News this Week

Science  02 Jun 2000:
Vol. 288, Issue 5471, pp. 58

    Penn Report, Agency Heads Home In on Clinical Research

    1. Eliot Marshall

    In the 8 months since a teenager died in a gene therapy experiment at the University of Pennsylvania, clinical researchers have been on tenterhooks to learn what the consequences would be for Penn—and for national policy. Last week, they began to find out. Several federal agencies put forward proposals for sharply increasing the surveillance of human trials, especially those involving the use of viral carriers in gene therapy. And Penn, which has been in the hot seat for several investigations, announced a more rigorous system for approving and monitoring the use of human subjects that could add significantly to the cost of some types of academic research.

    The most dramatic move was a decision by Penn president Judith Rodin to trim the sails of its Institute for Human Gene Therapy (IHGT). The institute, directed by James Wilson, will no longer conduct any clinical trials, but will focus on basic science and animal studies. IHGT's six active clinical protocols had already been put on hold by the Food and Drug Administration (FDA); their fate is unresolved. However, 12 outside-sponsored gene therapy trials that are still under way elsewhere at Penn will continue. Wilson, who received this news in his office as Rodin delivered it to the press on 24 May, issued a short statement referring to “my continuing role” as director and promising to “refocus our efforts in the preclinical area.”

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    Rodin's comments came partly in response to the findings of an outside panel headed by William Danforth, former chancellor of Washington University in St. Louis. His seven-member group interviewed the IHGT staff and submitted its report on 27 April. The report studiously avoids issuing clear-cut findings of fault. Instead, it hints at its feelings through a series of questions. For example, it asks: “[Does it make] sense to have an entire institute devoted to gene therapy?” And in another section, the report observes that IHGT is a place where young investigators can administer potentially toxic viral vectors to patients almost like a new drug. It asks: “Are the risks well enough understood to promote widespread testing in inexperienced hands?” Without answering, the Danforth panel got across its message that administrative change was needed.

    The report does make some explicit general recommendations, however. One is that Penn review its policies on conflict of interest, noting that “equity positions by an investigator and/or the university may be ill advised” because of the perception of a conflict, whether or not it is real. (Both Penn and Wilson had an equity stake in a company that supplied reagents for the clinical trial in question.) Most importantly, the report urges Penn to be as meticulous as industry in adhering to federal regulations, even to the point of hiring professional staff to ensure compliance.

    Penn plans to follow that advice, Rodin says. Starting this year, it will ask all clinical researchers to submit a detailed safety monitoring plan that must be approved prior to the start of a new clinical trial. Ongoing trials will also get reviewed. Those posing a minimal risk to subjects will be handled by a new in-house office of five to 10 regulatory professionals. Those posing higher risk will be managed by an outside contractor. Penn is also allocating additional resources—including a new computerized data tracking system—to its Institutional Review Board, which clears protocols for ethical and safety concerns. In addition, the university will review its policies on conflicts of interest.

    Rodin said the goal is “to meet the highest possible standards for academic excellence and patient safety and care.” Provost Robert Barchi added that the extra cost of outside monitoring will in itself be “very significant”—about $100,000 to $200,000 for each small trial. “This is an important issue for clinical research nationally,” he noted.

    Responding to congressional concern about the same gene therapy trial, several federal agencies have also announced plans to boost surveillance of clinical research (Science, 26 May, p. 1315). On 25 May, William Raub, deputy assistant secretary for science policy of the Department of Health and Human Services (HHS), testified before the Senate's public health subcommittee, chaired by Senator William Frist (R-TN), along with officials from FDA and the National Institutes of Health (NIH).

    Raub issued a long list of promises. HHS, he said, will soon propose guidelines asking its grantee institutions to audit clinical records and to make sure that research subjects have given proper consent. In a new requirement, clinicians will be asked to inform participants about any serious adverse events relevant to them and have them “reconfirm” their consent. NIH intends to ask clinicians to submit plans for monitoring the safety of smaller phase I and phase II plans, something not required in the past. New reporting requirements are being considered that would require sharing more data from ongoing trials with local review boards.

    The witnesses also pledged changes in clinical research standards. This summer, NIH and FDA will sponsor a national dialogue on conflicts of interest. Raub said these discussions will lead to new guidelines on financial disclosure “which will apply to all NIH-funded research.”

    The renewed attention to financial conflicts has already had an impact. Last week Harvard Medical School, which was considering a proposal to relax its strict limits on faculty members' involvement in outside commercial ventures, decided to table the proposal. In a 25 May memo to faculty explaining this decision, medical school dean Joseph Martin wrote, “I believe that the most important role academic medicine can have in clinical research today is to try to bolster the public's faith in the veracity and ethical underpinnings of this noble endeavor.”

    Frist was not impressed with HHS's efforts, however. He took the government officials to task for not moving more rapidly to increase surveillance and enforcement of clinical research rules. “I am very disappointed” with HHS's progress to date, Frist said, adding that “your response absolutely must be more comprehensive.”

    Even so, one intrepid witness—Savio Woo, president of the American Society of Human Gene Therapy in Milwaukee—offered a contrary view. He suggested that it would be unwise to rush forward with some new regulations and warned that doing so could have damaging consequences. By requiring even small clinical trials to be managed by someone other than the principal investigator, Woo said, the government could impose “excessive costs that will stifle academic clinical research.” Innovative studies of rare diseases would be hit hardest, he added.


    Brain Cells Reveal Surprising Versatility

    1. Gretchen Vogel

    When a team of scientists reported last year that stem cells from the brains of adult mice could become functional blood cells, many scientists were intrigued, if a bit skeptical. Now, these versatile cells have shown even more surprising abilities: When injected into embryos, it seems, they can develop into nearly every type of tissue in the body. The work, described on page 1660, leaves a number of questions open. Even so, the cells' apparent flexibility is “amazing; it's really quite spectacular,” says developmental biologist Janet Rossant of Mount Sinai Hospital in Toronto.

    Scientists are amazed because decades of study had suggested that as development proceeds, cells become more and more specialized, and more restricted, in what they can do. According to widely accepted dogma, only embryonic stem (ES) cells, which are isolated before key differentiation steps occur, can become any tissue in the body. The latest results are another blow to that idea, showing that cells from adult animals are “able to revert into essentially ES cells” when they receive certain signals from the environment, says developmental neuroscientist Derek Van Der Kooy at the University of Toronto.

    The findings may also have political implications. Because of the broad developmental potential of ES cells, researchers want to explore whether they can be used to provide replacement tissues for treating conditions such as spinal cord injuries, Parkinson's disease, and diabetes. But because human ES cells have to be taken from embryos, the U.S. Congress currently prohibits using federal funds to produce them. If certain molecular signals can indeed induce adult stem cells to develop into many different kinds of tissue, the work may fuel the arguments of the opponents of ES cell research who have testified that federal funding of human ES cell research is unnecessary, because cells from adults are equally promising. However, most scientists caution that the research on both adult and embryonic stem cells is too premature to compare the potential of the two.

    Clues that adult stem cells might have wider abilities than expected began to accumulate last year, as researchers reported that mouse brain cells could become blood and cells taken from bone marrow could become muscle (Science, 25 February, p. 1418). Scientists have had trouble replicating some of these findings, and developmental neuroscientist Jonas Frisén and his colleagues at the Karolinska Institute in Stockholm decided to put adult stem cells to an even more rigorous test: to see if they could duplicate the characteristic feat of mouse ES cells, which can incorporate into another embryo and contribute to all the tissues of the resulting chimeric mouse.

    Postdoctoral researcher Diana Clarke began by removing cells from the brains of adult mice and culturing them for about a week, to separate stem cells from fully differentiated cells, which die in culture. She and her colleagues then injected early mouse embryos either with neurospheres, aggregates of neural stem cells that form in culture from single cells, or with a group of dissociated cells, and allowed the embryos to develop until embryonic day 11. Because the researchers had derived the stem cells from mice that express a bacterial enzyme called _-galactosidase, they were able to follow their fates by applying a sugar derivative that releases a blue dye when cut by the enzyme. The team found blue-stained descendents of the stem cells in various organs—including the heart, liver, intestine, and nervous system—in six of the 600 embryos injected with dissociated cells, and 11 of the 94 embryos injected with neurospheres.

    They had even better success with a different model. Mouse ES cells can incorporate themselves into developing chicks, and when Clarke injected neurospheres into the amniotic cavity of early chick embryos, she and her colleagues found progeny of the mouse cells in the liver, spinal cord, stomach, and kidneys of about one-quarter of the surviving embryos.

    Both sets of experiments produced a puzzling result, however: Neural-derived cells did not appear in the blood systems of either the mouse or chick embryos. In light of last year's results, that is a “glaring, interesting conundrum,” says neuroscientist Fred Gage of the Salk Institute for Biological Studies in La Jolla, California. The cells' absence in the bloodstream “doesn't mean they can't” become blood, he says, “but it leaves open the possibility that they don't.”

    Even more important, several researchers say, is the question of exactly what type of cell formed the various other tissues. Frisén and his team cannot tell whether the cells that contributed to the various embryonic tissues are some sort of rare, undifferentiated cell or whether something in the embryonic environment actually reprograms a cell that had already begun to differentiate. Scientists would dearly love to know the answer to that question, as it would help them understand what molecular factors allow stem cells to change their fates.

    Rossant notes that it would also be nice to know whether the neural-cell chimeras would continue to develop into normal adults as ES-cell chimeras can, and especially whether the neural cells could become mature sperm and eggs. Nevertheless, she says, the work “is another demonstration that adult stem cells have more potential than we thought. Now we have to figure out how to harness that potential.”


    Statistical Physicists Phase Out a Dream

    1. Barry Cipra

    For decades, the Holy Grail of statistical mechanics has been a mathematical problem known as the Ising model. Introduced in the 1920s by German physicist Ernst Ising, the Ising model is a powerful tool for studying phase transitions: the abrupt changes of state that occur, for instance, when ice melts or cooling iron becomes magnetic. Although they've learned much from approximate solutions and computer simulations, physicists have long sought an exact mathematical solution to the Ising model, which would provide much more information about such still-mysterious transitions.

    Unfortunately, it looks as if that's not in the cards. Sorin Istrail, a theoretical computer scientist at Celera Genomics in Rockville, Maryland, has proved that the Ising model—at least in its most general, three- dimensional (3D) form—belongs to a class of problems that theorists believe will remain unsolved forever. “People have always thought the 3D solution was just around the corner,” says Alan Ferrenberg, a computational physicist at the University of Georgia, Athens. “It really means now that numerical analysis is the only way we've got to approach [the Ising model].”

    The Ising model deals with objects—say, atoms—laid out in a regular array, such as a rectangular grid or a honeycomb arrangement. The array can be 1D (think of beads on a string), a 2D grid, or a 3D lattice. What makes the model so useful is that it helps physicists understand how a large system of objects, each interacting only with its nearest neighbors, can combine to create a large-scale order. In a ferromagnet, for example, each atom has a magnetic moment that points either up or down. Pairs of neighbors with opposing moments raise the total energy of the system, while those with parallel moments lower it.

