News this Week

Science  15 Mar 2002:
Vol. 295, Issue 5562, pp. 1988
  1. APPOINTMENT PENDING

    Zerhouni Seems Headed for NIH, and New Scrap Over Stem Cells

    1. Eliot Marshall

    A Baltimore radiologist with an entrepreneurial bent is expected to be named the next director of the U.S. National Institutes of Health (NIH).

    The Washington rumor mill was humming last week with reports that Elias Zerhouni of Johns Hopkins University School of Medicine was in line for the nomination, and although government officials declined to comment publicly as this issue of Science went to press, leaders of the U.S. biomedical establishment were taking it as a fait accompli. Former NIH institute chiefs are already showering Zerhouni with friendly comments and expressing their delight that a delay of more than 2 years in filling the top NIH job may soon be over. However, media reports on the expected nomination also pointed to a potential cloud on the horizon: Zerhouni's stance on the politically charged issue of using human embryonic stem cells in research.

    “He's one of these rare triple-threat people, a good researcher, a good clinician, and an incredibly well- organized business leader,” says his boss and radiology colleague, Hopkins president William Brody. At the same time, Brody dismisses speculation in The Washington Post and elsewhere that Zerhouni had “assured leading social conservatives” that he would not expand the use of human embryonic stem cells in research. That's “absolutely ludicrous,” says Brody, noting that Zerhouni helped create and run a new $58 million institute at Hopkins dedicated to stem cell research. “He wouldn't sell out for things he doesn't believe in.” (Zerhouni could not be reached for comment; nominees for government posts rarely speak to the press before the U.S. Senate completes the confirmation process.)

    Almost home.

    Johns Hopkins's Elias Zerhouni could soon be head of Bethesda-based NIH.

    CREDIT: JOHNS HOPKINS UNIVERSITY GAZETTE

    Zerhouni, a 50-year-old U.S. citizen, has spent virtually his entire medical career at Hopkins. Algerian by birth and a graduate of the University of Algiers Medical School, Zerhouni came to the United States in 1975 for his medical residency. In 1981 he became an assistant professor in the medical school. After a brief foray to Eastern Virginia Medical School in Norfolk, Zerhouni returned to Hopkins in 1985 as an associate professor, rising to full professor several years later. In 1996 he succeeded Brody as chair of radiology when Brody became Hopkins president. Since 1997 Zerhouni has also served as Hopkins's vice dean for research, guiding several new ventures, including a Hopkins-backed spin-off called Surgi-Vision Inc. in Gaithersburg, Maryland. This private company is developing ideas and patents co-authored by Zerhouni to market magnetic resonance imaging (MRI) sensors small enough to fit inside blood vessels (see sidebar).

    Colleagues in radiology praise Zerhouni for his intellect and originality, although his research is not widely known outside his field. Brody, who was developing a new MRI machine in Palo Alto, California, before coming to Hopkins, was in California trying to interest people in his new MRI system when he first met Zerhouni. At that time, Brody notes, “people were writing articles about how [the system] wouldn't work.” Zerhouni came to evaluate it for Hopkins, and, according to Brody, he concluded that the idea would succeed.

    Brody says that Zerhouni may be best known for pioneering noninvasive methods of analyzing the movements of the heart by electrically “tagging” the muscle wall with superimposed magnetic lines and tracking the motions with MRI. Magnetic tagging has enabled physiologists to analyze and compare living healthy and diseased hearts in three dimensions, without surgery. Noninvasive imaging of this sort, says James Thrall, chair of radiology at Massachusetts General Hospital in Boston, has become the “guiding hand of medicine” in the last decade. Thrall also credits Zerhouni for helping support radiologists' efforts to gain a stronger presence on the NIH campus through creation of the National Institute of Biomedical Imaging and Bioengineering. Congress approved it in 2000, despite opposition from former NIH chief Harold Varmus.

    Zerhouni's résumé lists him as “consulting” adviser to the White House during the Reagan Administration, and he currently serves on the scientific advisory board of the National Cancer Institute (NCI). Co-panelist Herbert Kressel, a radiologist and president of Harvard University's Beth Israel Deaconess Medical Center in Boston, calls Zerhouni “one of those people who can see the entire playing field and all the relationships on it.” Zerhouni is “personable,” Kressel says, but he has never discussed politics or mentioned his views on embryo research.

    Former NCI director Richard Klausner, who recruited Zerhouni for advice on tumor imaging, calls him “a clear thinker. … [Zerhouni] is particularly interested in technology,” Klausner adds, but he's also “very supportive of science and the culture of science” despite lacking experience as a basic bench scientist. Varmus, now president of the Memorial Sloan-Kettering Cancer Center in New York City, is also upbeat about Zerhouni's talents. He was “smart, insightful, and knowledgeable” about deploying the center's resources during a review of its radiology program, Varmus says: “I hadn't heard of him 3 years ago, but I have a lot of respect for him.”

    Despite the praise, Zerhouni could run into some flak in Senate confirmation hearings. Questioners will be poised to ask if, as reported, he passed a political “litmus test” on stem cell policy that other candidates flunked. For example, one knowledgeable NIH insider says news reports are essentially correct that another leading candidate, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, failed to promise to restrict research on human embryonic stem cells.

    The idea of measuring an NIH nominee's politics is distasteful to many basic scientists, who worry that such screening could weaken NIH's stature as the government's biomedical crown jewel. “If someone as thoughtful and careful and balanced as Tony Fauci was unacceptable,” says Steven Hyman, provost of Harvard University and former mental health chief at NIH, “that really does raise some questions.”

  2. APPOINTMENT PENDING

    A Spin-Off With Vision

    1. Eliot Marshall

    To understand how Elias Zerhouni makes things happen, colleagues say, look at a company he started 4 years ago. Zerhouni and six others founded the outfit, called Surgi-Vision Inc., now based in Gaithersburg, Maryland, with patents licensed from Johns Hopkins University. Their goal was nothing less than to revolutionize the way magnetic resonance images are produced and used, says Nancy Taylor, Surgi-Vision's CEO. Rather than put the patient inside a bulky scanner that captures images from the outside, Zerhouni and colleagues devised a magnetic resonance imaging (MRI) sensor small enough to go inside the gut, heart, or even blood vessels and collect high-resolution data. The resulting cross-sectional images, the inventors reasoned, should be as sharp as x-rays—and wouldn't require ionizing radiation.

    Inside view.

    Minisensors gather MRI imagery from within the body.

    CREDIT: SURGI-VISION

    “It was [Zerhouni's] vision” that got the project moving, says Taylor. Zerhouni recruited outside talent, including Paul Bottomley, a former General Electric MRI biomedical engineer and M.D., and electrical engineer Ergin Atalar, now both at Johns Hopkins School of Medicine. Zerhouni “came up with the ideas, and I made them work,” says Atalar. Zerhouni also chaired a small committee that solicited patentable ideas from faculty members and passed the more promising ones to Hopkins's intellectual property office, says Bottomley, adding that Zerhouni was the “driving force” on investor “road shows” and helped raise more than $15 million in outside money.

    Surgi-Vision has gotten off to a promising start. The privately held company has formed a distribution partnership with General Electric and won approval from the Food and Drug Administration to begin marketing three types of internal MRI imagers. Zerhouni is on Surgi-Vision's scientific board, says Taylor, declining to comment on his financial stake in the company.

  3. STEM CELL RESEARCH

    Studies Cast Doubt on Plasticity of Adult Cells

    1. Gretchen Vogel

    Opponents of research on human embryos have raised a politically powerful argument against work involving embryonic stem (ES) cells: Such research can be avoided because adult stem cells may offer similar promise. Defying scientific dogma, numerous reports have suggested that adult stem cells can morph into many types of cells, raising hopes that adult cells could eventually be used to treat diseases—without the ethical baggage that accompanies ES cells.

    Now two papers in this week's early online publication of Nature suggest that some of the surprising plasticity of adult stem cells might be explained by simple cell fusion, not “reprogramming.” The new evidence does not explain away all of the potential of adult stem cells, but it does raise a caution.

    For years, researchers have assumed that development is a one-way street: A cell that starts down the path to become a neuron, for instance, can become only a brain cell. But studies in the past few years have suggested that cells might indeed be coaxed to turn back and take another path. Nearly a dozen teams have reported that cells from one tissue—blood, muscle, or brain, for example—could, when exposed to the right environment, contribute to an entirely different tissue (Science, 8 June 2001, p. 1820).

    Although politicians have trumpeted the results, many developmental biologists have been skeptical. In the new papers, two groups, working independently, provide evidence for one alternative explanation. Both report that cells from adult tissues can fuse with ES cells in culture, producing a hybrid that looks like a reprogrammed adult cell but has the pluripotent characteristics of the embryonic cell. The hybrid cells also show chromosomal abnormalities, suggesting that they might not be a reliable source of healthy replacement tissue after all.

    More than enough.

    Cells that appear to have been “reprogrammed” have enlarged nuclei (top) and twice the normal number of chromosomes (bottom), suggesting that two cells fused together.

    CREDITS: Q.-L. YING ET AL., NATURE ADVANCE ONLINE PUBLICATION, 13 MARCH 2002 (DOI10.1038/NATURE729)

    Cell biologist Naohiro Terada of the University of Florida College of Medicine in Gainesville and his colleagues were eager to coax adult cells to “dedifferentiate” into cells with unlimited potential. Other work had suggested that some factor produced by ES cells might kick-start the process. To test that idea, Terada, Edward Scott, and other colleagues cultured adult cells from mouse bone marrow tagged with green fluorescent protein together with ES cells that did not carry the marker. The researchers soon found evidence for green cells that behaved like ES cells. But when they looked more closely, they found that all the “dedifferentiated” cells had twice as many chromosomes as usual: They were the product of fusion between two cells. Terada doesn't think that fusion explains all the other reprogramming results. “We're not denying any of those data. We're just saying, 'Be careful'” about possible explanations for unexpected results.

    Developmental geneticist Austin Smith of the University of Edinburgh, U.K., says he and the team “approached the issue with open but skeptical minds.” “All our other data said cells do become lineage restricted”—unable to form new kinds of tissues—as they progress toward becoming a certain cell type. He and his colleagues grew cells from adult mouse brains in a culture that also contained mouse ES cells. They then selected for cells that expressed Oct4 (a protein characteristic of undifferentiated ES cells) and also carried a gene present only in the brain cells. The team recovered more than two dozen cell colonies that seemed to have been reprogrammed. But on closer inspection, the cells had enlarged nuclei and twice as many chromosomes as normal: signs of hybrid cells, not reprogrammed ones.

