# News this Week

Science  18 Mar 2005:
Vol. 307, Issue 5716, pp. 1702
1. BIOETHICS

# Anticloning Forces Launch Second-Term Offensive

1. Eli Kintisch

The once-solid political coalition in the United States that opposes any form of human cloning is showing signs of splintering over strategy. Supporters of cloning research are paying close attention to the rift, first reported in the Washington Post last week, wondering whether it may work to their advantage or lead to new laws restricting research that stretches ethical boundaries.

One camp, led by Senator Sam Brownback (R-KS) and pro-life groups, seeks to renew the fight to pass a comprehensive ban on all cloning of human embryos. Brownback, who plans to reintroduce legislation this week, and others have tried to capitalize on the near-universal aversion to the notion of cloning a human to also ban the use of somatic cell nuclear transfer (SCNT) to create early-stage embryos for research. Citing SCNT's potential to elucidate and perhaps treat diseases such as Parkinson's, research and patient groups have thwarted such legislative efforts to date.

In recent months a new camp has emerged, led by Leon Kass, chair of the President's Council on Bioethics, and Eric Cohen, editor of the conservative bioethics journal The New Atlantis. Frustrated that Congress has repeatedly failed to pass anticloning measures, they call for a broader ban on novel reproductive approaches, including cloning humans. Arguing that semantics have trumped ethics in the cloning debate thus far, they also want to “delink” restrictions on novel reproduction from those on research cloning by dealing with them in separate bills—an approach that those in favor of research cloning have advocated in the past.

One of several position papers Kass and others have discussed during informal meetings, recently posted on a Web site,* calls first for legislation that would protect “the Dignity of Human Procreation.” It seeks to ban reproductive cloning and other procedures including transferring a human embryo into an animal or using sperm or eggs from fetuses to create a child. A “ban on all human cloning does nothing to prevent other ways of making children that would be unwise or unethical,” explains Cohen. (An aide to Brownback says the senator will introduce additional legislation soon that would outlaw ethically questionable reproductive methods.)

The document recommends lobbying for a second law that would ban “the creation of any human embryo [through cloning or IVF] solely for research and destruction.” It's this tactic, in particular, that has divided the two anticloning camps. Brownback and others say that delinking reproductive and research cloning would give supporters of research cloning a political advantage. “Tactically, [the first] might pass, and you would weaken the case for the other,” says David Prentice, senior fellow at the conservative Family Research Council.

Others say the new proposals are unlikely to change the political deadlock. “Congress could pass a ban on reproductive cloning with or without these other prohibitions, and we're going to stay divided on the research cloning,” says Kathy Hudson, director of the Johns Hopkins University Genetics and Public Policy Center in Washington, D.C.

But Kass argues in an e-mail that a clarified debate on basic morals could win “a very broad range of people, left and right”—including support from scientists. “Far from undermining the effort to ban all human cloning, I think the new agenda builds on its core principles,” added Cohen in an e-mail. “Should we produce human embryos solely as research tools, and should we begin down the road of making babies in radical new ways. … This is the debate America deserves.”

As a third prong in its self-identified “offensive,” the document suggests that the National Institutes of Health fund research into methods of obtaining stem cells that do not require the destruction of an embryo (Science, 24 December 2004, p. 2174).

Kass thinks time is of the essence: “We have today an Administration and a Congress as friendly to human life and human dignity as we are likely to have for many years to come,” the document says. “[These goals] allow us to respond to the inability to pass the cloning ban not by yielding ground but by seizing the initiative.”

Others warn against new laws governing an ever-changing scientific landscape and suggest that the research community should continue to police itself. “A blanket opposition [to advanced biotechnical procedures] could throw out things that could be beneficial and nonobjectionable,” said David Magnus, director of the Stanford Center for Biomedical Ethics.

2. BIOETHICS

# U.N. Settles on Nonbinding Resolution

1. Gretchen Vogel

In an attempt to break nearly 4 years of deadlock, the United Nations General Assembly passed a nonbinding resolution last week urging member countries to draft laws that forbid human cloning. However, the vague wording of the measure and the fact that it doesn't require countries to act means it will have little impact, either on attempts to clone humans or on researchers who hope to use nuclear transfer techniques, which involve the creation of a cloned embryo, as part of research into disease.

The text, which was approved on 8 March, says member states are “called upon to prohibit all forms of human cloning inasmuch as they are incompatible with human dignity and the protection of human life.” Representatives from countries that had pushed for a ban on all human nuclear transfer experiments, whether for reproductive or research purposes, called the vote a victory. But if it is a victory, it is a hollow one, says Christian Much, legal adviser at the German mission to the United Nations. “This will be forgotten 6 months from now,” he says. “It was the cheap way out after countries realized there was no way to reach a consensus.”

A German and French proposal to draft an international ban on attempts to clone a human received wide support in 2001. But efforts to draft a treaty fell apart when the United States and several other countries insisted that any treaty must ban so-called therapeutic cloning, in which nuclear transfer technology is used to create lines of embryonic stem cells for research. But in a mirror of the stalemate that has scuttled U.S. legislation on the issue (see main text), countries with laws permitting human nuclear transfer research, including the United Kingdom, said they would not endorse such a treaty. Three years of debate followed, ending in deadlock (Science, 29 October 2004, p. 797). The final vote on the nonbinding resolution was 84 in favor to 34 against, with 37 abstentions.