    Solving the model means counting the number of arrangements that add up to each given energy level. Some versions of the Ising model can be solved exactly. Ising himself solved the 1D ferromagnetic model—and found it had no phase transition. In 1944, the Norwegian chemist Lars Onsager discovered an exact formula for the 2D model, which does possess a phase transition. But scientists have never been able to extend Ising's and Onsager's solutions to the physically realistic realm of three dimensions. “We now know why,” says Istrail. “What these brilliant mathematicians and physicists failed to do, indeed cannot be done.”

    While working at Sandia National Laboratories, Istrail proved that computing the energy states for the general 3D Ising model is what computer scientists call an NP-complete problem—one of a class of recalcitrant calculations that theorists believe can be solved only by arduous brute-force computations. In effect, an exact solution to the Ising model would provide the key to efficient algorithms for solving thousands of other computational problems, ranging from factoring large numbers to the notorious traveling salesman problem, in which the salesman must find the most efficient route through a given number of cities. Although no one has proved that such a sweeping solution is impossible, theorists are fairly certain the NP-complete problems really are as hard as they seem to be. If so, the 3D Ising model is intractable, too.

    To reach that dismaying conclusion, Istrail started by translating the Ising model into terms of graph theory. A mathematical graph is just a collection of points called “vertices,” pairs of which are connected by “edges”—just as in the Ising model pairs of neighboring atoms are linked by the interactions between them. The edges may be weighted with numerical values. In the traveling salesman problem, for example, the weights are the distances between pairs of cities. For the Ising model, the weights describe the amount by which parallel or opposing magnetic moments of neighboring atoms increase or decrease the energy.

    Computing the lowest energy state for the Ising model, it turns out, is equivalent to cutting the corresponding graph in two by plucking off the edges whose weights add up to the smallest possible number. For planar graphs—that is, graphs that can be drawn on a piece of paper without any of the edges crossing—that calculation is a relative breeze. But 3D lattices are inherently nonplanar, and that, Istrail recognized, is the key. He has shown that any nonplanar graph throws up a barrier of computational intractability.

    It might still be possible to find exact answers for some special cases of the Ising model, Istrail notes. In particular, the ferromagnetic case of the 3D Ising model may turn out to be simple enough to solve. Nevertheless, the overall message is clear. “We need a paradigm shift,” Istrail says. “Instead of waiting for the mathematics to advance, we have to accept this impossibility.” And the computational complexity of the Ising model could be just the tip of the iceberg. “There is something about this world that doesn't allow us to understand it.”


    Reports See Progress, Problems, in Trials

    1. Laura Helmuth

    Ten years after its scathing report on the National Institutes of Health's failure to include women in clinical research, the General Accounting Office (GAO) has concluded that the NIH is doing much better. Women are clearly taking part in clinical studies—in even greater numbers than men. And the amount of money devoted to diseases, such as breast cancer and depression, that disproportionately afflict women has risen steadily, outpacing increases in the NIH's overall budget. But NIH-supported researchers aren't always putting their data on women subjects to use.

    The 2 May GAO report, amplified by a study in the June Journal of Women's Health & Gender-Based Medicine, shows that only a small fraction of publications based on NIH-funded research report a sex analysis of the data. “It's important to have women in clinical trials,” says Phyllis Greenberger, head of the Society for Women's Health Research (SWHR) in Washington, D.C., “but not for the hell of it. The point is to do the gender analysis.”

    Such analyses are crucial, she and others note, because women respond differently to some drugs, carry a higher risk of certain diseases, and can present with disease symptoms different from men's. Without a comparison of the sexes, both men and women miss out on sensitive diagnostics and tailored treatments. The director of NIH's Office of Research on Women's Health, Vivian Pinn, acknowledges the importance of gender-based analyses but points out that NIH has no control over whether grantees carry out and report them. “We don't dictate editorial policies for journals,” Pinn says.

    Researchers had historically been reluctant to include women subjects, says molecular biologist Regina Vidaver of the SWHR, because they didn't want to deal with potential birth defects or variability in responses due to hormonal changes during the menstrual cycle. The problem was exacerbated in 1977 after the Food and Drug Administration barred women of childbearing age from participating in early clinical trials because of fear of birth defects. In 1985 the U.S. Public Health Service pointed out the obvious repercussion: The lack of information could seriously compromise health care for women. The NIH, in response, urged researchers to include women in their clinical studies.

    Not much had changed by 1990, according to a GAO study, which along with outrage over studies showing the benefits of exercise and of aspirin for preventing stroke—conducted in men only—prompted NIH to act. By the end of the year, the NIH began to require the inclusion of women and minorities in research. In 1993, Congress passed the NIH Revitalization Act that established guidelines for accomplishing that.

    By many measures, the past decade's efforts have succeeded. Women constitute 62% of all subjects in clinical studies funded by NIH grants to outside researchers. For phase III protocols, the last stage of clinical trials before a treatment is approved for widespread use, 75% of subjects are women. Even when sex-specific studies, such as those focusing on ovarian or prostate cancer, are excluded from the analysis, more than half the remaining subjects are women.

    The GAO report cautions that NIH bookkeeping methods preclude a detailed analysis of funding for women's health research. But funding for some conditions that disproportionately affect women grew steadily between 1993 and 1999. Research expenditures went up 78% for osteoarthritis, 59% for breast cancer, and 73% for depression and mood disorders. For comparison, the overall NIH budget rose by 29% during that time. The NIH also collaborates with other federal agencies in the Women's Health Initiative, a study of 164,000 postmenopausal women that is examining the effects of hormone replacement therapy, diet, and vitamins on cardiovascular disease, breast cancer, and the bone-thinning disorder osteoporosis.

    The problem, Vidaver points out, is that NIH-funded researchers still aren't breaking down their data by sex. Her team examined hundreds of NIH-funded, non-sex-specific studies published in The New England Journal of Medicine, The Journal of the American Medical Association, the Journal of the National Cancer Institute, and Circulation between 1993 and 1998. Of those, 80% included women. But only 25% to 30% of the studies with women subjects reported a gender analysis, which may have been as brief as a statement that there were no significant sex differences. That share remained constant over the period, Vidaver adds.

    NIH's Pinn says that the analysis is premature, because the studies would have been funded before the 1993 law was implemented. But Greenberger counters that the NIH began urging the inclusion of women starting in 1986, adding that “we thought at least we'd see a trend” toward more gender analyses.

    The society isn't waiting for NIH to make things happen. On 25 May, it wrote to the editors of 32 leading journals, calling on them to revise publication guidelines to require a sex analysis.


    Radical Steps Urged to Help Underserved

    1. Martin Enserink

    Bethesda, MarylandThese are miraculous times for researchers working on vaccines for the world's major scourges. For years, their plea for more funding, political attention, and greater involvement from the pharmaceutical industry fell on deaf ears. But recently, their cause has been embraced by politicians around the world—indeed, President Clinton seems determined to make it part of his legacy—and industry leaders have promised to do what they can. Suddenly, anything seems possible.

    So when a broad group of researchers, big-pharma CEOs, and public health experts met last week at Clinton's request to discuss the main obstacles on the road to new vaccines for AIDS, malaria, and tuberculosis, * meeting organizers urged them to think big. “Now is your chance, folks!” beamed Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), who said the ideas would help shape the Administration's future policy. The participants were happy to comply, with proposals that range from a 10- or 20-fold budget increase to a new, more flexible funding agency to circumvent the National Institutes of Health's (NIH's) bureaucracy. A few even proposed a crash effort akin to the Apollo program that put a man on the moon within a decade.

    Epidemiologists say vaccines are the only practical way to cut the death toll from AIDS (currently estimated at 2.6 million annually), TB (which kills 1.5 million to 2 million), and malaria (more than a million). Doing so would also be a boon for development, economists point out: In Africa, especially, sickness and death take a huge toll on the economy.

    Yet funding for most types of vaccine research has been hard to come by because the big killers overwhelmingly afflict the developing world. NIH currently spends a paltry $6.5 million a year to find a vaccine for TB and $25 million for malaria. (Vaccine studies for AIDS, which poses more of a threat to the U.S. population, will get an estimated $250 million this year.) Pharmaceutical companies have been reluctant to bet much of their R&D budgets on these vaccines, as expected returns are low, and developing countries don't always respect industry patents. For the same reasons, cash-starved small biotech companies have a hard time attracting venture capital.

    To help break the pattern, Clinton proposed a Millennium Vaccine Initiative in January, which includes increased funding for NIH, a $50 million contribution to the Global Alliance for Vaccines and Immunization, and a $1 billion tax break on vaccine sales to stimulate industry investments. Several bills before Congress would do more or less the same, and some European countries are considering similar steps. The issue will also be on the agenda when leaders of the eight major industrial nations meet next month in Okinawa, Japan.

    Not all of the proposals to come out of the NIH meeting, however, are likely to make it onto the table, at least in their current form. The malaria researchers, for instance, want the president to initiate an “aggressive malaria vaccine program” and raise funding to $500 million a year. The group also thinks the U.S. should agree to purchase $500 million a year worth of vaccines, if one gets developed, to guarantee that there is a market. The AIDS group pleaded for a 10-fold funding hike for vaccine studies in general, while the TB researchers suggested setting up something akin to the Defense Advanced Research Projects Agency—which prides itself on attracting daring ideas and funding them swiftly—and endowing it with $3 billion. “We need out-of-the-box thinking,” says Barry Bloom, dean of the Harvard School of Public Health in Boston.

    The meeting ended without a set of recommendations, but NIAID's Fauci says his institute will write a summary and pass it on to Health and Human Services Secretary Donna Shalala. Most participants, like Malegapuru Makgoba, president of the Medical Research Council of South Africa, were optimistic that tangible results are within reach: “I'm confident that we'll see an AIDS vaccine in the next 5 or 6 years.”

    But the lack of clear-cut plans on how to proceed left some a tad disappointed. “We shouldn't continue to have these very general meetings, where a shopping list is read out,” says Richard Feachem, director of the Institute for Global Health in San Francisco and a veteran of similar gatherings, some with the same cast, over the past year. “This is a very special time,” he asserts. “There's an energy now that we need to harness quickly, because it might be lost.”

    • *Vaccines for HIV/AIDS, Malaria and Tuberculosis: Addressing the Presidential Challenge, 22 to 23 May, at NIH.


    Furtive Glances Trigger Radioactive Decay

    1. Charles Seife

    Quantum physicists love to shatter conventional wisdom—even their own. Take radioactive decay. Common sense says you can't keep an atom's nucleus from decaying simply by looking at it. Quantum mechanics says you can. Now two Israeli physicists have come up with a way in which watching a nucleus might make it decay faster.

    The decay-preventing process, known as the quantum Zeno effect, has fascinated physicists for 25 years. It takes its name from the paradox-mongering Greek philosopher who imagined himself repeatedly interrupting an arrow's flight to chop its trajectory into smaller and smaller bits—thus proving (he thought) that motion was impossible.

    In the quantum case, what is ruined by interruption is not motion but processes such as nuclear decay. Imagine an alpha particle, two protons and two neutrons, lodged inside a much larger, radioactive nucleus. The particle is there because it can't hurdle the nuclear “energy barrier” that holds it in. Sooner or later, though, the particle probably will escape, causing the nucleus to decay. It can do that by tunneling through the barrier, in a strange quantum way. At first, the particle is firmly stuck on one side of the barrier, but as time goes on, it “spreads out” and starts to exist in a “superposition” of bound and free states that puts it, in effect, on both sides of the barrier at the same time. From this superposed state, the particle may decide that it is on the far side of the barrier, break free, and escape.