    Several of the original researchers are not dissuaded. “What they're saying is, 'Hey, fusion happens,'” says Diane Krause of Yale University, who has reported that cells from bone marrow can become a variety of tissues when injected into adult mice. Her lab is now checking whether its apparently reprogrammed cells formed from fusion of donor and recipient cells. Jonas Frisén, whose lab reported that brain cells can become a variety of tissues when injected into embryos, is also checking for evidence of hybrid cells, but he does not believe that cell fusion can explain all of their results.

    The new papers come on the heels of two others that have cast doubt on the reported malleability of adult cells. In the March issue of Nature Medicine, Derek van Der Kooy, Cindi Morshead, and their colleagues at the University of Toronto report that they could not replicate earlier reports that cells from adult brain could become blood cells (Science, 22 January 1999, pp. 471 and 534). Instead, they report, cells kept in culture for many generations—as occurred in the original research—tend to accumulate genetic alterations that might lead to an apparent reprogramming.

    And in February, Margaret Goodell of Baylor College of Medicine in Houston clarified one of her earlier reports on cells from adult mouse muscle. As she explained in the Proceedings of the National Academy of Sciences, the adult cells that seemed to give rise to blood cells were in fact rare blood stem cells that reside in the muscle.

    The new results are a needed reminder for the field to stay vigilant, says van Der Kooy. “Our own data fail to replicate transdifferentiation, but there are so many reports out there. I'm still unwilling to believe all of them are false.”

  4. GRADUATE TRAINING

    South Korea Scrambles to Fill Ph.D. Slots

    1. Mark Russell*
    1. Mark Russell writes from Seoul, South Korea.

    SEOUL—Jae-Gwang Won is a member of an increasingly rare breed: a Korean graduate student working on a homegrown science Ph.D. This month Seoul National University (SNU), long considered the country's most prestigious university, failed to fill its quota of graduate slots for the new semester. More embarrassing still, SNU would have fallen short even if it had accepted every applicant.

    Korea's postwar economic boom in the 1960s and 1970s certainly benefited from the belief that technical know-how was essential for a rising standard of living. Although many of those scientists were trained abroad, the strategy paid off: By 1995, for example, Korea's economy was the 11th largest in the world, and the country was second behind the United Kingdom in the percentage of its college-age population with technical degrees. “It was a good time for science in Korea,” says Sung H. Park, SNU's dean of natural sciences, and there were plenty of good jobs.

    Faith in technology as an economic driver hasn't disappeared, but it's being undermined by several factors. One is a loss in status. “When I was in high school, science was prestigious,” says 53-year-old Yoon Soon-chang, an SNU professor of atmospheric science and associate dean of planning. “Being a scientist meant being proud.” But today's students are more interested in careers that pay well, Yoon says.

    The country's rising standard of living is another part of the changing equation. From the 1950s to the 1970s, only the smartest students could study abroad by qualifying for scholarships, says Jung H. Shin, an associate professor of physics at the Korea Advanced Institute of Science and Technology (KAIST) in Taejon. With greater wealth, however, a growing number of less exceptional students are able to study abroad by paying their own way.

    Minority view.

    Jae-Gwang Won, seated, with SNU dean Yoon Soon-chang, is part of a dwindling pool of grad students.

    CREDIT: SEOUL NATIONAL UNIVERSITY

    A third important factor is what Yoon and most Koreans simply call “the IMF era.” That's shorthand for the financial restrictions imposed on the country by the International Monetary Fund after the economic crisis of 1997-98. Before the crisis, Korea's chaebol, or business conglomerates, hired large numbers of Ph.D. candidates, often after their third year. But many researchers lost their jobs as their companies shrunk or went bankrupt, and few new slots have opened up. The downturn has contributed to a plunge in the proportion of high school students who say they plan to study science or engineering, from 50% in 1997 to 26% last year.

    At SNU, a combination of those factors resulted in only 800 students applying this year for the university's 884 Ph.D. slots in the sciences. (The size of graduate programs is set by the government.) Some 632 were accepted—an enviable outcome for students, perhaps, but one not conducive to maintaining high standards. Many of these students may not go the distance, some scientists suspect, and others may be driven by forces other than a love of learning. “To be honest,” says the 30-year-old Won, who is close to completing his Ph.D. in earth and environmental sciences, “about one-third of my decision to go to graduate school was because it exempted me from mandatory military service.”

    SNU is not the only science institution feeling the pinch. At Pohang University of Science and Technology, the proportion of undergraduates who plan graduate studies in science had dropped in the past 2 years from 79% to 61%. And last year at KAIST, says H. W. Lee, dean of academic affairs, “the chemical engineering program had no preliminary Ph.D. applications” from undergraduates, forcing professors to beat the bushes for a few worthy students. At the same time, Lee hastens to add, “our electrical engineering and computer science programs are doing extremely well,” because Korea's computer industry has weathered the latest economic storm and is once again growing strongly.

    But government officials aren't content to leave the country's technological future in the hands of market forces. In 1999 the government launched the Brain Korea 21 (BK21) program, which provides generous stipends for graduate students in addition to supporting their research and providing a travel allowance. “BK21 has really helped,” says Won, noting that it allowed him to spend 6 months at U.S. and Japanese universities and attend several meetings. The overseas trips were an eye opener, he says: “When I was in America, I was surprised and happy to discover my education was at the same level.”

    But although Won looks forward to a research career in either the United States or Korea, he's part of an apparently shrinking minority. A recent survey of Korean junior high school students found that only 20% plan to study science or engineering in college; even at the country's elite science high schools, the figure is only 60%. Those numbers suggest a tough road for SNU and other universities promoting the value of graduate training in science.

  5. SUPERCONDUCTIVITY

    New Observations Give Stripes Theory a Lift

    1. Adrian Cho*
    1. Adrian Cho is a freelance writer in Boone, North Carolina.

    If three sightings make a trend, then a controversial theory of high-temperature superconductivity may have become a little more chic. The “stripes” theory states that current flows without resistance along lines of electric charge inside copper-and-oxygen-based superconductors. Such charge stripes had been spotted in only one superconducting material until two groups reported this month seeing them in two other superconductors, and a third group offered evidence that stripes do indeed conduct electricity.

    The new data indicate that stripes are a common feature of all so-called cuprate superconductors, says Steven Kivelson, a physicist at the University of California, Los Angeles, and a co-inventor of the stripes theory: “This means that this phenomenon is widespread. The evidence is crisp and clear.” But others stress that the link between stripes and superconductivity remains murky, and some researchers think the new data reveal some more complicated pattern of charge.

    For 15 years physicists have struggled to understand the cuprate superconductors. The materials consist of parallel planes of copper and oxygen atoms, with atoms of elements such as lanthanum, barium, and strontium sandwiched between the sheets. Sometimes an atom that is between planes will pluck an electron from a copper atom, leaving behind a positively charged “hole” that can move from copper atom to copper atom. Holes pair to glide along the planes without losing energy, but it's not clear how the like-charged holes manage to embrace one another.

    Easy street.

    According to the stripes theory, holes fall into long lines along which they pair and move without resistance.

    CREDIT: C. SLAYDEN

    The stripes theory provides a controversial explanation (Science, 19 February 1999, p. 1106). An isolated hole meets stiff resistance when it tries to hop from one copper atom to the next because the magnetic fields of neighboring copper atoms naturally point in opposite directions to create an up-down-up-down pattern. When an isolated hole moves, it disrupts this pattern, and that costs energy. To avoid the energy penalty, the stripes theory posits, the holes gather into stripes, which serve as little runways with no magnetism. Once in a stripe, holes can lower their energy even more by pairing.

    Unfortunately for proponents of this theory, only one superconductor, lanthanum strontium copper oxide (LSCO), showed such activity. Now, three different groups are reporting similar results.

    Herb Mook and colleagues at Oak Ridge National Laboratory in Tennessee have used a beam of neutrons to study the structure of a jumbo 25-gram crystal of yttrium barium copper oxide (YBCO), the most widely studied of the cuprate superconductors (Science, 1 February, p. 787). By carefully monitoring the reflected beam as the crystal rotates, the researchers detected stripes of holes lying along every eighth row of copper atoms, as they reported in the 4 March issue of Physical Review Letters. Meanwhile, Aharon Kapitulnik and colleagues at Stanford University in Palo Alto, California, used a tiny fingerlike probe known as a scanning tunneling microscope to study the surface of a crystal of bismuth strontium calcium copper oxide (BSCCO). They observed stripes of charge along every fourth row of copper atoms, as they report in a paper posted on the Los Alamos preprint server (arxiv.org).

    Also, Yoichi Ando and colleagues at the Central Research Institute of the Electric Power Industry in Tokyo report that in nonsuperconducting LSCO and YBCO, the electrical resistance is smaller for current flowing in the direction in which the stripes are thought to run. That indicates the stripes are conductive, they argue in a paper to be published in Physical Review Letters.

    Any theory that explains superconductivity in the cuprates must now account for their stripes, Kivelson says. But the larger question, says Douglas Scalapino, a theorist at the University of California, Santa Barbara, is whether stripes help superconductivity or—as most researchers believe—hinder it: “Do you really need these stripes? Or are the stripes something that compete with superconductivity?"

    On the other hand, Shoucheng Zhang, a theorist at Stanford, argues that the pattern of charge in BSCCO looks more like a checkerboard than stripes. One-dimensional stripes may be a special case of a more general two-dimensional “charge ordering,” Zhang says. If he's right, then next year's fashionable theories may exchange stripes for plaids.

  6. INDIA

    Academic Science Gets Big Boost in Budget

    1. Pallava Bagla

    NEW DELHI—Indian university researchers are cheering the government's new science budget, which includes a doubling of funding for academic infrastructure. The overall $300 million increase, to $1.5 billion, brings the R&D budget close to 1% of the country's gross domestic product; Prime Minister A. B. Vajpayee has pledged to raise it to industrial-world levels of 2%. Scientists are also heartened that the 25% growth in civilian science will keep pace with increases for atomic energy, space, and defense, which have historically received the lion's share of the country's research dollars.

