid sequence, although different from that of tubulin, had enough of a resemblance that many thought the proteins might be related. Moreover, like tubulin, FtsZ also plays a role in cell division; it helps dividing bacterial cells pinch in two. But x-ray crystallographers had trouble making good crystals that could be resolved at the atomic level.

Amos and Löwe succeeded, partly because they used the FtsZ gene from Methanococcus jannaschii, a microbe that lives in deep-sea hot vents. When they made the protein by cloning the gene in the bacterium Escherichia coli, they found they could get good crystals but had trouble getting enough FtsZ to work with because the bacteria degraded the protein rapidly. By heating up the E. coli, Löwe and Amos caused the enzymes that degrade FtsZ to break down, while the FtsZ, which had evolved to tolerate heat, remained stable. As a result, they could produce crystals in sufficient quantity for x-ray studies and have now solved the protein's structure to a resolution of 2.8 angstroms. This revealed that FtsZ, which is just a single protein, looks most like β-tubulin, especially in the GTP-binding region. In both cases, the nucleotide binds to the tip of the proteins, rather than deep within an interior fold as in most other GTP-binding proteins.

Other aspects of the two proteins' structures are also similar, even though their amino acid sequences show only minimal homology. But there is one notable difference: FtsZ lacks two helices found on one end of tubulin. These helices make up the outer surface of the microtubule; there they could provide points of contact for a range of other molecules, such as the motor proteins that transport molecules along the microtubules. “My guess is that [the helices] have been added so that the special motor proteins could interact [with the microtubule],” says Amos.

With both structures in hand, Löwe hopes to be able to apply what's known about the polymerization of tubulin to learn about polymerization by FtsZ, which is much less well understood. “We can try to predict what the FtsZ polymer would look like,” he explains. That should lead to a better understanding of the exact role FtsZ plays in bacterial cell division.

Other researchers will use the structures to make sense of work they have already done on microtubule structure and function. They want to know, for example, what causes microtubules to grow in certain directions and how transport along them can be unidirectional. “An awful lot of people have been working on tubulin for 20 years,” Downing points out. “This really provides the framework for understanding their results.”

12. CELL BIOLOGY

Immortality Gene Discovered

1. David Ehrenstein

For cells, aging and cancer are often opposite sides of a genetic coin: With “heads,” cells will eventually stop dividing, reaching a permanently quiescent stage called senescence, as do normal human cells in lab cultures. With “tails,” the cells with genetic defects can become immortal and never stop dividing—a common characteristic of cultured cancer cells. Now, a group at Baylor College of Medicine in Houston has found a gene that may help determine which side the coin lands on.

Last month, at the annual meeting of the American Society for Cell Biology,* Michael Bertram reported that his group at Baylor, led by Olivia Pereira-Smith and James Smith, had cloned a gene that, when mutated, helps make some types of cells immortal. Although researchers have identified many genes in which mutations lead to loss of normal growth control, at least for a number of generations, this is the first one specifically linked to immortality. The finding “is going to give us insights into the whole process of [cellular] immortality,” predicts Harvey Ozer, a molecular and cell biologist at the New Jersey Medical School in Newark.

The Baylor team doesn't know exactly how the new gene works. But the structure of the gene, called MORF4 (for MORtality Factor from chromosome 4), suggests that it makes a transcription factor, a protein that controls the activity of other genes. The hope is that it will be possible to track down those genes, shedding light on both the cellular causes of immortality and its opposite number, senescence and aging. In addition, the work could also help provide a better understanding of cancer, because MORF4 may act as a tumor-suppressor gene—one whose loss or inactivation contributes to cancer development.

The discovery of MORF4 is an outgrowth of previous work, in which the Baylor group and others showed that mutations in any one of four different sets of genes can cause cultured cells to become immortal. They did this by fusing various kinds of immortal cells with either normal senescent cells or with one another. These experiments showed that the gene defects causing immortality are recessive: They could be corrected by the presence of the normal gene. The researchers also found that all of the 40 lines of immortal cells they examined fell into four distinct groups, each apparently having different gene mutations, because the hybrids between members of different groups showed normal senescence.

By fusing immortal cells with “microcells” containing only single chromosomes, the Baylor team and others identified chromosomes carrying the mutations, but the amount of DNA on each chromosome stymied their efforts to identify the genes themselves. They succeeded in identifying only MORF4—one of perhaps a number of genes responsible for immortality in the group designated B, which includes brain and cervical cancer cells—through “pure serendipity,” Pereira-Smith says.

Two years ago, when a graduate student tried to introduce chromosome 4 into a cell line for unrelated experiments, only a small piece of it was properly incorporated. “Just for the heck of it,” recalls Pereira-Smith, the student decided to check if that small piece contained the critical senescence gene. To the group's surprise, putting the DNA chunk into group B cells made them senescent, an indication that the segment carried the normal version of a gene whose mutation was critical to those cells' immortality.

The Baylor team found that the piece contained five genes. Of these, only one—MORF4—caused group B cells to become senescent, while having no effect on other immortal cells. They also found that the gene was up-regulated in senescent and quiescent cells, but down-regulated in actively dividing cells. The researchers still do not know exactly what MORF4 does, although they suspect it encodes a transcription factor, because its protein product contains two “motifs”—a helix-loop-helix and leucine zipper—found in known transcription factors.

The Baylor team now hopes to find the genes this protein might regulate and to understand their functions. That might put them on the way to learning how cells can live forever—and how normal cells age.

• *The meeting was held in Washington, D.C., from 13 to 17 December 1997.