    But there's a twist. If someone observes the particle, by, say, bouncing a photon off it, whatever superposition there is “collapses,” and the particle must instantly decide which state it is in—inside or outside the barrier. “You make your measurement and, bingo! You're in one and only one state,” explains Peter Milonni, a physicist at Los Alamos National Laboratory in New Mexico. By repeatedly measuring and prodding the particle, a scientist can keep destroying the superposition before it gets established, drastically reducing or even eliminating the possibility that the particle will tunnel through the barrier. “The exponential decay process could be slowed down or completely interrupted by the Zeno effect,” says Gershon Kurizki of the Weizmann Institute of Science in Rehovot, Israel. In short, the watched pot never boils. Physicists think they've seen this quantum Zeno effect in experiments with photons and with trapped ions.

    Now Kurizki and his colleague Abraham Kofman argue in this week's issue of Nature that the reverse can happen: Under certain conditions, the watched pot always boils. Kurizki and Kofman think of the Zeno effect as an interaction of overlapping energy states. Before tunneling, a particle can take on a certain range of energies; after tunneling, it has another range. A particle can tunnel only if those energy ranges overlap. Energy ranges, however, can change. If you knock a particle by measuring it, for example, the jolt from the photon broadens the range of energies the particle can take on. The faster you repeatedly measure the particle, the broader the range gets. With more energy options to choose from, the particle spends less time in any particular part of its range. Thus, by repeatedly observing a before-tunneling particle, physicists can ensure that it spends almost all its time at energies that don't overlap with after-tunneling energies. The result: no tunneling, and no nuclear decay.

    Kurizki and Kofman realized that the exact opposite can happen. Suppose, they said, your before-tunneling energies and after-tunneling energies don't overlap to begin with. In that case, the particle can't escape. But repeated measurements might broaden the range of before-tunneling energies so that it creeps into the after-tunneling zone, allowing the nucleus to decay. “If you do it sufficiently fast, you would see an increase of the decay rate,” Kurizki says. “The same procedure leads to the opposite of what is expected.”

    Although nobody has yet seen the anti-Zeno effect in action, Kurizki believes experiments will verify it within a few years. In fact, he thinks the anti-Zeno effect ought to be much more common than the Zeno effect—“the rule rather than the exception.” If so, that could be bad news for scientists trying to develop quantum computers. Some physicists have proposed using the Zeno effect to keep quantum bits from losing the information they contain. But a repeated measurement might induce an anti-Zeno effect instead, Kurizki says. “It might have the opposite effect.”


    Closed Ethics Case Sparks Dueling Bills

    1. Jeffrey Mervis

    A 2-year-old case of financial impropriety by a former National Science Foundation (NSF) senior staffer has exploded like a time bomb on Capitol Hill, sending the agency running for cover. The surprise battleground is new legislation to reauthorize NSF's programs, a process normally carried out with little fanfare. The dispute pits the chair of the House Science Committee, James Sensenbrenner (R-WI), against Nick Smith (R-MI), chair of the panel's basic research subcommittee. Caught in the crossfire is NSF Director Rita Colwell, who needs both men as allies in the annual fight for federal dollars.

    On 17 May Sensenbrenner proposed cutting the director's travel budget, staff levels, and her ability to temporarily transfer employees to outside organizations as part of legislation, H.R. 4485, to authorize NSF's programs for the next 4 years. He says it's a response to the “fiasco” stemming from NSF's reaction to rule-breaking by Luther Williams, former head of the education directorate. Williams was fined $24,900 in June 1998 for improperly accepting outside honoraria (Science, 26 June 1998, p. 2053). “They completely mishandled the case,” Sensenbrenner says about NSF's decision to reprimand Williams but allow him to keep his job for more than a year. Then, last summer, the agency reassigned him under the Intergovernmental Personnel Act (IPA) to a new program run by Louisiana's Tulane University (Science, 13 August 1999, p. 997).

    In particular, Sensenbrenner says he's incensed because Williams was allowed to retire 5 months after the reassignment, rather than return to NSF, and because the Tulane program's founder, president emeritus Eamon Kelley, also heads the National Science Board. “[The first] is a violation of the rules regarding IPAs,” he says, “and [the second] doesn't pass the smell test.” An NSF spokesperson said that Colwell did not wish to comment on the matter.

    The reauthorization bill, which sets funding levels for individual programs, would prohibit NSF from detailing staff to any outside organization as an IPA, mandate ethics training for all NSF staff, and require Colwell to update Congress twice a year on the training and related matters. “It's an attempt to make sure that this stuff never happens again,” says Sensenbrenner. He calls the language “a preemptive strike” to protect NSF against legislators who might use the controversy as an excuse to trim the agency's budget. The bill matches the president's 17% requested increase for NSF in the fiscal year that begins on 1 October and includes much more modest annual increases—from 2.5% to 3.3%—for the next 3 years. “I'm a fan of NSF, but sometimes basic research is a hard sell,” he explains.

    Two days after Sensenbrenner introduced his bill, Smith introduced his own version, H.R. 4500. It hews closely to Sensenbrenner's on most counts—but omits the prohibition on IPA transfers as well as the travel cuts and the ethics program. Legislative aides say it is highly unusual for a subcommittee chair to introduce a bill that competes with one by his boss. In another bizarre turn, H.R. 4500 was actually Smith's second NSF authorization bill. The day before, he introduced H.R. 4491, which retains all of Sensenbrenner's punitive language and differs only in proposing two, rather than four, years of future budgets. Smith declined to comment on either of his bills, but Capitol Hill sources speculate that the earlier version had been filed in haste.

    Sensenbrenner says that he hopes the full science committee can take up his bill sometime this month. Such a move would bypass Smith's basic science subcommittee, which oversees NSF, but Sensenbrenner says it is standard practice. The move would also make it harder for Smith to hold a hearing on his legislation.

    Even if approved, however, Sensenbrenner's bill stands only an outside chance of being considered by the full House before Congress adjourns in the fall. It also lacks a counterpart in the Senate. The bill's demise certainly wouldn't upset NSF officials, who hope that the flap doesn't affect their long-term relationship with their closest congressional overseers.


    Patients Help Track Down Disease Gene

    1. Elizabeth Pennisi

    In the Terry household, patient advocacy is a family affair. At age 11, Elizabeth Terry testified before Congress to promote biomedical research. Her mother travels around the country seeking out patients with pseudoxanthoma elasticum (PXE), the disease Elizabeth and her younger brother, Ian, were diagnosed with some 5 years ago. Their father makes regular trips to the local medical library to follow up leads.

    Together, they established and run a patient advocacy group from their house, one that is promoting “a new breed of advocacy,” says Francis Collins, director of the National Human Genome Research Institute in Bethesda, Maryland. Like the Hereditary Disease Foundation, which played a pivotal role in coordinating research and tracking down the gene for Huntington's disease, the Terrys' organization has become “aggressively involved in the science,” says Collins, as well as in securing funding and working with PXE patients. In the past few weeks, their relentless work has paid off in a big way.

    Their organization, PXE International, has helped three research teams pinpoint the identity of the gene for this rare inherited disorder. Two labs, led by Charles Boyd at the University of Hawaii, Honolulu, and Arthur Bergen at the Netherlands Ophthalmic Research Institute in Amsterdam, report their results in the June issue of Nature Genetics; the third group, led by Jouni Uitto at Thomas Jefferson University in Philadelphia, published its findings in the 23 May Proceedings of the National Academy of Sciences.

    But PXE International isn't the only patient group to play a key role in unmasking the identity of the PXE gene. An older, albeit less media-savvy, organization called the National Association for PXE (NAPE) teamed up with the March of Dimes, a Texas dermatologist, and a Harvard genetics lab to help place the gene for this disorder on the genome map—literally—in 1997. Now, the collaboration, led by Klaus Lindpaintner, a physician-geneticist at Harvard's Brigham and Women's Hospital, has also identified the gene itself. It reported its results online in the 26 May Journal of Molecular Medicine.

    All the researchers say that having a group of families willing to work with them was critical to their success. “If the patient community had not been involved, there would have been no studies,” agrees Sherri Bale, a geneticist with GeneDX, a start-up in Rockville, Maryland, that makes genetic diagnostic tests.

    The four teams converged on a little-studied gene, called ABCC6 or MRP6, on chromosome 16 as the culprit in PXE. Traditionally considered a skin disease, PXE causes calcium to accumulate in connective tissue of the eye, gut, heart, and skin, sometimes causing vision loss, gastrointestinal bleeding, and heart as well as skin problems. The researchers do not yet know how mutations in the gene, which seems to be involved in transporting material in and out of cells, lead to the disease. One puzzle is that the gene is most active in the liver and kidneys, and the researchers have found very little evidence of the protein in the skin, as they would have expected. That leads Uitto to speculate that “it may well turn out that PXE is primarily a metabolic disorder, and the connective tissue manifestations are secondary phenomena.” He adds, “Once we figure out what the normal gene does, we might be able to help these patients.”

    The hunt for this gene has been long and frustrating. Indeed, several groups put their efforts on hold in the late 1980s, and the search languished until around 1994. Then, after a chance meeting, Lindpaintner teamed up with Kenneth Neldner, a dermatologist at Texas Tech University Health Sciences Center in Lubbock. Neldner had been working with NAPE, an organization started in the late 1980s by Diane Clancy, a PXE patient in Albany, New York, out of her living room. The two researchers contacted NAPE members and got PXE patients and their families to donate the blood samples they needed to track down the gene. By 1997, Neldner and Lindpaintner had narrowed their search to the short arm of chromosome 16; Bergen had also found a connection between PXE and that part of chromosome 16.

    Shortly before that connection was made, Sharon and Patrick Terry entered the picture. Concerned that too little work had been done to understand PXE, they turned to the Washington, D.C.-based Genetic Alliance, an umbrella group of patient organizations, for advice on setting up their own advocacy group. After consulting with geneticists, the Terrys established a blood bank, persuading PXE patients and families from all over the world to send in blood samples and to have their family histories documented. When she learned about Lindpaintner's and Bergen's success in localizing the gene, Sharon Terry helped organize a meeting of all the researchers on the trail of the PXE gene. At first it seemed the groups would collaborate. But tensions arose over sharing data and, eventually, NAPE and Lindpaintner went their own way.

    Because the relevant section of chromosome 16 had been sequenced and studied by then, the various teams knew there were six genes in that region. None looked like an obvious candidate for causing the disease, so the researchers simply scanned for mutations, working painstakingly one gene at a time. Boyd recounts that his team found nothing interesting in the first five genes they examined. But “the moment we started looking at the ABCC6 gene, we ran into mutations,” he says. Individuals with PXE had several distinctive changes in the gene, whereas DNA samples from 100 healthy individuals showed no mutations. The evidence, Lindpaintner agrees, “is very much cut and dried,” leaving little doubt that this is the right gene.

    Even before the gene's function is understood, it may prove useful in diagnostic tests. PXE symptoms and age of onset vary quite a bit. Now it should be easier to get definitive confirmation of the disease, says Boyd, and also to identify asymptomatic carriers. Both Boyd and Lindpaintner suspect that, depending on the mutation, apparently asymptomatic carriers may face unrecognized risks—such as a greater propensity toward heart disease or eye problems early in life that might be reduced by modifying the diet or monitoring eyesight carefully to detect early signs of vision loss.