    “It's a very welcome sign,” says Martanda Varma Sankaran Valiathan, a cardiac surgeon and president of the Indian National Science Academy. “And it was long overdue.”

    The budget, presented in Parliament on 28 February, awards a 52% increase to the Department of Science and Technology (DST). Within its $152 million allocation, the department plans to double the $10 million Fund for Improvement of Science and Technology, created in 2000-01 to augment laboratory instrumentation and facilities in universities. The fund is being extended to cover school libraries, including electronic databases. Indian scientists have complained bitterly in recent years about the steady erosion and aging of scientific facilities, and last year a draft of the government's Millennium Science and Technology Policy declared that “there is an urgent need to revitalize the scientific enterprise” (Science, 14 December 2001, p. 2269).

    Good listener.

    Science minister M. M. Joshi (left) appears to have gained the ear of Prime Minister Vajpayee in this year's budget.

    CREDIT: P. BAGLA

    Last year the fund supported 180 science departments within 50 universities. But more than 1000 departments came up empty-handed. One successful application was from a group at North Eastern Hill University in Shillong, Meghalaya, which received an automatic nitrogen-15 analyzer to aid in their search for strains of cyanobacteria that could enhance the productivity of local rice farmers. “Without this sophisticated instrument, our work was really suffering,” says Ramesh Sharma, head of the university's biochemistry department. The Tata Institute of Fundamental Research in Mumbai used the fund to help purchase a $5 million, 900-megahertz nuclear magnetic resonance facility for studying biological samples.

    DST also plans to double its $10 million program for multidisciplinary basic science, with substantial funding for a new program in nanotechnology. Seismic research will get a boost with a $2.5 million airborne laser terrain-mapping project by the Survey of India in Dehra Dun. All in all, says Valiathan, the new budget suggests that the government has finally embraced the idea that basic research is as important as mission-oriented science in strengthening the country's economy.

  7. AIR POLLUTION

    Small Particles Add Up to Big Disease Risk

    1. Solana Pyne*
    1. Solana Pyne is a writer in New York City.

    Breathing polluted air may be nearly as bad for you as living with a cigarette smoker. A new study, the most extensive of its type, shows that long-term exposure to tiny particles of air pollution increases the risk of dying from heart or lung disease or lung cancer by about the same amount as long-term exposure to secondhand smoke. Although the mechanism by which the particles cause disease is still up for debate, the latest study supports existing U.S. air-quality standards that have been attacked by industry and state governments.

    A number of studies have shown that more deaths from heart and lung diseases occur on days with high concentrations of fine particles. These particles, byproducts of burning wood and fossil fuels, are smaller than 2.5 micrometers across, or less than 1/40th the width of a human hair. Landmark studies in 1993 and 1995 suggested that heart and lung diseases could be caused by chronic exposure to fine particles, but some scientists argued that the findings were unreliable because researchers hadn't sufficiently accounted for the individual risk factors and differences among communities (Science, 4 August 2000, p. 711).

    To gain a better understanding, environmental epidemiologists Arden Pope of Brigham Young University in Provo, Utah, George Thurston of New York University (NYU) School of Medicine, and Daniel Krewski of the University of Ottawa tracked people over a longer time and controlled more extensively for individual risk factors. The team compared data on particulate and gaseous air pollution with data on the cause of death among 500,000 people followed for 16 years by the American Cancer Society. After compensating for smoking, diet, obesity, and other risk factors, as well as possible regional differences, the researchers found that every 10-microgram increase in fine particles per cubic meter of air produces a 6% increase in the risk of death by cardiopulmonary disease, and 8% for lung cancer.

    Breathtaking.

    Fine-particle pollution in places such as Los Angeles ups one's risk of lung cancer and other diseases.

    CREDIT: MARK J. TERRILL/AP

    Reporting in the 6 March issue of the Journal of the American Medical Association, the team found that the risks are highest in Los Angeles, which averaged 20 micrograms of fine particles per cubic meter in 1999 and 2000. Chicago clocked in at 18 and New York City at 16. But small cities are not necessarily safer, Thurston points out: Huntington, West Virginia, has higher average fine-particle concentrations than New York because of its proximity to coal-fired power plants. Douglas Dockery, an environmental epidemiologist at Harvard University who helped design one of the original studies linking long-term particulate exposure to heart and lung disease, says the study's key contribution is highlighting the role of particulates in lung cancer.

    It's logical that fine particles would cause heart and lung problems, Thurston says: “The particles are loaded with carcinogens, and they reside in the lungs for a long period of time.” Researchers are still trying to pinpoint the most lethal particles, however, and sort out how they cause disease. They may lodge in the lining of the lungs, inflaming them and contributing to infection. Fine particles can also generate highly reactive oxygen-containing chemicals that can trigger inflammation and allergies and might damage the heart. And the smallest of the fine particles can pass from the lungs into the bloodstream, where they can travel to other sites and wreak further havoc.

    As with cigarette smoke, many different compounds and mechanisms are probably involved, says Morton Lippmann, an environmental health scientist at NYU School of Medicine and director of one of five centers set up by the Environmental Protection Agency (EPA) to study the health effects of fine particles. “We don't know why some people get serious heart problems and others get lung disease,” he says. “But that's not an excuse not to regulate fine particles.”

    In 1997, EPA established standards for fine particles under the Clean Air Act. It set the annual average at a maximum of 15 micrograms per cubic meter of air, with a 24-hour maximum of 65 micrograms per cubic meter. Several industry groups and three states challenged the standards, which were upheld last year by the Supreme Court after a lengthy legal fight. Meanwhile, EPA has collected 3 years of data on fine particles and hopes by the end of the year to designate which cities are not meeting the standards. Even then, however, it could be a decade or more before states implement plans to clear the air.

  8. ASTRONOMY

    Two Satellites Get New Lease on Life

    1. Andrew Lawler

    Last week proved a happy one for astronomers whose orbiting instruments are hard to reach. While spacewalking astronauts won headlines for refurbishing the Hubble Space Telescope, ground controllers quietly revived a valuable ultraviolet satellite —given up for dead last December— without ever leaving their seats.

    Astronauts successfully replaced solar arrays, added new instruments, and installed a new power unit on the aging Hubble during five demanding forays into the open space-shuttle bay. The crew then released the telescope, which faces several months of testing before it can again start collecting data (Science, 22 February, p. 1448).

    Meanwhile, the Far Ultraviolet Spectroscopic Explorer (FUSE) is already transmitting scientific data after a team on the ground pulled off what Paul Hertz, FUSE program director at NASA headquarters in Washington, D.C., labels “a miracle.” FUSE was launched in 1999 on a 3-year mission to examine conditions shortly after the big bang, including the properties of gas clouds that form stars and planetary systems and the dispersal of chemical elements in the universe. The mission, which includes Canadian and French participation, was extended for 2 more years after revealing, among several findings, that the Milky Way galaxy sits in the middle of a tenuous bubble of gas with temperatures of about 1 million degrees (Science, 25 January, p. 616).

    Better than new.

    Shuttle astronauts upgraded instruments on the Hubble Space Telescope.

    CREDIT: AP/NASATV

    Disaster struck in December 2001, however, when the second of four key guidance systems failed. “I would have bet good money that it was the end for the mission,” says Hertz. But a team of engineers and scientists from NASA, industry, and Johns Hopkins University used electromagnets in the satellite and Earth's own magnetic field to keep the spacecraft oriented. Engineers had theorized that they could use a magnetic field to steer a satellite, but the approach had never been tried. “I am thrilled that the FUSE team proved me wrong,” says Hertz.

    The team is still fine-tuning the new guidance system, which allows controllers to lock onto guide stars for accurate pointing. In the meantime, researchers are thrilled that an old friend has regained its good health. “I am very excited to have FUSE back,” says George Sonneborn, a project scientist at NASA Goddard Space Flight Center in Greenbelt, Maryland.

  9. SPAIN

    New Cancer Center Makes a Big Splash

    1. Xavier Bosch*
    1. Xavier Bosch is a science writer in Barcelona, Spain.

    BARCELONA—When Mariano Barbacid returned home in 1998 to establish a cancer research center, his compatriots lauded him as a lodestar for a wayward scientific community. In a few weeks, Barbacid will march his growing staff at the National Cancer Research Center (CNIO) from temporary quarters into a new $32 million facility in the heart of Madrid. Supporters commend Barbacid for putting together an impressive team that, they say, will anchor CNIO in the world's firmament of stellar cancer centers. Others, however, complain that CNIO has had an unfair advantage in winning government support and worry that it could devour scarce resources.

    Barbacid built his reputation at the U.S. National Cancer Institute (NCI) branch in Frederick, Maryland, where in 1982 he led one of three teams that independently reported the first isolation of a human oncogene. Promised a free hand in creating Spain's own NCI, Barbacid left a management position at the drug giant Bristol-Myers Squibb and moved back to his birthplace.

    Once home, Barbacid lured back several top Spanish researchers from elsewhere in Europe. Last year, for instance, he recruited Luis Serrano, head of the Department of Structural Biology and Biocomputation at the European Molecular Biology Laboratory in Heidelberg, Germany, to start a similar department at CNIO that will focus on drug design. CNIO now employs 130 scientific staff members, a figure that will swell to 450 after the move.

    The new center starts life with a silver spoon. Among its high-tech accoutrements, CNIO can generate its own DNA chips, each studded with more than 7000 genes, that researchers will use to study how to design treatments based on tumor gene expression patterns. CNIO will also maintain the National Tumor Bank Network, a young project that so far has accumulated a stockpile of 3000 tumor tissue samples.

    Waiting game.

    Mariano Barbacid and his team are weeks away from moving into their new National Cancer Research Center.

    CREDITS: CNIO

    Although researchers are pleased at the new peak on their country's research landscape, some are bothered by the shortcuts taken to get there. The center was conceived without input from the scientific community or from Parliament, says medical oncologist Francisco Real of the Municipal Institute of Biomedical Research in Barcelona, and Barbacid himself boasts that Prime Minister José Maria Aznar has personally guaranteed CNIO's progress free of stumbling blocks. The health minister, Celia Villalobos, persuaded a trade group representing 300 drug companies to donate $26 million a year from 2001 to 2004 to help fund, among other projects, CNIO and a second new facility, the Spanish Cardiovascular Research Center. In return, says molecular biologist Pere Puigdoménech, director of Barcelona's Molecular Biology Institute, the government pledged not to cap drug prices over the next few years.