    Both the patient groups and the researchers are now planning their next steps. “We realize [the gene] is not the end of the road,” says NAPE spokesperson Carol Daugherty. In the works are efforts to learn more about how the gene functions in cells and whether the variability in the disease's course is linked with particular mutations. Daugherty says she regrets that NAPE and PXE have been unable to join forces. Nevertheless, she adds, “each group takes its separate road to what I'm sure is a common goal—improving the lot of individuals with PXE.”


    Clinton to Expand Marine Reserve Areas

    1. David Malakoff

    A wave of announcements last week lifted the spirits of marine conservationists and researchers. Standing on a sun-dappled Virginia beach, President Bill Clinton on 26 May ordered federal agencies to develop an expansive new network of marine reserves in U.S. waters. The move came a few days after The Pew Charitable Trusts established a high-profile oceans commission that supporters hope will energize efforts to study and protect the sea. Adding to the bounty, federal officials also announced that they will shift shipping lanes away from environmentally sensitive areas off California, while researchers began an ambitious effort to count all forms of marine life (see p. 1575).

    In his appearance at the Assateague Island National Seashore, Clinton outlined a new executive order that seeks to protect a bigger portion of U.S. waters—which stretch for 320 kilometers offshore—from fishing, drilling, and other activities. Currently, less than 1% of the vast U.S. coastal territory is protected, demarcated by a dozen marine sanctuaries and other wildlife refuges or parks (Science, 25 July 1997, p. 489). To boost the total, Clinton ordered the Interior and Commerce departments to come up with a plan for designating and managing an integrated system of marine protected areas. To start, he wants improved safeguards for 12,000 square kilometers of coral reefs in the Northwest Hawaiian Islands, home to nearly 70% of U.S. reefs.

    While it's not clear if such bureaucratic efforts will pay off, “I can't think of a better way to begin the first summer of the new century,” said Elliott Norse, president of the Marine Conservation Biology Institute in Redmond, Washington. He and others are pushing to increase U.S. protected waters to 20% of the total by 2015.

    The new Pew Commission on Oceans, to be led by New Jersey's Republican governor, Christine Todd Whitman, and packed with political and business heavyweights, hopes to repeat the impact of an earlier oceans panel. The 1969 Stratton Commission, chartered by Congress, sparked the creation of the National Oceanic and Atmospheric Administration and new coastal conservation legislation. But it also unintentionally encouraged overexploitation of the sea's once seemingly limitless resources, says Carl Safina of the National Audubon Society in New York City.

    The new panel, Safina says, has a chance to take a “clear, cold look at what's needed and what is appropriate now—and that's long overdue.” The commission will hold its first meeting in July, with a final report due in 2002.


    Stephen Straus's Impossible Job

    1. Erik Stokstad

    The new head of alternative medicine at NIH faces what may be a superhuman task: evaluating unconventional treatments—and pleasing both believers and skeptics

    Why in the world would a respected researcher like Stephen Straus leave a topflight lab at the National Institutes of Health to run NIH's new National Center for Complementary and Alternative Medicine (NCCAM)? After all, the center's predecessor, the Office of Alternative Medicine (OAM), was a child of politics that was widely denounced by mainstream researchers. Conceived by Senator Tom Harkin (D-IA), a die-hard fan of alternative medicine and ranking Democrat on the subcommittee that approves the entire NIH budget, the office was earmarked into existence in 1992. It soon gained a reputation as a counterculture enclave for pseudoscience. After just 2 years, the office's first director resigned in protest. Harkin, he claimed, had stacked the advisory board with credulous advocates and was meddling in OAM affairs.

    The office's reputation didn't improve under the tenure of the next director, a homeopathic physician. High-profile scientists continued to condemn OAM for sponsoring inconclusive research and bestowing prestige on practices that sometimes resembled “witchcraft.” In 1997, former presidential science adviser D. Allan Bromley and others urged Congress to abolish the office. Instead, Harkin kept boosting its budget, from an initial $2 million to nearly $70 million this year. And in 1998, he succeeded—over the objections of then-NIH director Harold Varmus—in elevating the office to a full-fledged center with its own authority to award research grants.

    So, last fall, when Varmus recruited Straus, a battle-hardened mainstream clinical investigator, to head up the new center, even critics of OAM lauded the choice. But they and even some of his colleagues wondered why Straus accepted. “It takes guts to take on a job like this,” says Anthony Komaroff, a former collaborator with Straus and physician at Harvard Medical School in Boston.

    Some, like Komaroff, think Straus has the right combination of receptiveness to new ideas and scientific rigor to pull it off. A longtime NIH physician and virologist, the soft-spoken Straus has strong scientific credentials earned during his studies of infectious diseases, from AIDS to herpes. And from his high-profile research on chronic fatigue syndrome, Straus is no stranger to controversy.

    Even so, Straus faces formidable challenges. His goal is to bring scientific rigor to a field that many of his peers would just as soon see disappear. His reputation, and that of the center, will hinge on how well he can do that. Straus will need a deft political touch to avoid the ire of alternative medicine advocates—including those who hold NIH's purse strings in Congress—yet also engage first-rate scientists in evaluating these untested therapies. Indeed, some doubt that anyone can succeed. NCCAM “is a political creation, through pressures of congressional believers and deluded supporters,” says Wallace Sampson of Stanford University, a longtime critic of alternative medicine. “Unless Straus plays footsie with them, he will not last.”

    So why did Straus agree to put himself in this hornet's nest? He says he was attracted to the chance to have a bigger impact on public health than he could as a bench scientist and lab director. He says he relishes the challenge. And his job, he enthusiastically explains, is to marshal the best science to figure out which of these therapies work and which don't, and then inform the American public, whose judgment he thinks is vastly underestimated. Therapies that work should be incorporated into mainstream medicine, Straus says; as for those that don't, the public needs to know that, too.

    Big business

    Scientific rigor is sorely needed in this enormously popular but largely unscrutinized field. Alternative medicine—loosely defined as treatments and practices not commonly taught in medical schools, not generally used in hospitals, or covered by insurance companies—is big business. Americans spent $27 billion on unproven remedies in 1997. St. John's Wort, a herb taken for depression, alone racked up an estimated $400 million in U.S. sales last year. According to a 1998 study in The Journal of the American Medical Association (JAMA), 42% of Americans have tried some sort of alternative medicine, from megavitamins to energy healing, up from 34% in 1990.

    Most of these substances and treatments have not been tested for either safety or efficacy. Thanks to heavy lobbying by the supplements industry, the 1994 Dietary Supplement Health and Education Act classifies botanicals as a kind of food supplement; these are not regulated by the Food and Drug Administration (FDA). As a result, manufacturers do not have to demonstrate that their products work or even that they are safe. Nor are they required to report adverse effects. Instead, the FDA must prove a danger before a supplement can be banned. For most, the risks and benefits are simply unknown.

    Straus, 53, has the kind of training necessary to get answers. During his 23 years at the National Institute of Allergy and Infectious Diseases (NIAID)—including 8 years as chief of the Laboratory of Clinical Investigation—Straus has investigated a range of diseases, a track record that has earned him the respect of NIH institute directors, Varmus says. That's a “key ingredient” in making this job work, adds Varmus, as most of the center's clinical trials are done in collaboration with other institutes.

    Equally important for relations with the wider scientific community, Straus wants to allay fears of NIH-sponsored quackery. In his warm bedside manner, Straus insists he is not an advocate of alternative therapies, only an advocate of good science. He doesn't practice alternative medicine, nor does he take any. The closest he has come to prior hands-on experience with the field was a clinical trial he designed and participated in to investigate whether capsaicin, the active component of hot peppers, might help against herpes simplex virus. (It didn't.)

    Yet Straus does not reject alternative practices out of hand. As a physician, he sometimes referred his patients with chronic fatigue syndrome and acute postherpetic pain to hypnosis, acupuncture, and other practices if they weren't satisfied with his standard care. To Straus, respect for patients and different practices is key. “He seriously listens to people, and he's got a scientific ability to think how to assess these problems without being contentious or confrontational,” says John La Montagne, deputy director of NIAID. “He really is an ideal person for this job.”

    Straus has also weathered the intense scrutiny of his peers and the wrath of advocates. While he was principal investigator for a clinical trial of an experimental drug for hepatitis B, called fialuridine, five of 15 patients in a related trial died from liver or pancreatic damage. The FDA sent letters to Straus and several other investigators, accusing them of not reporting side effects promptly and understating “foreseeable risks.” (Panels appointed by NIH and the Institute of Medicine found no wrongdoing, and NIH praised the trial as “the best of current practice.”)

    On the flip side, when Straus was investigating chronic fatigue syndrome, he concluded that the disease has a psychological component. This finding enraged some advocates, who unsuccessfully tried to get him sacked. But Straus refused to budge from his scientific principles. Notes La Montagne: “He gained in credibility and stature because of that.”

    Straus says the experience taught him a valuable lesson: Keep advocates plugged into the research. “I learned that one needs to listen to advocates and incorporate them into the research process, rather than marginalize them, because they're far better as partners than as your adversaries.”

    Science or quackery?

    The kinds of therapies Straus is charged with investigating—from homeopathy to shark cartilage to coffee enemas—would make many of his colleagues smirk. But where others might despair of ever designing a rigorous study of, say, energy healing, Straus sees room for creative clinical design. At the top of Straus's list of therapies to study are those that are widely used and for which there is some preliminary evidence that they work. Straus is most enthusiastic about clinical trials of compounds, such as botanicals or shark cartilage, because these can be tested in double-blind, placebo-controlled trials—the height of scientific rigor. Large clinical trials (see table) take up 21% of NCCAM's 2000 budget. The beauty of these types of studies, Straus says, is that “we don't have to reinvent the wheel. We can take what has worked, has been rigorous, and has given the best and most definitive answers.”

    View this table:

    Yet principles aside, Straus also has to follow the mandate of Congress—and some of its, well, less-than-scientific members. NCCAM is stuck funding a 5-year, $1.4 million trial of an unusual protocol designed to treat terminal pancreatic cancer by physician Nicolas Gonzalez. The so-called Gonzalez Protocol—a hodgepodge of pancreatic enzymes, coffee enemas, and up to 150 dietary supplements a day—caught the attention of Representative Dan Burton (R-IN), who in 1998 encouraged the National Cancer Institute (NCI) to study it. Even though Straus considers the evidence just an “aggregate of interesting anecdotes,” he defends the trial—albeit lukewarmly. “I'm more comfortable and find it easier to approach and fund things that already make a lot more sense to me,” he admits. “But the mandate here is … to be willing to take more risks for things that are novel.”

    NCCAM's other trials are more firmly grounded in science. For example, following up on a 1997 lead published in JAMA, NCCAM is co-funding with the National Institute on Aging a 6-year trial of an extract of Ginkgo biloba to prevent age- related dementia. Researchers from the University of Pittsburgh School of Medicine will coordinate the trial, which will include 3000 people in four clinical centers. Just like any other NIH trial, the Pittsburgh team was chosen as the principal investigators by peer review, says Richard Nahin, NCCAM's director of Extramural Research Training and Review.

    Another of the large trials already under way is a 4-year study of glucosamine and chondroitin—substances found in and around the cells of cartilage—for treating pain related to osteoarthritis of the knee. NCCAM and NCI are also supporting a phase III clinical trial of shark cartilage for advanced lung cancer. All patients will receive standard chemotherapy, but half will also take the shark extract. The other half will be given a placebo, and the researchers will then compare survival rates between the groups.

    Straus is confident these trials will be informative. As an example, he points to recent studies of St. John's Wort, funded by other institutions, that show both the potential and the danger of this botanical. In an 8-week trial of 263 patients with moderate depression, St. John's Wort was more effective than a placebo—and just as effective as a standard drug, according to a trial by researchers from the Bezirkskrankenhaus in Landshut, Germany. But a small NIH study showed that taking St. John's Wort reduces the efficiency of a widely used AIDS drug. Without the study, Straus says, AIDS patients would not have been aware of this danger.

    Even straightforward trials such as these face unusual hurdles that are not encountered when testing conventional drugs. Foremost is the quality and consistency of the product being tested. Sometimes the active ingredient may not even be known. Often unknown is the bioavailability and shelf life of the compound, or basic toxicological data. To help glean information about safety, efficacy, and biological action, NCCAM last fall began to co-fund (with the Office of Dietary Supplements, ODS) two botanical centers, one at the University of California, Los Angeles, and one at the University of Illinois, Chicago. Both will analyze botanicals for active ingredients and test their effects on everything from fighting tumors to lowering cholesterol. NCCAM also funds nine other centers that conduct research on alternative medicine for various conditions, such as arthritis, or groups, such as children.

    Investigating the implausible

    Trials that don't involve drugs are even harder to design. “If you're studying massage therapy, obviously you can't do a double-blind, randomized control trial,” Straus says. “But massage can be compared to other kinds of physical interventions or other standard care.” But what's usual care for massage? In setting up a trial on the efficacy of alternative therapies for lower back pain, for example, researchers at the Center for Alternative Medicine Research and Education at Beth Israel Deaconess Medical Center in Boston struggled to standardize treatments given in acupuncture, massage, and chiropractic.

    Straus emphasizes that large, expensive trials begin only after smaller studies have shown evidence that a therapy might work—barring congressional interference, of course. To that end, 22% of NCCAM's budget is funding investigator-initiated grants on such topics as the role of meditation in coronary heart disease and the effect of high-dose vitamin E on arteriosclerosis.

    But the center isn't limited to the merely plausible. Earlier this year, NCCAM's advisory board, which includes advocates and a range of alternative medicine practitioners, unanimously approved a proposal to investigate what they call “frontier medicine.” This includes therapies for which there are no plausible biological mechanisms, such as magnets, energy healing, and homeopathy. The rationale is that the public uses these therapies despite a lack of rigorous evidence for whether or not they work.

    Not surprisingly, frontier medicine serves as a lightning rod for all the complaints people have about the center and alternative medicine in general. This kind of science isn't worth any time or money, and it attracts charlatans, says Stanford's Sampson. “NCCAM serves as an employment agency for opportunists and a source for aberrant and biased science. As long as the money is there from ideologues, there are people who will go after it,” he says. “The present situation is a scientific disgrace.”

    The ever-optimistic Straus defends the program, saying it holds “exciting new opportunities.” And he is willing to invest $600,000 for each of three exploratory grants. “We're not funding quacks,” Straus says. “We will fund experienced investigators at institutions with track records in research.” Straus does concede that it could be tough to find top-notch investigators who want to spend their time probing the implausible.

    Balancing act

    In taking this job, many observers say, Straus is walking a tightrope. Skeptical scientists and powerful supporters of alternative medicine will both be measuring his performance by their own criteria. In addition to Harkin's sway over the NIH budget, Representative Burton is also a hard-nosed supporter of alternative medicine; over the past 2 1/2 years he has held at least 10 hearings on alternative medicine to urge NIH to examine alternative remedies such as EDTA chelation therapy for cardiovascular disease.

    Many advocates swear by therapies that have not been scientifically shown to work, and these groups “are likely to make a lot of noise if the studies do not support their value,” Harvard's Komaroff predicts. At the same time, Straus is spending public funds on research that some accomplished scientists think is pointless. But Straus claims he isn't worried. He insists he can maintain credibility with both scientists and advocates by talking straight to both of them and letting solid science speak for itself.

    In some cases, alternative remedies won't pan out, and Straus is confident that the public will respond to a conclusive thumbs down—despite the massive marketing and hype pumped out by an essentially unregulated industry. If other alternative treatments hold up to serious scrutiny, Straus hopes to integrate them into mainstream medical practice. That's why NCCAM is funding fellowships and training grants for established medical schools (see p. 1571).

    Meanwhile, NCCAM is growing by leaps and bounds. The senior staff has doubled since November, and Straus is setting up an intramural research program. Congressional supporters would like to see even more growth; in March, for instance, Harkin called NIH's funding for alternative research “woefully inadequate.” But Straus is cautious about upping the budget too fast. To spend $80 million on solid research this year, he told Science, would have been difficult. His goal is for NCCAM to become more critical rather than less, and to some extent, he says that requires “maturation of the scientific community.”


    Bastions of Tradition Adapt to Alternative Medicine

    1. Eliot Marshall

    Fueled by popular interest, alternative medicine is gaining ground at scores of universities; now deans want to add it to the curriculum

    Catherine Chu, a first-year student at Harvard Medical School in Boston, says she chose Harvard because she believed that it had a “progressive” outlook on alternative medicine. She became intrigued with the field after getting to know a naturopath and a massage therapist in her undergraduate years in Seattle. Chu was eager to meet the Harvard faculty she'd heard about—Herbert Benson, who coined the term “relaxation response” based on his studies of Tibetan monks, and David Eisenberg, founder of Harvard's Center for Complementary and Alternative Medicine Research.

    After Chu arrived on campus, however, she was “disappointed” to find that alternative medicine was “peripheral” to the curriculum. Like most medical schools, Harvard does not ask students to take courses in nontraditional medicine, which have yet to make it into the core curriculum. And alternative medicine studies are scattered among several different centers. But that somewhat haphazard approach may soon change.

    A medical school panel voted in May to establish a new Division of Complementary and Alternative Medicine that will embrace Eisenberg's center and the Division of Nutrition, according to Dean of Education Daniel Federman. The aim is to bring more of the school's talent to bear on research in and evaluation of alternative medicine, Federman says, and to enable Harvard physicians to be well informed about offbeat therapies they may encounter. Presumably, Harvard would also like to capture some of the government's ballooning funds for alternative medicine (see p. 1568). Eisenberg will be the division's first chief, starting 1 July.

    As Harvard goes, so goes the nation. Medical schools across the country are gingerly bringing alternative medicine into their hallowed halls—much to the consternation of some faculty members. More than 70 U.S. universities, including Columbia, Duke, Stanford, Georgetown, and several branches of the University of California, now offer some sort of alternative medicine program. Even the Association of American Medical Colleges in Washington, D.C., has jumped on the bandwagon. It invited integrative medicine guru Andrew Weil of the University of Arizona, Tucson, to address its elite council of deans earlier this year. And in November, a select academic meeting sponsored by the Josiah Macy Jr. Foundation will consider how best to add alternative medicine to traditional medical curricula.

    Alternative medicine advocates are keen to see such initiatives grow, and medical school administrators are hopeful they will attract more grants and patients. But in some institutions, traditional faculty members have raised vocal objections to what they see as an erosion of standards in pursuit of easy cash.

    One of the most unyielding critics of trendy alternative clinics is Wallace Sampson, a professor at Stanford's Medical School and editor of The Scientific Review of Alternative Medicine. Sampson says that nearly all the alternative medicine courses and centers he examined in a recent survey were “developed and driven by advocates.” The movement is “really a secular religion,” Sampson asserts, and poses a threat to scientific medicine that's “more serious than anyone realizes.” Sampson believes that academicians have not raised a clamor because, if you want to advance in medicine, “you don't make waves.” Arnold Relman, former editor of The New England Journal of Medicine, agrees: “It is becoming politically incorrect for the movement's critics to express their skepticism too strongly in public.”

    Even so, there have been a few scuffles. For example, some faculty members at the medical school of the State University of New York, Stony Brook, complained to the president when administrators established an alternative medicine center in 1997—and gave the director, Samuel Benjamin, a salary and benefits of $320,000 at a time when other departments were facing cutbacks. Some also objected to the decision to let Benjamin retain an interest in a company that sells herbal medicines and broadcast advice weekly on a radio show. One pharmacology professor said the package was a desperate attempt to recruit patients and “take money from an unsuspecting public.” But Benjamin survived the criticism.

    Weil, perhaps the best-known champion of alternative medicine, has flourished in the heart of a major medical school, creating one of the rare centers where unorthodox methods are being taught to resident trainees. In addition, Weil teaches a mandatory course for medical students.

    After finishing his medical training at Harvard in the 1960s, Weil resorted to psychedelic drugs in a search to understand the mind-body relationship. Weil eventually returned to the clinic, adopting a hybrid style that combines standard and alternative medical practices. In 1996 he established the Center for Integrative Medicine at the University of Arizona. Relman has described Weil as articulate, intellectually nimble, and “wonderfully ambiguous.” But Relman dismissed some of Weil's views on health as “largely nonsense”; others, he wrote in a critical essay, “could result in dangerous delays in the diagnosis and the treatment of serious illness.”

    These slings and arrows have had little impact. Indeed, Weil's center now has a waiting list of 1500 patients, and it accepts four M.D. fellows each year for training in a 2-year smorgasbord of therapies that they offer to patients. A panel of 10 specialists in fields from acupuncture to oriental medicine reviews each patient's case and recommends therapies. Fellows consult with patients and jointly create a treatment plan. The center contracts with local practitioners for therapy, and the patients pay.

    Weil's influence has spread far beyond Arizona, to the dismay of some of his critics. For instance, Weil follower Lewis Mehl-Madrona, a Stanford-trained M.D., until recently was firmly ensconced at the Center for Complementary Medicine at Shadyside Hospital near Pittsburgh, which is affiliated with the University of Pittsburgh Medical Center. As medical director, Mehl-Madrona promoted Native American “coyote medicine”—including the use of sweat lodges, guided visions, and massage therapy. A retired computer engineer, E. Patrick Curry, got so upset when he learned that the nearby university was supporting someone who wrote that he had treated cancer with massage that he went on the offensive, writing a scathing critique in Sampson's journal. In response, the university began an investigation; Mehl-Madrona agreed to resign last year. This year, he accepted a new medical director position—at the Center for Health and Healing at the Beth Israel Medical Center in New York City.

    The struggle for control of the medical school agenda isn't going away. It surfaced again recently in Washington, D.C., where both the traditionalists and the new alternative medicine practitioners have allies. The Senate appropriations subcommittee that funds the National Institutes of Health (NIH), chaired by Senator Arlen Specter (R-PA), invited Weil to testify on 28 March about the need to increase funding for programs like his. Weil praised the chair and ranking member, Tom Harkin (D-IA), for instructing the NIH to pay more attention to training physicians in integrative medicine. Noting that NIH had “refused to respond” to the Senate's encouragement, Weil requested that the senators appropriate “specific funds … to achieve this education and clinical training objective.”