    The government has promised to foot 60% of CNIO's $28 million annual budget —a hefty share of the $140 million that Spain spends each year on biomedical research. Most of the rest, says Barbacid, will come from competing successfully for public grants. However, some researchers outside Madrid feel they are operating at a handicap. “Our capacity to compete with him will always be lower,” says oncologist Josep Baselga of the Hospital Vall d'Hebrón in Barcelona. For that reason, Baselga argues, Barbacid has a responsibility to Spain's cancer research community at large. Acknowledging that debt, Barbacid says he hopes several more topflight cancer centers will be built outside Madrid to even out the playing field.

  10. NEUROSCIENCE

    Neurons Weigh Options, Come to a Decision

    1. Marina Chicurel*
    1. Marina Chicurel is a writer in Santa Cruz, California.

    Some decisions you can make in a snap. For others, you have to weigh the options and mull them over for a while. Monkeys in a new study wrestled with the latter type of task while researchers measured a sequence of neural activities involved in making such a decision.

    Previously, neuroscientists had observed operations necessary for some types of decision-making. For instance, they can monitor neurons encoding sensory information, comparing stimuli, and preparing commands to move. In the 14 March issue of Neuron, a team reports tracking a crucial step: neurons' ability to keep a trace of recent events in memory while making a comparison. Ranulfo Romo and colleagues at the National Autonomous University of Mexico in Mexico City observed the complete unfolding of a decision-making process as reflected by the activities of neurons in a brain region called the medial premotor cortex (MPC).

    “It's the first time somebody has done that,” says Michael Shadlen of the University of Washington, Seattle. “To make a comparison you have to hold the first stimulus in memory somehow, and this [study] involves this very special step.”

    The MPC is primarily involved in preparing body movements, but Romo and other researchers have suggested that it is also involved in sensory processing and is capable of holding fleeting memories. Romo and his colleagues suspected that this combination of powers would enable the MPC to participate in making decisions. To test this idea, the researchers applied a vibration to monkeys' fingertips for half a second using a pencillike probe. They waited 1 to 3 seconds and then applied a second vibration at a different frequency. The animals learned to press a button to indicate which of the vibration frequencies was higher, and researchers tracked the firing of single neurons in the trained monkeys' MPCs as the animals mulled over which button to push.

    Decisions, decisions.

    Some neurons (top cluster) increase and others (bottom cluster) decrease their firing rates while evaluating vibrations.

    CREDIT: R. ROMO/NATIONAL AUTONOMOUS UNIVERSITY OF MEXICO

    “They've got a task where the different things that a brain must do are spread out in time and characterized so that linking the activity of a neuron to a certain stage of processing is cleaner than in other studies,” says Jeffrey Schall of Vanderbilt University in Nashville, Tennessee.

    When the probe delivers the first vibration, Romo's team found, 14% of the neurons change their firing rate. When the vibration stops, approximately half of these responders keep firing at the altered rate. In addition, a group of neurons that hadn't originally responded to the vibration chime in. Just before the monkey receives the second vibration, therefore, about 28% of the neurons in the MPC appear to be holding a trace of the first sensation.

    During the second vibration, some neurons keep responding to the frequency of the first, while others that originally responded to the first vibration begin firing at a rate that correlates with the frequency of the second. A few milliseconds later, members from both groups, in addition to other neurons that had been uninvolved, begin firing as a function of the difference between the two stimuli—some boosting their activity when the first vibration is of higher frequency than the second and others when the second vibration's frequency is higher.

    At the height of the comparison, while the monkey is remembering the first vibration but feeling the second, 53% of the neurons are firing at rates that reflect the difference between the two vibrations. “It's like an avalanche,” says Romo. Then the number of participating neurons falls off as the second vibration ends and the animal moves its hand to press a button. Some neurons recruited late during the comparison period keep signaling the frequency difference up to the moment the monkey pushes the button. The authors conclude that neurons in the MPC reflect the entire decision-making process, with a few multitalented cells involved from start to finish.

    Romo and others aren't sure whether MPC cells are performing the computations that underlie decision-making themselves or simply echoing the work of other neurons. Romo says his unpublished studies indicate that nearby brain regions harbor neurons that behave similarly to those in the MPC. But then, it's not surprising that accurate decision-making—which wins the monkeys a squirt of fruit juice—requires a lot of neurons to pitch in.

  11. ASTROPHYSICS

    Stellar Pair Whirls in a 5-Minute Dash

    1. Robert Irion

    European astronomers have identified what they believe is the tightest pair of stars yet seen: two white dwarfs that dash around each other every 5 minutes. If confirmed, the whirling dervishes are revolving twice as fast as the previous closest pair. Moreover, says astronomer Gianluca Israel of the Astronomical Observatory of Rome in Italy, “this represents one of the most promising targets for detection of gravitational waves": eerie ripples in space-time that a future orbiting observatory will chase.

    Many stars come in binaries. If each is about as massive as the sun, they become white dwarfs—dense Earth-sized remnants of their cores—when they run out of hydrogen fuel. Perhaps 100 million such pairs fleck our galaxy. Most take years to orbit, but the closest together take mere hours or minutes. In the tightest pairs, astrophysicists believe, the more massive dwarf rips matter from its partner. When the gas crashes onto the dominant star, it emits x-rays.

    Such x-rays may stream from RX J0806.3+1527, a source in the constellation Cancer. A German satellite called ROSAT spotted the object in the 1990s, but not until 1999 did astronomers realize that its signal fluttered every 321 seconds. The x-rays vanished for half that time, as if a hot spot were rotating into and out of view.

    Now, two independent teams have studied the system with optical telescopes. Between 1999 and 2001, Israel and his colleagues used spectrographs on two of the four 8.2-meter telescopes in the European Southern Observatory's Very Large Telescope (VLT) array in Chile as well as other instruments to monitor a faint blue star that fluctuates with the same 321-second period in the same position. A team led by astronomer Gavin Ramsay of University College London also detected that cycle 2 months ago with the 2.5-meter Nordic Optical Telescope in the Canary Islands.

    Dashing dwarfs.

    Matter cascading between dead stars triggers x-rays that may have revealed the fastest binary pair yet.

    ILLUSTRATION: C. SLAYDEN

    A single star, such as a slowly spinning neutron star, cannot explain the patterns, both teams maintain. Rather, they think two white dwarfs are locked in a sizzling tango about 80,000 kilometers apart—just one-fifth of the distance from Earth to the moon. Their reports, posted online at xxx.lanl. gov/abs/astro-ph/0203043 and /0203053, will appear in Astronomy & Astrophysics and the Monthly Notices of the Royal Astronomical Society, respectively.

    Other astronomers are excited but await more results. “Misidentifications are easily made,” cautions astrophysicist Simon Portegies Zwart of the University of Amsterdam in the Netherlands. Simultaneous studies of the system in x-rays and optical light might clinch the case. X-rays from the massive dwarf should light up the closest side of its companion. As the tandem revolves and each dwarf shows its hot face, the x-rays should wax when the optical signal wanes, and vice versa. Israel and his team think they saw that pattern in November with NASA's Chandra X-ray Observatory and VLT, but they are still analyzing the data.

    Whether the white dwarfs collide in about 10,000 years or drift farther apart depends on their masses. In the meantime, their breakneck pace should whip the fabric of space like an eggbeater and churn out “easily detectable” gravitational waves, says astrophysicist E. Sterl Phinney of the California Institute of Technology in Pasadena. Phinney is a leader of the Laser Interferometer Space Antenna planned for launch within a decade that hopes to “hear” such binary systems (Science, 21 April 2000, p. 422). “There are thousands of similar systems in the galaxy,” says Phinney, “but this is the nearest and brightest.”

  12. PUBLIC HEALTH

    U.S. Vaccine Supply Falls Seriously Short

    1. Jon Cohen*
    1. With reporting by Katie Greene.

    A confluence of unrelated problems has created widespread shortages of medicine's best preventive against infectious diseases

    In January Walter Orenstein received a worried phone call from the pediatrician who treats his children. Orenstein, who heads the National Immunization Program at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, listened as the pediatrician explained that his concerns stretched far beyond Orenstein's children. His office, he said, could not purchase enough measles-mumps-rubella vaccine because Merck, the sole maker of the vaccine, had run low. The pediatrician was also waiting for Merck to make available more varicella (chickenpox) vaccine. A few months earlier, the doctor continued, shortages had forced him to delay vaccinating children against hepatitis B and pneumococcal disease. “What's going on?” he asked Orenstein.

    Orenstein knew the answer, and it wasn't reassuring. During the past 6 months, shortages have occurred with eight of the 11 childhood vaccines. Demand has also outstripped supplies of adult vaccines against influenza, tetanus, and pertussis. “I've been in immunization for 24-and-a-half years, and I've never seen anything like this,” says Orenstein.

    Indeed, CDC's National Vaccine Advisory Committee (NVAC) was so concerned that last month it held a 2-day meeting on the topic in Washington, D.C. The immediate shortages stem from a mix of factors, some as mundane as retooling a manufacturing plant or misjudging demand and others as fundamental as the need for companies to make money. But the comments of representatives from industry, academia, and the government also revealed a more troubling picture: The entire edifice for the manufacture and supply of vaccines in the United States is so fragile that even minor perturbations can lead to a collapse.

    Dwindling supplies

    Vaccines are nowhere near as profitable as drugs. According to GlaxoSmithKline, the world's largest vaccinemaker, worldwide vaccine sales in 1999 totaled $4.3 billion. In contrast, the cholesterol-lowering drug Lipitor now grosses upward of $6 billion a year. Not only do people use vaccines far less frequently than drugs—typically, a child receives a battery of shots and is protected for life—but vaccine prices are heavily influenced by the federal government.

    Vaccines are also trickier to manufacture than drugs. “Vaccines require the use of biological organisms, viruses, and bacteria, which will not always grow or respond on demand,” notes Wayne Pisano, an executive at Aventis Pasteur who works at the company's Swiftwater, Pennsylvania, branch. “It's not a matter of opening a tap and pouring out vaccine.”

    Painful predicament.

    Clinicians have struggled to purchase childhood vaccines that prevent eight different diseases.