    Australian 'Ranch' Gears Up to Mass-Produce Mutant Mice

    1. Elizabeth Finkel*
    1. Elizabeth Finkel writes from Melbourne.

    Chris Goodnow uses the latest technology and sequencing data to advance research on recessive mutations that cause adult-onset diseases

    CANBERRA, AUSTRALIA—The overpowering smell of mouse is a sure sign that all is well at the mouse ranch here at the Australian National University (ANU). The aroma means that the state-of-the-art ventilation system is working, protecting the animals from infection by vigilantly flushing would-be mouse germs out of the 20 small rooms where they are caged. Back in the airlock, a cadre of 30 attendants are in various stages of showering, gowning, masking, and slippering as they prepare to care for the 30,000 animals housed on the floor. And while the researchers at the John Curtin School of Medical Research swelter as they toil in aging labs, the mice live in air-conditioned luxury, snug in the Kleenex nests they build to soften their wire cages.

    Kid-glove treatment, to be sure, but understandable given the expectations placed on them by their keeper, Chris Goodnow. Goodnow, an ANU immunologist, sees the mice as the key to relieving one of the greatest bottlenecks facing biologists: how to assign functions to the glut of human genes about to appear on computer screens around the world as the Human Genome Project nears completion. The plan is to generate mutants on a massive scale—10,000 mice in 6-month batches for the next 5 years—at an estimated cost of $500,000 a year. “This is big science,” says University of California, San Francisco (UCSF), cancer biologist Doug Hanahan. Among the 30,000 are mice with cancer, heart defects, dwarfism, obesity, and immune defects, all resulting from random mutations introduced into their genes. Isolating the responsible genes may allow researchers to find their function. And because mouse genes are thought to do the same thing as their human counterparts, scientists hope to translate the knowledge into clinical studies.

    Defying dire predictions from respected colleagues, Goodnow's operation is moving ahead and winning plaudits. “Biology's great strength is science of this sort; it will bring tremendous riches,” says Yale University geneticist Richard Flavell. “It's the wave of the future,” declares Hanahan.

    Goodnow, 40, has been a mouse maître d' for a long time, although not until recently on such a grand scale. Raised in the United States, he migrated to Australia with his family at the age of 12. During graduate study at Sydney University, he developed a strain of transgenic mice whose antibody-secreting B cells, rather than producing a repertoire of millions, were all tricked into producing a single self-reactive antibody. Immunologists used transgenic mice like these to see, for the first time, how self-reactive B cells were either culled or frozen into inactivity at various points of their life cycle.

    After arriving at Stanford in 1990, Goodnow used the mice as a microscope to see what goes wrong in mouse mutants that are models of autoimmune diseases. “It's only by understanding things at the level of which cells, what stage, and what biochemical pathway that we can figure out why some people are predisposed to making antibodies that attack their own cells,” explains Goodnow. But by 1996, Goodnow had run out of mutants. “The key question was, ‘How were we going to move forward?’”

    The answer, he concluded, was to delay his research on autoimmunity and instead set up a large-scale operation to create new mutant mice, much like those that fruit fly geneticists have used for decades to identify new genes. Indeed, mouse geneticists have long dreamt of having that capability, but some formidable obstacles stood in the way. Producing the mutations was easy. The chemical, ethylnitrosourea (ENU), has shown phenomenal mutation rates in mouse sperm cells, some 10-fold over what had been achieved in flies. Even so, tens of thousands of mice would be needed to ensure that the random mutations would eventually cover every gene. And housing and caring for that many mice would require a new lab and lots of steady funding.

    Beyond the cost considerations were technical problems. Once an interesting mutation is found in fruit flies, it is mapped to a rough location on the chromosome by crossing the fly to a strain that carries chromosomal markers. But mapping mutations in the mouse is a slow and imperfect art, taking 3 months per cross. And once researchers get the approximate location of their mutant gene, they still have to pinpoint its identity. In the past, that could take 20 people working a year to do. They would have to move incrementally along the chromosome interval where the gene was located, sequencing every adjacent chunk of DNA to see if it differed between mutant and normal animals.

    Recent advances in gene mapping and sequencing have made the hunt for mutant genes in mice much simpler. One such development came in 1996, when Eric Lander's group at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, provided 7000 new landmarks for the mouse genome. Those landmarks make it possible to map new mutations to within a region of some 50 genes. And the imminent availability of the sequence of the entire human genome means that much of the final work of finding the mutant gene could be done by computer.

    Goodnow could also make use of the virtual correspondence over short lengths of the genome between human and mouse genes, which are like a pack of cards that have been shuffled differently. Once a mutation is mapped to within a 50-gene chunk of the mouse chromosome, for example, the researcher need only call up the sequences of these 50 genes from the human database. Within days, all 50 of those genes in normal and mutant mice can be resequenced to see which gene is defective. “I could see that it was no longer going to be necessary to have a big physical mapping lab,” he says.

    To make full use of these technological advances, Goodnow needed access to a huge mouse-rearing facility. With land and labor costs in Stanford prohibitively expensive, Goodnow realized that he was going to have to look elsewhere. ANU was an attractive choice, especially because the costs of rearing mice are about one-seventh those at Stanford. In addition to offering him a job, ANU's John Curtin School joined with the Australian Cancer Research Foundation to put up $1.5 million for a state-of-the-art screening facility.

    After taking 2 years to set up his lab, Goodnow has begun to turn the crank and start churning out mutants. Every 6 months, he injects some 100 males with ENU and screens the offspring for defects. The first two batches have already produced 60 mutants with immune system defects, cancer, skeletal abnormalities, obesity, and dwarfism. Over the next 5 years he hopes to bombard every gene in the mouse.

    The results so far have laid to rest some concerns about whether Goodnow's strategy would work. The major concern related to his attempting the most ambitious type of screen, that for recessive mutations affecting adult mice. Goodnow wanted to screen for recessive mutations because these usually mean the gene has lost its activity and, thus, can provide straightforward information about its function. By contrast, dominant mutations often result from a gene gaining a new function that may bear little relation to the gene's normal activity.

    Unfortunately, the logistics of a recessive screen are far more tortuous than those for dominants. Recessive mutations only show up when both paternal and maternal versions of the gene are affected. So rather than being all over in one generation, as in a screen for dominant mutations, Goodnow's screen had to wait for three generations of father-daughter matings just to breed double recessive offspring—in this mating scheme, only one-eighth of the progeny.

    In addition, the types of mutations Goodnow was after, those affecting the maturation of the immune system, are best studied in adult mice. Previous attempts to make mice with a double dose of mutant chromosomes had not required the mice to reach adulthood, and skeptics doubted whether such a mouse could survive. But Goodnow has had little trouble producing and breeding mice that carry double copies of mutant chromosomes.

    Finally, ENU is such a powerful mutagen that each animal produced from the treated sperm carries numerous mutations. The scientists didn't know if the clustered mutations would interfere with each other and make it impossible to identify the effect of individual mutations. But although each pedigree, by his estimate, carries about 100 mutations, the effects of the mutations appear to be decipherable. “We get simple Mendelian traits almost always,” he says. “We can lay to rest the concern of getting horribly complicated mice.”

    The next big step is to keep the operation humming. In particular, the ANU team has to deal with the logistical nightmare of keeping track of thousands of little black mice for several generations. During the first couple of years of operation, the ANU team used paper records to keep track of all these animals. That was a dangerous situation for Goodnow, a numerical dyslexic. “A typical 3% error could destroy the screen,” he says. Now, the researchers have switched to a new automated system, devised by computer programmer Greg Quinn, that uses bar codes on the cages to keep track of the animals in much the way supermarkets keep track of their thousands of products.

    Now that Goodnow has proved that a large-scale screening operation can work, other researchers have been quick to share the booty. Hematologists Warren Alexander and Doug Hilton, at the Walter and Eliza Hall Institute in Melbourne, are studying blood cell development using mutants with defects affecting the formation of red blood cells, the clot-forming platelets, and white blood cells known as granulocytes. As part of a project funded by the U.S. National Cancer Institute, UCSF's Hanahan is waiting for delivery of mutants that affect the course of skin and cervical cancers induced in mice by human papilloma virus.

    These formal collaborations are only a start, says Goodnow, who plans to make the mutant mice available to the general research community. In an effort to facilitate such collaborations, Goodnow has devised a simple materials transfer agreement that gives ANU 10% of the revenues from any commercially valuable mutant after the recipient university deducts its costs.

    With the ANU screen providing a proof of principle, labs all over the world are gearing up to try recessive screens. “This is just what we hoped for,” says Goodnow. “People told me I'd end up 2 years down the line with nothing but a lot of mice. Now when anyone [else] encounters resistance, they can point to us!”


    Grants Kick Off Ambitious Count of All Ocean Life

    1. David Malakoff

    Scientists around the world take on a grand challenge to dramatize the need for more marine research

    J. Frederick Grassle believes in the power of numbers. A marine biologist at Rutgers University in Camden, New Jersey, Grassle has spent years advocating more research on life in the world's oceans. During a conversation a few years ago with Jesse Ausubel, a program officer with the Alfred P. Sloan Foundation in New York City, the pair hit upon a promising idea for igniting the public's passion for marine research: What about counting all the living creatures in the vast deep?

    Last week the idea, a “Census of Marine Life,” took a big step toward reality when eight research groups were awarded $3.7 million to develop model Internet atlases that display everything from the distribution of squids to the DNA sequences of tiny zooplankton. The projects, administered by the Washington, D.C.-based National Oceanographic Partnership Program, kick off what could become a 10-year, billion-dollar effort to use everything from dip nets to airborne lasers to enumerate and map marine life. “The census is driven by three questions,” says Ausubel: “What did, what does, and what will live in the ocean?”

    Answering the trio of questions, he admits, is a “grand challenge.” Although researchers have described some 15,000 kinds of marine fish, for instance, they estimate that at least 5000 more species, along with countless crustaceans, shellfish, and worms, have eluded detection. And often the numbers and distribution of even known species are sketchy.

    The census aims to reduce such uncertainty by making existing data more accessible and useful to researchers, and by creating computerized libraries that can accommodate a flood of new numbers from studies of selected ocean patches. By applying new technologies for identifying marine species from afar, census planners also hope to give conservationists and regulators better tools to estimate marine populations, and provide the public with a global snapshot of marine diversity. Some environmentalists worry that identifying hidden populations could unintentionally hasten their exploitation. But researchers say that the potential conservation benefits outweigh the risk. “One reason we've done a woeful job of conserving marine biodiversity is that we lack an understanding of what and where it is,” says Elliott Norse of the Marine Conservation Biology Institute in Redmond, Washington.

    A grand challenge.

    Like many big ideas, the Census of Marine Life was born partly of frustration. Despite increased public concern about threats to global biodiversity, financial support for marine biology has lagged. The antidote that Ausubel and Grassle proposed in 1997 was a “census of the fishes.” But it morphed into a census of all marine life after protests from biologists working on scaleless creatures.

    Many scientists were initially skeptical that a census would be technically feasible—let alone affordable. But after attending workshop presentations on the rapid advances in a wide range of sensing technologies, from plankton-spotting satellites to biomolecular tests that can sniff out an organism's chemical signature, many were won over to the cause. Environmentalists, however, tempered their support with concern that governments might be unable to prevent a rush to exploit any new populations uncovered by the census.

    Keeping such concerns in mind, Grassle assembled a team of researchers from the United States, Canada, Europe, and Japan to sketch out an action plan. Although a complete draft won't be ready until later this year, the group agreed that its first step would be “to take the best data we already have—which is often in some researcher's notebook—and make it widely available in a standard format,” says Grassle. Researchers dubbed this concept the global ocean biogeographic information system (OBIS).

    The eight 2-year grants—ranging from $350,000 to $500,000 and involving 63 institutions in 15 nations—are designed to jump-start OBIS. A team led by Edward Wiley of the University of Kansas's Natural History Museum in Lawrence, for example, hopes to link 21 databases holding information on 39 million fish specimens through FISHNET, a Web-based archive. Others, such as Dale Kiefer of the University of Southern California in Los Angeles, will develop tools for displaying and manipulating information from a particular region, in his case the Gulf of Maine. The eventual goal is point-and-click maps that can display data on everything from water temperature to sea bottom contours within a particular swath of ocean.

    Some grants tackle species often overlooked by fisheries biologists. A team led by Philip Lee of the University of Texas, Galveston, for instance, hopes to put squids squarely on the map. His world-renowned National Resource Center for Cephalopods has accumulated more than 5000 slides and hundreds of hours of video of squids, cuttlefish, and nautiloids over the last 25 years, and is eager to share them over the Internet. Deborah Steinberg of the Bermuda Biological Station for Research in Ferry Reach has a different task in mind for her partners: counting minute crustaceans called copepods. Since 1988, her Bermuda Atlantic Time-Series Study has collected millions of pieces of data—including zooplankton samples that may contain as many as 1000 species, including 150 types of copepods—from a site in the Sargasso Sea. With help from experts from Russia and the United States, she will now identify the critters, giving the database even more depth.

    Technological fixes.

    Steinberg's work will rely on some of the technologies that the census is counting on for success, including silhouette-recognition software that can identify zooplankton species from photos. By 2003, planners hope to begin pilot projects that will “test how far we can push” other technologies for both mapping and identifying species, says Grassle. Surface-layer- piercing airborne lasers that combine the speed of light with the range of an airplane, for instance, “have opened up the possibility of quickly surveying much larger areas” than once considered possible, notes steering panel member David Farmer of the Institute for Ocean Sciences in Vancouver, British Columbia. Farmer's own work with side-scanning sonar (see graphic) has shown that it is possible to identify individual fish from up to 10 kilometers away. Such sensors, mounted on seagoing “tollgates” installed along migratory routes, could provide valuable insights into population movements.

    One major problem for the census takers will be deciding where to deploy such relatively expensive technologies. “The question is how many cleverly designed projects you'll need to put together a good global picture,” says Ausubel. Possible targets for the next phase of the census include poorly understood environments, such as sea mounts and deep-sea vents, and heavily fished regions, such as the Gulf of Maine or the Alaskan coast.

    The census has won support from biologists involved in policy-making, such as Mike Sissenwine of the National Marine Fisheries Service in Woods Hole, Massachusetts. “It's a wonderful grassroots scientific effort, and the spin-offs will be tremendous,” he predicts. Grassle hopes the census will also revive such fields as systematics and biogeography. “They used to be central themes in marine science, but they've become peripheral,” he says. “We want to bring them back to the center.”

    Achieving that will require money, and Ausubel and others are optimistic that the United States, Japan, and European nations will help foot the bill, along with private foundations. At the same time, the organizers are careful not to promise too much. “We're still developing exactly what we mean by census,” says Grassle, whose working definition is “not counting everything, but doing a much better job of surveying ocean life.” Such an effort would still represent a compelling opportunity, says Ausubel: “Even if the full census is never realized, this is something that will be very useful.”


    Reopening the Darkest Chapter in German Science

    1. Robert Koenig

    As historians dig up disturbing new details about the complicity of German researchers in Nazi-era crimes, officials are calling for full disclosure

    BerlinMore than a half-century after it happened to her, Eva Mozes Kor can still recall the mysterious injections, the frequent blood tests, and the dark-haired young man with a hawklike brow who hovered over her bed one day, waiting for her to die. Kor would disappoint her tormentor: Neither she nor her twin sister, Miriam, succumbed to Nazi physician Josef Mengele and his World War II experiments on prisoners, mostly Jews, at the Auschwitz-Birkenau concentration camp. But the sisters did not emerge unscathed. To this day, Kor says she agonizes over not knowing what Mengele injected into her and Miriam, and for what nefarious purposes their blood was used. And she has waited in vain for an apology from any scientific institution whose Nazi-era predecessors had used Mengele's results. An apology, says Kor, who lives in Terre Haute, Indiana, “would mean a great deal to survivors. Why can't they do this simple thing?”

    That question reverberates through the modern-day German scientific community, which regards Mengele as a murderous maverick but is now focused on the complicity of more legitimate researchers. Last month, at a meeting* here sponsored by the country's main science granting agency, DFG president Ernst-Ludwig Winnacker acknowledged that the wartime DFG “had allowed itself to be made into an instrument of a criminal regime. As part of Hitler's state, it allowed crimes against humanity under the guise of science.” And new evidence involving Nobel laureate Adolf Butenandt, wartime director of the biochemistry institute of the prestigious Kaiser Wilhelm Society, suggests that the cover-up of certain Nazi-era abuses, and the postwar scientific community's embrace of dozens of tainted researchers, was more widespread than previously imagined.

    With the past appearing in an ever more sinister light, both Winnacker and Hubert Markl, president of the Kaiser Wilhelm's postwar successor, the Max Planck Society, contend that a public apology would be a hollow gesture. Instead, they have launched separate historical inquiries into the abuses of the Kaiser Wilhelm institutes and the DFG during the Nazi era and postwar years. “We need to do this not only for the victims but for future generations of scientists,” Markl says. “We must make clear how murders and other criminal acts could have been conducted in the name of science in Germany.”

    Exposing the past.

    Much is already known about the horrors of Nazi-era science. Although Mengele found refuge in South America, details about his research emerged from eyewitness testimony. In his infamous twins study, for instance, Mengele would inject one twin with a toxic substance or pathogen while using the other as a control. At the postwar Nuremberg “doctors' trial”—which ended in 1947 with the conviction of 15 defendants, seven of whom were hanged—prosecutors outlined a series of cruel experiments to test the limits of endurance. Prisoners were exposed to everything from mustard gas and malaria to freezing-cold seawater and high-altitude conditions of low pressure and scarce oxygen. The evidence also shows how the Kaiser Wilhelm Institute of Psychiatry exploited Nazi pogroms to obtain the brains of mentally ill people for analysis. However, many scientists in the Nazi regime escaped punishment by claiming that they were pawns—not willing participants—in the research.

    Today, science historians are accumulating new details on this dark chapter of German society through painstaking analyses of fresh archival materials (see table below). “We aren't limiting ourselves to the old Kaiser Wilhelm Society files; we are examining the full range of archives, both in Germany and abroad,” says Carola Sachse, a historian who directs the Max Planck commission's six-person historical research team in Berlin.

    View this table:

    Earlier this year, Markl gave this group access to the sealed personal files of Butenandt, a biochemist who won a Nobel Prize in 1939 for isolating sex hormones. The Max Planck team offered the first crack at the files of Butenandt, who died in 1995, to Robert N. Proctor, a history professor at Pennsylvania State University, University Park. In a lecture in Berlin last week, Proctor, an expert on Nazi medicine, said letters in the archive show that Butenandt was aware of and supported a research project involving blood samples from Auschwitz in an unsuccessful effort to find disease-fighting proteins specific to race.

    The project, first detailed by German molecular geneticist Benno Müller-Hill in his 1984 book Murderous Science, was led by Butenandt's friend Otmar von Verschuer, then director of the Kaiser Wilhelm Institute for Anthropology, Human Genetics, and Eugenics. Many of the blood analyses were carried out by a Butenandt subordinate, Guenther Hillmann. Given Butenandt's close ties to Verschuer and Hillmann, Proctor told Science, “it is reasonable to assume that he knew where the samples came from”—although no document unearthed so far confirms this. To his death Butenandt denied that he was aware of Auschwitz or the Verschuer-Hillmann project during the war.

    Proctor has managed to cull a few other nuggets from the 80-meter-long Butenandt archive, despite his observation that it appears to have been “highly sanitized.” Near the war's end, Butenandt ordered Hillmann in a letter to destroy all files that lay in an institute safe marked “Geheime Reichsache”—a top-secret Nazi classification. Proctor also found evidence that Butenandt participated in a series of Luftwaffe (Air Force) experiments at the Rechlin flight-test station, although the nature of the research remains unclear. Earlier historical work had documented that one of Butenandt's postdocs had put six epileptic children in a Luftwaffe low-pressure chamber to try to distinguish inherited from noninherited epilepsy.

    Immediately after the war, Proctor says, Butenandt became “a one-man whitewashing machine,” defending Verschuer and other prominent scientists during the period in which the victorious Allied powers decided which former Nazi scientists should keep their posts. Butenandt became one of the most influential figures in postwar German science, heading the Max Planck Society from 1960 to 1972.

    Butenandt's defenders contend, as he always maintained, that he had no direct connection to any of the villainous Nazi projects involving his institute. “Idoubt very much whether he knew any of the details related to Verschuer's project,” says German biochemist Peter Hans Hofschneider, who knew Butenandt for many years.

    Also coming under increasing scrutiny are the DFG's activities during the Nazi era. At the Berlin meeting, Ruhr University historian Lothar Mertens charged that DFG leaders who were members of the Nazi party, such as Rudolf Mentzel, had “misused their power” by allowing Nazi policies to influence their grant-supervision duties and by ordering “a systematic destruction of files” that documented the DFG's pre-Nazi support of Jewish professors. Nearly all of the professors were later expelled from German universities.

    Winnacker says he is appalled by the sheer number of scientists engaged in questionable research during the Nazi era who, after the war, were handed prominent university positions—not to mention DFG funding. One was Verschuer, whose Nazi ties prevented him from establishing a postwar Max Planck institute but who did become a professor at Münster University. There he formed what became a major West German center of genetics research. “There were many others like him,” says Winnacker.

    Coming to terms.

    As new revelations come to light, German science officials are groping for the best way to respond—and lay the ghosts to rest. Müller-Hill, for one, has urged Markl and Winnacker to bring Kor and others to Germany to discuss historical findings and to apologize. “Max Planck and the DFG should jointly invite some survivors and show that German science can fully face its past,” Müller-Hill says.

    But Markl and Winnacker have indicated that they want as complete an accounting as possible of the collusion between the Nazis and the scientific community before formulating an appropriate response from their organizations. Today's science historians “owe it to the survivors to fully investigate research during those terrible years and to inform the world of exactly what did happen,” says Winnacker. To that end, the DFG has set up an expert panel to oversee groups that, over the next several years, will scrutinize the agency's history.

    Max Planck has already begun such a review. Saying in 1998 that the society “has done too little, for too long, to explore its predecessor's history,” Markl set up a commission that's now analyzing wartime research at the Kaiser Wilhelm institutes. Markl wants to wait until the commission completes its work—perhaps in 3 years—before deciding on an appropriate formal response to the Nazi-era abuses. Some members of the Max Planck history team assert that enough is known already to warrant a formal apology. But Paul Wiendling, an expert on Nazi-era medical research at Oxford Brookes University in the United Kingdom, suggests waiting until the research is more complete: “You need to know what you are apologizing for,” he says. In the meantime, the society is willing to share what information it possesses. If victims of Nazi-era research request documents relating to their cases, says Markl, “I would not withhold anything. I would send their letter to the commission and ask that they provide any materials that are available.”