    CREDIT: RUSS CARMACK/THE NEWSTRIBUNE/AP

    These economic forces have helped drive many companies out of the vaccine market. In 1967, says Kathryn Zoon, director of the branch of the Food and Drug Administration (FDA) that oversees vaccines, FDA had licensed vaccines made by 26 different manufacturers. By 1980, the number had fallen to 17. Today it stands at 12, of which only four are large pharmaceutical companies.

    The U.S. government has intervened in several ways to try to ensure adequate vaccine supply. In 1983, CDC began to stockpile vaccines, and 3 years later Congress created a no-fault compensation program for people injured by vaccines. That step dramatically limited the liability of vaccinemakers—a key reason many cited for leaving the business. But the current shortages underscore the limits of these fixes. Some critics in fact say other government vaccine programs have actually exacerbated the problem by substantially decreasing the profit margin for most companies.

    Snowball effect

    The current wobbliness of the U.S. vaccine supply first became apparent during the flu season 2 years ago. “We had a very rude wake-up call,” says Nancy Cox, who heads CDC's influenza branch. The program had been working so well for several years, explains Cox, that “people stopped paying attention to the fact that the influenza distribution system was fragile.”

    Making a flu vaccine poses unique challenges. The most daunting is that manufacturers must reformulate it each year to combat the new strains of influenza virus in circulation. Some strains do not grow well, complicating the process that transforms them into vaccines. And the seasonality of flu forces companies to deliver the vaccine on a tight timeline.

    In 2000, the four licensed manufacturers had exceptional difficulty growing one strain of influenza. Coincidentally, FDA cited two manufacturers, Wyeth Lederle (a division of American Home Products) and Parkdale Pharmaceuticals, for quality-control infractions. Parkdale decided to drop its flu vaccine program. About the same time, CDC increased the pressure on the remaining manufacturers by broadening the “primary target group” to include anyone over 50, rather than 65.

    This flu season, the trio of Wyeth, Aventis Pasteur, and Evans Vaccines (a subsidiary of PowderJect Pharmaceuticals) produced 87 million doses for the U.S. market. Although that was a record supply, about one-third of it was not available by October, when demand for the flu vaccine typically peaks (see graph at right).

    SOURCE: CENTERS FOR DISEASE CONTROL AND PREVENTION

    Equally troublesome was Wyeth's decision in January 2001 to stop making vaccines against tetanus and diphtheria. The company was increasing production of a new and significantly more profitable vaccine that protects children from pneumococcal disease, says spokesperson Douglas Petkus, leaving it without “the capacity” to continue production of older products.

    Wyeth's withdrawal left Aventis as the only national producer of the diphtheria-tetanus vaccine. Pisano says that the company did not have enough advance notice of Wyeth's plans to crank up extra production. As a result, supply of this vaccine, which is given in combined form to adolescents and adults, has dropped by an estimated one-third since 1998 (see graph at left).

    For infants, the tetanus and diphtheria vaccines are combined with yet another product, acellular pertussis, creating what is known as DTaP. In 2000 Wyeth scotched DTaP from its production line, as did North American Vaccine, which also ran into quality-control problems with FDA. Aventis Pasteur and GlaxoSmithKline still make DTaP, but neither was able to increase production to meet demand after two of their competitors left the market. CDC estimates that the current supply of DTaP meets only about three-fourths of demand. (Ironically, Wyeth has struggled to fill orders for its pneumococcal vaccine because of a higher-than-expected demand.)

    The vaccine shortage escalated in August 2001 when Merck, which makes six vaccines that protect against nine diseases, voluntarily decided to change its manufacturing procedures. A few weeks later, Merck stopped production again for scheduled modifications to its production facility. CDC estimates that Merck, the sole manufacturer of both varicella and measles-mumps-rubella vaccines, supplied 65% less varicella vaccine this winter than the previous year and only about half the needed measles-mumps-rubella vaccine.

    Tweaks or overhauls?

    Stockpiles are the best hedge against shortages, vaccine experts concluded nearly 20 years ago. Theoretically, the stockpile creates an artificially large marketplace, and manufacturers that run short of a vaccine can “borrow” product from the stockpile. But the reality is quite different.

    CDC initially focused on critical vaccines that only one manufacturer produced. To increase efficiency, CDC also selected vaccines that have a predictable marketplace, reducing the likelihood of wasting these perishable products. Currently, the stockpile contains just three vaccines: polio, measles-mumps-rubella, and a small amount of diphtheria-tetanus. But since the early 1980s, a half-dozen new vaccines have come online. “We need to get stockpiles of all the other vaccines,” acknowledges Orenstein.

    Expanding the stockpile is probably the best immediate solution to offset vaccine shortages, says Boston University's Jerome Klein, a pediatrician and NVAC member. “It's a quick fix that legislators can understand.”

    But even that answer is not as simple as it appears. Demand for a new vaccine, like the one that prevents pneumococcal disease, is difficult to predict until it has been on the market for a few years. The stockpile is not practical for flu vaccine, which changes annually. Most vaccines also have a shelf life; to stay current, the stockpile must rotate out its inventory every 6 months.

    Orenstein suggests that the government may have to “overpurchase” vaccines each year, knowing that some will go to waste. “Society needs to be prepared for [the waste] if we want that insurance,” he says.

    Although most eyes have turned to the federal government to solve the supply problems, industry charges that one intervention helped create the shortages. Congress launched the Vaccines for Children program in 1993 to increase immunization rates among the poor. As part of this program, the government purchases about 35% of childhood vaccines on the U.S. market, says Orenstein, and supplies states and other public programs with another 17%. That means manufacturers sell 52% of the childhood vaccines used in the United States at a price, negotiated by the federal government, that is significantly lower than that paid by private purchasers.

    Although the Vaccines for Children program does not aim to manipulate the market, it does give the government huge negotiating power. Vaccinemakers and their lobby, the Pharmaceutical Research and Manufacturers of America, argue that the price caps—which limit increases that companies can charge for their products—in particular serve as a disincentive and help explain why so few companies are in the business.

    Orenstein disagrees. Besides guaranteeing a large marketplace and a fair price, he says, the government creates huge markets for products it endorses, such as the new pneumococcal vaccine required of all school-age children. As for the influence of price caps, Orenstein notes that the 1993 program set limits only for existing vaccines—but that shortages have also occurred with newer ones that had no price controls.

    One cost-free tactic that won widespread support at last month's meeting was greater communication among everyone involved. Shortages could be averted if manufacturers gave their competitors better advance warning before dropping a product, says Aventis's Pisano, or if the government were allowed to share confidential supply information with the private sector.

    Confronted with the obvious failure of market mechanisms, some have long favored a radical overhaul of the system. The current crisis, coupled with the increased concerns about bioterrorism following 11 September, have revived a 1993 proposal by the Institute of Medicine (IOM) for a National Vaccine Authority that has at its center a government-owned vaccine manufacturing plant. The authority would oversee production and distribution of all vaccines, monitor supply and demand, and fill in gaps with government-made products. “We are not talking about competing with the private sector,” stresses IOM president Kenneth Shine at the meeting. Senators Edward Kennedy (D-MA) and William Frist (R-TN) and other lawmakers have shown serious interest in the idea, which is widely opposed by industry representatives.

    Instead, companies would prefer tax incentives, especially to refurbish manufacturing plants for older and cheaper “commodity” vaccines. The federal government, for example, pays 15 cents a dose for diphtheria-tetanus vaccine, whereas the new pneumococcal vaccine sells for $58.75.

    Companies need to be able to make money on vaccines, says Klein. He and others say the most pressing problem is convincing the public to pay a fair price for vaccines that can save millions of lives. “You have to be as willing to pay for DTaP as you are for Viagra,” he says. Unfortunately, it may take a resurgence in vaccine-preventable diseases to drive home the importance of these critical medicines.

  13. PUBLIC HEALTH

    Gates Foundation Rearranges Public Health Universe

    1. Jon Cohen

    SEATTLE, WASHINGTON—A large AIDS meeting held here last month had an unusual keynote speaker: Bill Gates. The world's richest man had never spoken at a medical research conference, and a few years ago many in the audience would have wondered why he was there. But since 1999, the Microsoft CEO and his wife Melinda have created the world's largest philanthropy, with current assets of $24.2 billion, and improving the health of the world's poor is at the top of its agenda. So far, the Bill and Melinda Gates Foundation has spent $2.5 billion on global health—more than twice the annual budget of the World Health Organization.

    The foundation has rearranged the public health universe so speedily that many have yet to comprehend the change. “They're having a huge impact,” says Barry Bloom, dean of Harvard School of Public Health in Boston, which, along with his own lab, has received some of the Gates Foundation's largesse. “There is no other money like that anywhere in the world.” The $400 million investment in AIDS projects, for instance, is having a major ripple effect, says epidemiologist Peter Piot, who heads the Joint United Nations Programme on HIV/AIDS, by “shaming many 'donor' governments” into spending more.

    Gates's interest in public health grew out of his own reading on the topic, in particular a 1993 World Bank report, Investing in Health. “Every page screamed out that human life was not being treated as being nearly as valuable in the world at large as it should be,” Gates told the audience at the 24 February meeting. But when Gates and his wife decided to spend their vast wealth on creating a more equitable world, they realized they needed help.

    Helping hand.

    Melinda Gates vaccinates a Thai child against polio. Below, selected Gates Foundation grants.

    CREDIT AND SOURCE: THE BILL AND MELINDA GATES FOUNDATION
    View this table:

    In the beginning, Bill's father, a Seattle lawyer with the same name, and a family friend, former Microsoft executive Patty Stonesifer, oversaw grants and quizzed experts. The few foundation staffers worked in a modest space atop a pizza shop. But as the foundation's assets quickly grew, they hired one of those experts, family planning and child health specialist Gordon Perkin, to run the foundation's global health program. They also brought in William Foege, former head of the Centers for Disease Control and Prevention (CDC). “Probably 80% of our grants were made with a staff of five or less,” laughs Perkin, sitting in the sleek offices the foundation recently occupied near the Seattle waterfront. For many of the grants, he explains, they asked for short, clear proposals and simply tried to ascertain whether the applicants were the world's best in their field. “It was an immensely satisfying challenge,” says Perkin.

    The foundation's interests have stretched from AIDS to reducing maternal mortality, bolstering nutrition, and improving treatment and prevention for several tropical diseases, including malaria, tuberculosis, lymphatic filariasis, dracunculiasis, schistosomiasis, and trachoma. Nearly half of the global health money has gone to vaccines, including a whopping $750 million to the Vaccine Fund. This fund, in turn, supports the Global Alliance for Vaccines and Immunization and its drive to close the “vaccine gap” between rich and poor children—3 million of whom die each year from diseases that vaccines can prevent.

    In keeping with its recent growth spurt, the young foundation is increasing its staff and restructuring how it awards grants. Global health is now split into three divisions. Perkin heads the reproductive and child health program. The HIV/AIDS and tuberculosis program is run by Helene Gayle, a well-known AIDS epidemiologist whom Gates lured from CDC. Sally Stansfield, an epidemiologist who has worked extensively on public health in Cambodia and Ethiopia, is acting director of grants that involve vaccines and infectious diseases. “There is no single human who can master all of the decisions,” says Stansfield. “It is really important to know the subculture and the players in each area.”

    The newly structured foundation will place even more emphasis on accountability and aggressively pursue projects that mesh with its agenda. “We'll have a little more bandwidth now,” says Stansfield. That targeting will inevitably make it “less responsive to what comes in the door,” says Gayle, a transition that may rankle some. “It's tough when you're seen as a large, caring foundation—and I think people do perceive Gates as both caring and not just rich—and an important idea is not part of our priority.”

    Although Bill and Melinda choose how to spend the foundation's money, Perkin, Gayle, and Stansfield evince a sense of wonder about having the opportunity to affect public health in such a dramatic way. “If I stop and think about it,” says Stansfield, “the excitement is heart stopping.”

    Bloom suspects that if the Gates Foundation can demonstrate that its money has improved public health, the foundation will have an impact far beyond the projects it supports. “If Gates can do it,” says Bloom, “there are a lot of other people who can do it, too.”

  14. PUBLIC HEALTH

    Dead Virus Walking

    1. Martin Enserink,
    2. Richard Stone

    Smallpox, humankind's greatest scourge, was banished from the wild decades ago. New fears that bioterrorists may try to resurrect the virus have thrown two controversial research programs into high gear

    KOLTSOVO, RUSSIA—Stalin's gulags have long since vanished from Siberia, but one remote outpost lays claim to the mantle of horror. The world's worst killers, among them Ebola, hantavirus, and Marburg, are kept here in a maximum-security facility, the State Research Center of Virology and Biotechnology. An urgent overhaul has turned this prison, better known as VECTOR, into a fortress. A new fence topped with razor wire encircles the lab complex, forming a no man's land between it and the old concrete wall. Entrance is via a checkpoint run by the military, but even that won't get you into VECTOR's inner sanctum. Only a handful of the staff can enter Building 6, wherein resides—Hannibal Lector-like—the most notorious inmate of all: smallpox.

    During a millennia-long reign of terror, smallpox killed hundreds of millions of people before a concerted worldwide eradication campaign finally routed it in the late 1970s. The enormity of the public health threat is such that if smallpox were to escape from its cell here on the outskirts of Siberia's largest city, Novosibirsk, VECTOR would put in motion a government- approved plan to quarantine the 1.5 million inhabitants.

    VECTOR is one of only two places on Earth where it is permitted to keep live smallpox virus, also known as variola. The other repository—the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta—guards its stock just as zealously. To access the virus storage, two CDC researchers have to enter the facility simultaneously with different keys. Armed security guards and cameras keep a close watch.

    Over the past few years, both labs have taken the virus out of the freezer for limited studies. And now, spurred on by the events of 11 September and the fear of new bioterrorist attacks, both labs are about to ramp up their research programs. Their goal: to develop modern-day diagnostics, safer vaccines, and new drugs against the disease.

    The researchers are in a hurry, because the variola virus may not be long for this world. In January, the executive board of the World Health Organization (WHO) recommended giving the virus—which had been slated for destruction several times before—another stay of execution to allow researchers more time to study it (Science, 25 January, p. 598). “It's clear we cannot destroy the virus at this stage,” declares virologist Antonio Alcami of the University of Cambridge, U.K., a mousepox expert and adviser to WHO's variola panel. But the decision to hold onto smallpox must be approved by the World Health Assembly (WHA) in May. Although nobody expects it, WHA could vote to proceed with the virus's scheduled destruction by the end of 2002. More likely, it may set a new deadline, say, 3 years from now.

    Pandora's box?

    Peter Jahrling takes smallpox samples out of deep freeze.

    CREDIT: ROBERT O. BAKER/USAMRIID

    That's why, starting later this month, CDC will devote one of its two maximum-containment laboratories exclusively to smallpox research, “for as long as it takes,” says James LeDuc, who leads the studies. “That's a huge commitment,” notes Jonathan Tucker, a smallpox expert with the Monterey Institute of International Studies in Washington, D.C. At VECTOR, too, scientists are preparing for an intensive 3-year variola program that may receive a large chunk of its funding from the Russian government, augmenting the grants it receives for such work from the U.S. government.

    Inner sanctum.

    VECTOR's Building 6 is reserved exclusively for research on the smallpox virus.

    The revved-up research effort is catching a fair share of flak. China and a handful of other countries frown on the U.S.-Russian monopoly on variola; they are expected to reiterate their desire to set a firm destruction date at WHA's May meeting. And vocal critics within the United States—many of them veterans of the battle to eradicate the disease—are lobbying the government to abandon the research. Pandora's box, they say, should remain closed (see p. 2005). Even CDC does not exude much enthusiasm about the project—if only because of the amount of maximum-security lab space it uses. “We were told to do it,” says LeDuc, “and we're doing it to the best of our ability.”

    But many of the scientists involved see the new program as a breathtaking opportunity—a last-gasp chance to modernize the world's armory against this scourge. “Smallpox was eradicated before the modern era of molecular biology,” says VECTOR's Nina Tikunova. “We have a chance to make great strides in the science of this disease.”

    On death row

    The eradication of smallpox was one of the triumphs of 20th century public health. Once it was complete, every country that held stocks of variola either transferred them to central repositories in Russia and the United States or annihilated them. In the 1980s, a consensus emerged that even those last two stocks should be destroyed, so that the world could forever be free of smallpox. That plan has been intensely debated ever since.

    Until the past few years, smallpox rarely made it out of the freezer at either location. Exceptions occurred in the early 1990s, when researchers at CDC and the National Institutes of Health (NIH) sequenced the entire 186,000-base pair genome of a variola strain called Bangladesh-1975. Russian scientists did the same for another strain, India-1967, and then joined forces on a third strain from Brazil. They viewed their efforts as a prelude to the virus's destruction—an effort to at least save its genetic blueprint before the remaining vials were sterilized.

    But that complacency was shattered in the early 1990s by a defector's revelations that the Soviet Union had developed a massive, illicit program to turn the smallpox virus into a weapon—raising questions about whether other countries, such as Iraq, Iran, or North Korea, have kept secret stashes of the virus as well. “Many countries studied smallpox before 1980, and at -20°C, it's easy to hold onto for decades,” says VECTOR's Alexander Ilyichev.

    Such fears prompted the U.S. government to start a new research program in 1999. Overseen by WHO and guided by a 1999 Institute of Medicine report, the program essentially aims to bring smallpox research into the 21st century. While the virus was dormant in its freezers, advances in molecular biology revolutionized virology and immunology, and researchers developed powerful antiviral drugs and vaccines with fewer side effects. “We had a lot of catching up to do,” LeDuc says.

    CDC has a collection of 461 different virus isolates, saved from epidemics across the globe. Working with 45 of them, the CDC team has since developed several new diagnostics tests, including one based on the polymerase chain reaction, which can detect the virus directly by looking for its DNA. The researchers also started charting genetic diversity across the isolates to better understand the threat different strains may pose and sequenced the genomes of eight new isolates.

    But to understand how the virus wreaks havoc in the body, researchers needed an animal model that mirrored the human disease. Creating one, however, proved dauntingly difficult. In mid-2001, a team from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland, finally succeeded. Working at the CDC lab in Atlanta, USAMRIID virologist Peter Jahrling managed to infect 14 cynomolgus monkeys, using one of two virulent strains and exposing the animals to extremely high doses, either by injection or by both injection and aerosol. All of the monkeys got sick and 12 of them died, most within 4 to 6 days.

    Portraits of a killer.

    From last year's monkey studies at CDC (clockwise from top): the smallpox virus in skin pustules, seen using light and electron microscopy, and a microarray measuring gene expression levels in a monkey 2 days after infection.

    CREDITS: (TOP TO BOTTOM) MARK MARTINEZ/USAMRIID; THOMAS GEISBERT/USAMRIID; KATHLEEN RUBINS AND ADELINE WHITNEY

    Critics of the smallpox program are unimpressed with the model. They argue that its similarity to human smallpox—and hence its usefulness—is limited because the infection route was artificial and the animals died fast. Jahrling agrees that it needs to be “refined” to cause a more protracted disease, which he intends to do this year. Still, “the great success of Jahrling was to get reproducibility” of the disease, says Lev Sandakhchiev, VECTOR's director-general.

    The USAMRIID team took large numbers of samples during and after the study, for instance measuring the levels of antibodies and other key molecules involved in the immune response, as well as virus levels in various organs. A group led by Stanford University's David Relman studied the expression levels of about 15,000 genes in the sick monkeys using DNA microarrays. Although he's still processing the data, “some striking stereotypic patterns are emerging,” says Relman.

    A void to be filled?

    Turning their bioweapons expertise to peaceful research, VECTOR scientists have been busy as well. In 1991, VECTOR researchers led an expedition to a Siberian town to see whether 19th century smallpox victims interred in the permafrost might still harbor live virus (see p. 2002). And over the past few years, VECTOR's smallpox researchers have teamed up with their U.S. counterparts on several key projects. One concern they've probed together is whether the eradication of smallpox from the wild has created a void that other poxviruses might fill. The biggest perceived threat is monkeypox virus, which has triggered several outbreaks in humans over the past few decades but has not yet spread beyond Central and Western Africa.