    For her part, Kor, 66, holds out little hope of learning more about Mengele's experiments. She continues to wonder whether they contributed to the death of her sister Miriam in 1993 from an unusual kidney ailment. Liberated from Auschwitz when she was 11, Kor later founded an organization of twins who survived Mengele's research. According to Kor, many of the 100 or so surviving twins who are members of C.A.N.D.L.E.S.—after “Children of Auschwitz; Nazi Deadly Lab Experiments Survivors”—are in poor health. And all are haunted by the same question, she says: “What was done to me, and for what scientific purpose?”

    • *“Science and Science Policy: Interactions, Continuities, and Inconsistencies From the Late Empire to the Early German Federal Republic/Democratic Republic,” 18 to 20 May.


    Mount St. Helens, Revisited

    1. Richard A. Lovett*
    1. Richard A. Lovett is a writer in Portland, Oregon.

    The devastating eruption 20 years ago has transformed scientific thinking about the nature of volcanoes and how ecosystems recover from them

    At 8:32 a.m. on 18 May 1980, a little-known peak in the Washington Cascades erupted, unleashing a blast that felled trees over an area of about 600 square kilometers. The blast was followed, in quick succession, by the largest avalanche in recorded history (comprising 2.3 cubic kilometers of rock), mudflows, scorching heat, and billowing ash that turned day to dusk at least 100 kilometers downwind. But the eruption did more than rearrange the landscape near now-famous Mount St. Helens; its intellectual aftershocks have continued to reorder scientific wisdom in both volcanology and successional ecology.

    At a meeting* commemorating the 20th anniversary of the explosion, volcanologist Kathy Cashman of the University of Oregon, Eugene, said that prior to the event, geologists thought huge debris avalanches such as the one that roared off Mount St. Helens were fairly rare. But Mount St. Helens has taught geological sleuths how to recognize the traces of such avalanches, enabling them to identify more than 400 prehistoric slides—some on a scale that would dwarf the one from Mount St. Helens. Another lesson was that seemingly minor eruptions, like those that followed the events of 18 May, can have devastating consequences—unleashing surprisingly severe mudflows—if hot ash or lava falls onto snow (Science, 19 May, p. 1181).

    Using satellite imagery, geologists were also able to track Mount St. Helens' ash plume with unprecedented accuracy. Although such plumes are the least deadly of volcanic perils, they are a threat to airplanes, whose engines can be overheated by the abrasive ash.

    Far more dangerous than ash plumes are lava dome eruptions, which occur when sporadic eruptions extrude pasty lava, like toothpaste from a tube. At Mount St. Helens, a dome began forming in late 1980; by the time volcanic activity ceased in 1986, it had reached a height of about 280 meters.

    Lava domes pose a threat if they collapse and tumble down the mountain during the course of an eruption—a common occurrence when they form on steep slopes, as happened a few years ago on Montserrat in the West Indies, said Cashman. Volcanologists therefore seized the opportunity for closeup study of the sequence of 17 eruptions that created the dome on Mount St. Helens. Armed with seismological records and data gathered from clambering around the dome to measure swelling, cracking, and escaping gases, volcanologists became confident enough to predict similar events elsewhere. “This was incredibly important,” Cashman said, “because no one knew we could make predictions for this type of volcano. The most notable success was Mount Pinatubo in the Philippines, where hundreds of thousands of people were evacuated. It shows that we can live more safely with volcanoes.”

    Leftovers and chance

    In ecology as well as geology, the eruption of Mount St. Helens has rocked scientific thinking; indeed, many preblast theories were flattened along with the forest.

    Immediately after the blast, the land looked barren, lifeless. Millions of dead trees lay like windrows of hay, pointing in the direction of that all-consuming wind. Mostly they faced directly away from the mountain, but in some areas they fell in swirling patterns where the blast had been deflected around ridges or hillsides. Where slopes shielded them from the worst of the blast, their skeletal forms still stood in an eerie forest of ghostly, bleached trunks. According to ecological convention, the land should have been virtually sterile: Ecosystems would need to rebuild themselves from scratch in the slow process of succession.

    The truth turned out to be far more complex. Scientists now know that the mountain's remarkable recovery was driven by two previously overlooked forces: random chance and leftovers from the preblast landscape—which forest ecologist Jerry Franklin of the University of Washington, Seattle, calls “legacies” of the prior ecosystem (Science, 19 May, p. 1183).

    These legacies include both the “ghost forest” and the uprooted trees of the blowdown region. The decaying wood, it turns out, provided a banquet for wood- boring insects, which in turn attracted woodpeckers and flickers. Elsewhere, the roots of toppling trees dragged soil, seeds, and forest-floor plants high above the blanket of smothering ash, where many flourished.

    It was chance that dictated the nature of these legacies. Not only were individual plants and animals spared by simply being in the right place at the right time, but the date and time of the eruption were also vital to the course of the mountain's recovery. Regeneration would have been much slower—and different—if the eruption had occurred in midsummer, noted Charlie Crisafulli, a research ecologist with the U.S. Forest Service's Pacific Northwest Research Station in Olympia, Washington. In May, many lakes were shielded by 30-centimeter caps of ice, beneath which the blast had little impact. Similarly, lingering snow patches protected underlying vegetation, creating scattered ecological oases called refugia. Just as important, the blast occurred during the day, when nocturnal animals were safely in their burrows, giving those that weren't too deeply buried an opportunity to dig back to the surface.

    Even in an area called the “pumice plain,” where the old ecosystem was so deeply buried that there was little legacy to jump-start its recovery, chance played a much greater role than anticipated. Prior theory, noted Jonathan Titus, an ecologist at Biosphere 2 in Oracle, Arizona, said that each species of pioneering plant needs a distinct combination of such factors as moisture, slope gradient, soil stability, and elevation above sea level. But when his research team painstakingly measured these and other parameters at hundreds of sites in an attempt to determine the factors governing the locations at which each species had begun growing, they found little correlation. The seeds, Titus said, arrived on the wind and lodged in particular locations purely by chance. If they found enough moisture, they sprouted. “Another species could be there just as well,” he said.

    Amphibians and gophers

    Farther from the mountain, some of the most unexpected survivors were amphibians. In fact, at a time of worldwide decline in amphibians (Science, 30 April 1999, p. 728), those near Mount St. Helens are thriving.

    One species is the western toad, listed elsewhere as endangered. Part of the reason for the animal's population boom at Mount St. Helens, Crisafulli said, is that its predators—ravens, jays, and snakes—haven't yet recovered. But in addition, the tadpoles feed on algae in lakes, and the demise of tall, lakeshore trees has provided more sun for algal growth.

    The tailed frog, whose tadpoles live in creeks rather than lakes, presents a similar success story. Before the blast, said Charles Hawkins, a stream ecologist at Utah State University in Logan, the species was presumed to need the damp shade of creeks in old-growth forests. But on the edges of the blast zone, where scattered islands of trees survived, biologists were stunned to find 15 times more tadpoles than in undisturbed old growth. “This completely flew in the face of conventional wisdom,” Hawkins said.

    It turns out that only the adults need shade. Like young toads, frog tadpoles feed on algae, which is normally in short supply beneath an old-growth forest canopy. So the ideal frog habitat is a mixture of forest shade and sunny creeks—exactly the conditions created at Mount St. Helens. “One of the lessons we've learned is that homogeneous landscapes aren't all that good for animals,” Hawkins said. “Sometimes you need patchy landscapes—especially if a species has a complex life cycle, like the tailed frog.”

    At least as dramatic is the recovery of 12 of the region's 15 species of salamanders. In some of the lakes, Crisafulli said, salamander counts are among the highest he's ever seen. This is surprising enough in lakes that had salamanders prior to the blast. But the eruption created more than 120 new lakes and ponds, and somehow the water-loving creatures crossed kilometers of seeming desert to colonize them.

    The salamander survival story begins with the sheltering ice that covered their ponds at the time of the blast. But the tale Crisafulli told centers on their multistage life cycles. Classically, salamanders hatch and grow in ponds and then metamorphose into land-roaming adults, which return to the water to breed and lay eggs. Some reach full sexual maturity without growing lungs. These neotenic salamanders spend their entire lives in the ponds—ensuring that even in the sun-scorched blast zone, there will always be a next generation. Some members of that next generation will themselves be neotenic; others will metamorphose into terrestrial forms and will strike out overland in search of new homes. At Mount St. Helens today, most of these migrants die. But a few get lucky. Perhaps they encounter a fortunate series of rainstorms; perhaps they find seep springs at critical locations.

    The salamanders were also aided by pocket gophers, hailed by Crisafulli as “the unsung heroes” of the mountain's recovery. The gophers live underground in meadows and clear-cuts, where they eat roots and tubers. When the eruption converted the entire blast zone into one big meadow, it created “gopher heaven,” particularly as plants began to regrow. The gophers' excavations, in turn, brought seeds to the surface and mixed the rich underlying soils into the nutrient-poor ash and pumice. The gophers also created kilometer after kilometer of underground tunnels. The salamanders, Crisafulli discovered, found these gopher subways and used them to disperse far more broadly than they could have aboveground. It was an important lesson in the value of unexpected ecological linkages.

    Surprising boosts

    Ecologists were also stunned by the ability of small mammals to find refugia, or habitat islands, among barren pumice. Standard ecological wisdom said these animals could only reach these oases via migration corridors, and that they wouldn't cross broad, open spaces. But mice, voles, chipmunks, and ground squirrels seemed undeterred by multikilometer journeys; even shrews weighing as little as 7 grams somehow made the treks. Crisafulli now believes animals can reach isolated habitats so easily that when they are absent, biologists shouldn't blithely assume the reason is that they can't get there. Rather, he said, it probably means the habitat isn't ready for them.

    These and similar observations prompted him to speculate that ecological succession isn't driven by “average” events throughout a region. “It's the unusual events that make the difference,” he said. “The fact that most of the voles are in the blowdown zone isn't as interesting as the few that make it to the pumice plain.”

    Although recovery has been unexpectedly rapid, the landscape near Mount St. Helens has been irrevocably changed by the eruption. Even in areas where the only impact was a few centimeters of ashfall, the forest floor is visibly altered. Gone, for instance, are the lush mosses that once carpeted it, replaced by an unusually large number of baby trees. “It's going to be a long time before we have forests like we did before,” said Joe Antos, a terrestrial plant ecologist at the University of Victoria in British Columbia. The form these new forests will ultimately take is unknowable. Perhaps the overriding lesson from the eruption is that so-called “climax forests” are dynamic, not static. They are periodically affected by outside events, be they volcanic eruptions, forest fires, or massive windstorms. Each of these, Antos said, sets the ecosystem on a new trajectory, keeping it in a state of constant, long-term flux.

    Because the ecosystem will continue to change, monitoring must continue as well, said researchers, who note that the establishment of research plots immediately after the blast has made possible increasingly long-term studies. Said Peter Frenzen, the monument scientist for Mount St. Helens National Volcanic Monument: “Twenty years is really just the beginning. In some ways things are just beginning to get interesting.”

    • *Mount St. Helens: 20 Years of Biological Research and Lessons Learned, 13 May at Mount St. Helens National Volcanic Monument.

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