    A big question is whether monkeypox virus might mutate into a form that spreads more easily through the human population. To assess that potential, USAMRIID, CDC, NIH, and VECTOR jointly compared the genetic sequences of a monkeypox strain isolated in a 1996 outbreak in Zaire with the sequences of two smallpox strains. In FEBS Letters last November, they reported that although the central regions of the strains' genomes are “nearly identical,” there were “considerable differences” at the ends of the genome where genes for virulence and its affinity for different hosts are located. These differences mean that monkeypox virus cannot evolve into a duplicate of smallpox virus, says Bernard Moss, an NIH poxvirus expert who collaborated on the study. “Of course, this does not rule out the possibility that monkeypox could better adapt in its own way to humans,” he says.

    Vaccine revamp

    In the new round of research planned for 2002, U.S. and Russian scientists hope to test new vaccines—provided they can make their animal model more realistic. The currently available smallpox vaccine is a very crude preparation of the vaccinia virus that can cause serious side effects, even death, especially in those with eczema or weakened immune systems. A huge new batch of vaccine, currently manufactured by a U.S.-British company called Acambis, is essentially the same vaccine, although produced using a different method, and it is expected to have the same problems. But several more weakened vaccinia strains might serve as a future alternative—if they can be shown to be protective.

    The animal model could also be used to test new antiviral drugs against smallpox—or to treat serious side effects from the vaccine. One candidate developed is cidofovir, a drug already approved to treat cytomegalovirus infections in HIV-infected people. The drug works well in animal models with other poxviruses, but it has not been tried in smallpox. VECTOR, too, plans to test dozens of antiviral compounds against smallpox strains, first in cell culture and then possibly in monkeys. They will also continue characterizing the Russian smallpox collection and comparing it with the CDC strains. Examining differences between these strains, says VECTOR's top smallpox researcher, Sergei Shchelkunov, will aid in a Russian initiative to develop DNA microchips for rapid identification of the virus in the event of an outbreak.

    Both centers must report periodically to WHO's variola committee. In a few years' time at the latest, that panel will decide whether the smallpox research effort has better equipped the world to deal with an outbreak. “My prediction is that there will be new arguments for retaining the stocks,” says WHOadviser Alcami, such as pleas for additional time to develop promising antivirals. “They will never finish,” he says. To some scientists who think that smallpox has long outlived its time on death row, that's a chilling thought.

  15. PUBLIC HEALTH

    Is Live Smallpox Lurking in the Arctic?

    1. Richard Stone

    KOLTSOVO, RUSSIA—The scene: the village of Pokhodsk, high above the Arctic Circle, on a muggy July day in 1991. A team of Russian bioweapons experts in blue respiratory suits enters a wooden vault full of 19th century smallpox victims mummified in the permafrost. More reminiscent of the Blair Witch Project than a scientific project, a homemade documentary—rarely shown outside a small circle of experts—follows the scientists from the VECTOR laboratory near Novosibirsk and their Yakutian colleagues as they wade through icy cold water into the chamber. In the dim light, several corpses come into view. Some are intact and beginning to thaw.

    Worried that spring flooding might wash the remains into inhabited areas—and possibly resurrect the smallpox virus—authorities in Yakutsk had summoned the team to this nightmarish place near the Kolyma River. The camera zooms in as the researchers huddle around a mummified child half-submerged in thawing mud. They gently peel away a few layers of deerskin clothing to reveal blackened skin pocked with blemishes characteristic of smallpox pustules. As they cut into a wizened leg, liquid oozes from the spongy flesh. Some minutes later they finish their work and douse the tomb with disinfectant to try to prevent anyone else from carrying smallpox out with them—accidentally or otherwise.

    Back in the lab, VECTOR researchers said they failed to isolate live virus from the tomb samples. The pathogen may have been destroyed by severe temperature fluctuations, as the Pokhodsk victims had lain near enough to the surface to have thawed and refrozen numerous times. But that does not mean that smallpox cannot survive in frozen flesh. “I'm not sure if you would be able to recover infectious particles,” says Antonio Alcami, a poxvirus expert at the University of Cambridge, U.K. “But it's not impossible.”

    Citing persistent rumors that rogue nations may have secret stashes of smallpox, Russia and the United States have argued for retaining the smallpox stocks—sanctioned by the World Health Organization (WHO)—to test improved vaccines and new drugs in the event that terrorists were to unleash the virus. “Undisclosed stocks are the biggest threat,” says VECTOR virologist Elena Ryabchikova. But experts also worry that a sophisticated terrorist team might follow VECTOR's lead and go smallpox hunting on the permafrost. A terrorist “would only need to find a little bit of live virus to be successful,” notes Alcami. That's the urgent rationale for trying to discover whether the frozen ground might serve as a viral reservoir.

    Horror show.

    Team from VECTOR and Yakutsk inspects a corpse dug up from Siberian permafrost for signs of smallpox.

    CREDIT: E. BELANOV/VECTOR

    There are also purely scientific reasons for unearthing smallpox victims, argues Lev Sandakhchiev, VECTOR's director-general. During the 19th century, he says, Yakutia (now called the Sakha Republic) appears to have been ravaged by smallpox strains of extraordinary lethality. Comparing the genetic sequence of such a strain with the more recent strains in the WHO repositories might yield insights into which genes are most important for lethality and how smallpox strains have evolved, he says. “I don't know how much information you can get after 100 years; it depends on how much you could sequence,” says Alcami. “But I do like evolutionary studies.”

    VECTOR wants to mount another expedition to look for frozen smallpox, but a price tag of roughly $200,000 means it must look for international partners. So far, Sandakhchiev has failed to entice the lab's main foreign benefactor, the U.S. government. One U.S. official puts a decidedly Cold War spin on VECTOR's arctic aspirations. Noting that in 1991 VECTOR was still receiving most of its funding from the Ministry of Defense, the official charges that the expedition may have had more than just scientific goals.

    Sandakhchiev rejects that suggestion, insisting that the expedition was a quest for knowledge, not for an edge in bioweaponry. He also says that the Sakha government—not the military—footed the expedition's bills.

    The bottom line is that “it's still quite possible that live smallpox exists in the permafrost,” says VECTOR's Evgeny Belanov, who led the Pokhodsk expedition. That excites different feelings in different people. “I'll bet other countries might invest” in a reprise of the 1991 expedition, says the U.S. official, who nonetheless would prefer to see smallpox—live or dead—rest in peace in its icy tomb.

  16. PUBLIC HEALTH

    'Destructionists' Fight to Keep a Dream Alive

    1. Martin Enserink

    Seeing smallpox with your own eyes changes you forever, says Alfred Sommer: The agonizing death of the virus's victims instills a permanent hatred. That's why Sommer, dean of the Johns Hopkins School of Public Health in Baltimore, Maryland, admits that he went “berserk” last month after reading in a news article that a U.S. team had developed an animal model of smallpox by injecting monkeys with huge doses of the virus. Within minutes, Sommer had written an op-ed piece in which he labeled the research “abhorrent” and the scientists “idiots of the worst sort.” Then he hit the 'Send' button.

    His piece in the Baltimore Sun on 4 February was the latest flare-up in a long-running battle between destructionists—those who believe the last known stocks of the variola virus should be destroyed—and retentionists, who want to keep them around for study. Although the two sides have been at loggerheads for over a decade, Sommer's broadside was unusually harsh. “It was such a hysterical tirade,” huffs one of the more visible retentionists, virologist Peter Jahrling of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland.

    Many in the destructionist camp, including Sommer, helped flush smallpox from its last hideouts in the 1970s. Their intention was to rid the planet of the virus once and for all. After smallpox vanished from the wild more than 2 decades ago, the last known lab preps of live virus were consolidated in the United States and the Soviet Union and slated for destruction. Recently, the World Health Organization (WHO) recommended postponing the virus's annihilation to enable an ambitious new research program to proceed (see main text). The latest developments, fueled by bioterrorism fears after last fall's attacks, have left destructionists deeply disillusioned.

    Virulent debate.

    Alfred Sommer's op-ed (above), and D. A. Henderson, former leading opponent of variola research.

    CREDITS: (TOP TO BOTTOM) THE BALTIMORE SUN; PETER VERMIJ

    Jahrling and others argue that keeping the variola virus is essential to get new candidate drugs and vaccines tested and approved. Both are vital, he says: Without antiviral drugs, doctors would be powerless to treat patients with advanced smallpox, should an outbreak occur; and the current vaccine puts people with weakened immune systems and eczema at risk of serious side effects. “I don't think we can just write off these groups,” says USAMRIID's John Huggins.

    Sommer, however, says that developing any new antiviral is a costly enterprise that's unlikely to succeed anytime soon. And he says vaccine safety concerns could be addressed in different ways—for instance, by finding drugs that quell side effects. Destroying the virus, he argues, would send a strong signal to any country with illicit stocks that holding smallpox in reserve as a possible weapon is morally repugnant. “The world would be a much safer place if we all decided we want to get rid of it, instead of playing with it,” he says.

    For now, however, the retentionist philosophy is carrying the day. The 11 September terrorist attacks have “muted the criticism of the research pretty substantially,” says Jonathan Tucker of the Monterey Institute of International Studies in Washington, D.C. What's more, the destructionists recently saw one of their most formidable spokespeople decommissioned. Since joining the Bush Administration last fall to coordinate bioterrorism policy, D. A. Henderson, who led WHO's eradication effort and had argued aggressively for destruction, has hewed to the government's retentionist line—although few experts believe his private views have changed.

    Henderson's comrades in arms are forging on without him. Sommer—who admits his op-ed was a “gut reaction” that he wishes he had given another read—has circulated a more circumspect petition among the 31 deans of U.S. schools of public health, calling on the government to proceed on the path to destruction. About half are likely to sign it, he says. Although the manifesto is unlikely to alter U.S. policy, Sommer acknowledges, sustaining the debate may help keep the virus on death row.

    Jahrling, meanwhile, says he's bracing for more criticism, especially after he and others publish their latest results in the next couple of months. He insists he's not looking to pick a fight. “The less people are worried about what I'm doing, the better I like it,” he says. “Just let me do my job.”

  17. GÜNTER WÄCHTERSHÄUSER PROFILE

    Between a Rock and a Hard Place

    1. Michael Hagmann*
    1. Michael Hagmann is a writer based in Zürich, Switzerland.

    Günter Wächtershäuser had a radical theory of how life began, and he needed all his skills as a patent lawyer to persuade a skeptical community to take it seriously

    MUNICH, GERMANY—Overturning long-cherished theories, especially ones that underpin a whole field, can be a thankless task. Few theories are as iconic as the prevailing explanation of how simple chemicals in a cozy puddle of primordial soup first assembled themselves into the precursors of the earliest forms of life some 4 billion years ago. But such an elevated status does not prevent Germany's Günter Wächtershäuser from wanting to tear down the theory and replace it with one that puts the origins of life in seemingly hostile environments such as deep under the sea, on mineral surfaces around midocean hydrothermal vents.

    A practicing patent lawyer here for more than 30 years, Wächtershäuser is good at poking holes in things. “That's what I like about being a patent lawyer. To make your case, you have constantly got to turn things on their head and come up with new ways of looking at things,” he says. Despite having neither a lab nor a track record in the field, Wächtershäuser has spent the past 20 years on what he calls “the mother of all problems.” And slowly but surely, Wächtershäuser's argument that surfaces served as the cradle of life has found a home among biologists and biochemists.

    “He really added a breath of fresh air to the field,” says Norman Pace, an evolutionary biologist at the University of Colorado, Boulder. “Wächtershäuser brought surface chemistry to the attention of origin-of-life people. No one who thinks about the origins of life thinks about solution chemistry anymore.” James Ferris, a chemist at Rensselaer Polytechnic Institute (RPI) in Troy, New York, agrees: “The broth was probably much too dilute to bring the chemicals together to react in the first place. A mineral surface is a good way to concentrate the compounds.”

    But not everyone is ready to ditch the old broth theory. “Do—or did—the proposed chemical reactions actually take place in the real world?” asks organic chemist Jeffrey Bada of the Scripps Institution of Oceanography in La Jolla, California. “[His theory is] a bold step, but there's probably nothing there, because, otherwise, people would have found it already.”

    In a soup

    The pond, or primordial soup, theory was dreamt up by the German biologist Ernst Haeckel in the late 19th century. But it was largely ignored until 1953, when Nobel laureate Harold Urey and Stanley Miller, then at the University of Chicago, attempted to mimic the early Earth's atmosphere in a test tube. They showed that a gas mixture of hydrogen, methane, ammonia, and water vapor can produce a rich brew of organic molecules such as amino acids and nucleotide bases—if sparked by electric discharges similar to bolts of lightning. These compounds would rain down into the primordial oceans, so the theory goes, until somehow they self-assembled into multimolecular aggregates and, eventually, cell-like structures.

    In the mid-1980s, however, geologists began to question some of the assumptions Urey and Miller had made about the gas mixture. Methane and ammonia were too ultraviolet-sensitive to be stable under the conditions of the early Earth, they realized. At the same time, planetary scientists discovered that Earth's early days were anything but tranquil. For most of its first billion years, Earth was under constant bombardment from asteroids and comets, heating the atmosphere above 1000 kelvin and triggering much volcanic activity. And when marine biologists found bacteria that were able to thrive at temperatures as high as 80°C in hot springs and around oceanic vents, says Pace, “this meant that life was possible at much higher temperatures than we previously thought.”

    Enter hobby chemist Günter Wächtershäuser. Although not affiliated with any research institution, Wächtershäuser is far from being a stranger to science; he earned his Ph.D. in organic chemistry in 1965 at the University of Marburg, Germany, and served as a postdoc there for more than a year. But he fled the rigid German academic system because he felt that the university environment was not giving him enough freedom to come up with original ideas. So even while working on his thesis he began to take law classes because he had decided to become a patent lawyer, “one of the few options for a chemist at the time where you can be your own boss,” he says. He bid farewell to research in 1966, got married to Dorothy Gray, an American historian, opened his own law firm, and settled into a life poking holes in his clients' patent applications. “I thought I'd never go back to do science,” he says.

    He was wrong. In 1972 he came across a paper on the origins of life by Hans Kuhn, one of his erstwhile university teachers. Although the paper “got me thinking about the subject,” recalls Wächtershäuser, it wasn't until a decade later, after being dragged by his wife to a talk about scientific progress by the late philosopher Karl Popper, that Wächtershäuser was hooked. The two men became friends, and Popper encouraged Wächtershäuser to expand his efforts beyond a few sheets of hand-scribbled notes.

    Another chance encounter sealed his fate. A distant relative of Wächtershäuser's was working as a graduate student at the University of Illinois, Urbana-Champaign, under microbiologist Carl Woese, who had a long-standing interest in finding the last common ancestor of all living organisms on Earth and working out the evolutionary tree of microbial life. “Carl, you've got to meet this guy,” Woese recalls the student telling him. “He's got some interesting ideas about the origins of life.” Woese assured Wächtershäuser that the topic was worth pursuing, pointing to several inconsistencies in the broth theory.

    One flaw was what Wächtershäuser calls the entropy problem. The dilution of the organic compounds in the early Earth's vast oceans makes any chemical reaction between two molecules unlikely and a meaningful encounter improbable. “As far as I'm concerned, the soup theory is more of a myth than a theory, because it doesn't explain anything,” he says. Once he realized that molecules needed some place to meet, it took him only one night to sketch out a first draft of his theory. The meeting place is provided by the surfaces of iron-sulfur minerals such as pyrite, which abound around underwater hydrothermal vents. The formation of pyrite, he speculated, could even serve as a chemical power plant, adding the chemical energy needed to react volcanic gases.

    His new friends urged him on. “I was lucky,” he says about his relationships with Popper and Woese. “I met the right people at the right time. Without their support, this would have gone nowhere.” In 1988 Popper submitted Wächtershäuser's first paper on the subject to the Proceedings of the National Academy of Sciences. “It was my first scientific publication in 22 years,” he says.

    A series of purely theoretical papers followed, sketching out Wächtershäuser's “iron-sulfur world” in Earth's early days, a complex network of chemical reactions that the 64-year-old patent lawyer is happy to scribble down on scrap paper as he explains his theory. His theory-laden approach, with little observational evidence in sight, is pure Popper. In Popper's view, says Woese, true scientific progress is possible only by building a theory and then trying as best as one can to prove it false. “[Wächtershäuser's] opponents constantly objected to his 'paper chemistry,' saying it was nothing but theory. Well, I'd say that's about the only thing a lawyer without a lab can do,” says Woese, who refers to Wächtershäuser as “the last disciple of Karl Popper.”

    Woese suspects that some of the early attacks on the theory were fueled by the fact that Wächtershäuser “was not a card-carrying member of the origins-of-life community.” But where others might have recoiled from attacks by scientific heavyweights, Wächtershäuser leapt at the chance to battle them at conferences around the world. Microbiologist Karl Stetter of the University of Regensburg, Germany, recalls a squabble between Wächtershäuser and Nobel laureate Christian de Duve in which de Duve eventually backed down, saying “Dr. Wächtershäuser, we're no patent lawyers here.” Notes Stetter, “He is sort of the pugnacious type.”

    Wächtershäuser has his own take on the adversity he had to face: “A lot of people cling to their theories because they depend on them being true to attract research grants, students, and so forth. So they defend them fiercely.”

    Proving it

    But Wächtershäuser knew he needed more than words to put his theory on a solid footing; he needed to test it in a lab. Joining forces with Stetter, they published a paper in Nature in 1994, showing that pyrite formation could indeed be the driving force in the creation of amide bonds, which form the backbones of all proteins. But the bonds between the two men soon unraveled, causing an estrangement that continues to this day. “At first it was a very exciting collaboration; I was all for it,” says Stetter. “But then one day out of the blue I got a letter from [Wächtershäuser] telling me that our collaboration was over. I suspect he was afraid I'd steal the show from him.”

    Cradle of life.

    Could the heat and minerals around midocean hydrothermal vents have forged basic organic compounds?

    CREDIT: RALPH WHITE/CORBIS

    Wächtershäuser then turned to Claudia Huber, a chemist at the Technical University in Munich, and in 1997 the pair reproduced a key reaction: joining two carbon atoms to form activated acetic acid, a chemical at the core of many cellular metabolic pathways. A year later the team linked amino acids into short peptides, the precursors of proteins.

    In August 2000, a group led by George Cody of the Carnegie Institution of Washington in Washington, D.C., reported creating pyruvate, a crucial component of all living cells consisting of three carbon atoms, with a mineral catalyst under conditions similar to the ones Huber and Wächtershäuser use. Wächtershäuser believes that the pyruvate finding could be the missing link in a so-called autocatalytic cycle, a circular series of chemical reactions that can sustain itself and produce more and more of the same chemicals. “Autocatalysis is the chemical expression for reproduction, one of the key features and, hence, maybe the first form of life,” he says.

    Early last year, an international team led by geologist Simon Wilde of Curtin University of Technology in Perth, Australia, presented evidence that continental crust and primordial oceans already existed on Earth 4.4 billion years ago. This suggests that as far ago as then, just the right conditions of heat and subsea volcanic activity may have been nudging organic molecules toward the earliest life forms.

    The experimental results mean that “people can't just wipe [the theory] away as paper chemistry,” Wächtershäuser says. And recognition was not long in coming. Wächtershäuser was awarded an honorary professorship by the University of Regensburg and has received four research grants, amounting to $500,000, from Germany's DFG funding agency. Wächtershäuser still maintains his patent practice, leaving him to ponder the secrets of early life in his leisure time. He uses the grant money to fund Huber's lab work—as well as her salary. In 1998, Huber's university contract ran out, so Wächtershäuser stepped in and now employs her through his law firm, although she still uses lab space at the university.

    Even with this mounting evidence, some scientists believe that Wächtershäuser's theory is too simplistic. “Life is not just chemistry. Life as we know it is based on the passage of genetic information from one generation to the next,” says Scripps's Bada. And even scientists who agree with the theme of Wächtershäuser's iron-sulfur world say that he skates over the finer chemical details. “The energetics [of Wächtershäuser's reactions] are plain wrong,” says geochemist Mike Russell of the Scottish Universities Research and Reactor Centre in Glasgow. “Pyrite, for instance, plays no role at all. I don't consider any of his stuff significant except his [synthesis of activated acetic acid] in 1997.” Acetic acid and pyruvate, adds RPI's Ferris, “are still pretty simple compounds. The real question is how do you build more complex biomolecules.”

    Woese isn't troubled by the questions that remain unanswered. “They haven't achieved the point they want to be at, but they're well on their way,” he says. Along the way, in his pursuit of freedom of thought, Wächtershäuser has regained his love for science—and done it on his own terms.

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