3. CONFLICT-OF-INTEREST POLICY

# NIH Rules Make Some Pack, Others Plead

1. Jocelyn Kaiser

The ethics crackdown announced last month at the National Institutes of Health continues to reverberate across the Bethesda, Maryland, campus. Last week, three federal scientists whose consulting came under fire last year announced their departures. A group of senior scientists urged NIH Director Elias Zerhouni to adopt a more modest ethics plan. And rank-and-file researchers say the stringent new rules are upending their lives, perhaps even to the point of divorce.

Last week, National Cancer Institute (NCI) pathologist Lance Liotta and research partner Emanuel Petricoin of the Food and Drug Administration announced they're leaving shortly to head a new proteomics center at George Mason University (GMU) in Fairfax, Virginia. And the National Heart, Lung, and Blood Institute's Bryan Brewer, who the Los Angeles Times has suggested improperly endorsed a cholesterol drug, is retiring from NIH and joining a nearby hospital. NIH ethics officials had approved their outside activities. These cases helped trigger a ban on health-related consulting by NIH staff, even for nonprofits, and stringent limits on owning stock (Science, 11 February, p. 824).

Liotta and Petricoin co-invented a new method for detecting ovarian cancer by analyzing patterns of proteins found in blood. The approach led to a new clinical proteomics program at their two agencies. But the pair ran into trouble for consulting with a competitor to a firm that held an NCI cooperative agreement they oversaw (Science, 28 May 2004, p. 1222).

Liotta and Petricoin declined comment on their job move. GMU associate dean for research Vikas Chandhoke says the two men will be “strongly encouraged” to consult: “It's very healthy for science as well as faculty development.”

Meanwhile, NIH's intramural Assembly of Scientists released an alternative to what its leader, ethicist Ezekiel Emanuel, calls the agency's “draconian” rules. Their proposal would allow biomedical stock ownership and limited consulting by most intramural scientists. NIH Deputy Director Raynard Kington says NIH and the Department of Health and Human Services (HHS) will consider these comments, but that “the basic rules … are not going to change.”

The weeks since the new rules were announced have been very stressful, say NIH staffers. Scientists had until 4 March to end prohibited outside activities or request an extension. But biochemist Herbert Tabor of the National Institute of Diabetes and Digestive and Kidney Diseases is still waiting to confirm a temporary decision that he can continue a 30-year stint as editor-in-chief of the Journal of Biological Chemistry. And Ashani Weeraratna of the National Institute on Aging had to cancel a trip to New York City to speak at an international melanoma symposium because NIH failed to approve her acceptance of a $200 train ticket. It was “embarrassing” and a “hardship” for the organizers, wrote Weeraratna in a comment to HHS. Researchers also point to problems with NIH's plan to allow them to perform scholarly activities as federal employees. For example, Robert Nussbaum, a lab chief at the National Human Genome Research Institute and past president of the American Society of Human Genetics, is seeking an exception to serve on the society's board on his own time. Nussbaum says, “I realized it wouldn't work” as part of his day job because he wants to help the society raise funds and educate members about the political process. Another scientist worries about the propriety of reviewing grant proposals for work on human embryonic stem cells for a foundation, because federal funds cannot be used for some of this work. “They should have asked [us] what the impact would be on the ground,” says the scientist, who requested anonymity. Michael Brownstein, a 33-year veteran of the National Institute of Mental Health, says he is considering extreme measures to preserve his investments. Brownstein retired last fall because of “commitments I wanted to keep” with companies and foundations; he is moving to the Venter Institute. But his wife, neuroscientist Eva Mezey, still works at NIH. Because even biotech stocks owned by a senior employee's spouse are now verboten under the new NIH rules, the couple is weighing a divorce to avoid a July deadline for divesting. “It's a real option for us. Pretty stupid,” Brownstein says. 4. EVOLUTION # Special Hemoglobin Helped Swim Bladders Give Fish Diversity a Lift 1. Elizabeth Pennisi Scuba divers wear air-filled dive vests to move up and down in the water column. Researchers have now used the fish family tree to piece together how the piscine equivalent, an internal air sac called a swim bladder, evolved a complex capillary network and special hemoglobin molecule to inflate it with oxygen. Moreover, according to the proposal presented on page 1752 by Michael Berenbrink of the University of Liverpool, United Kingdom, and his colleagues, these innovations helped fish expand their species diversity. “The scenario developed presents a fascinating picture of the evolution and radiation of fish,” says Bernd Pelster, an animal physiologist at the University of Innsbruck, Austria. Herring and other fish with primitive swim bladders must surface and gulp air to keep their bladders full and their bodies buoyant. The more sophisticated species use oxygen in the blood, an advance that freed them from their air tether and allowed for the expansion into the deep ocean. These species depend upon a network of blood vessels to concentrate oxygen in their swim bladder. However, high oxygen concentrations usually inhibit the release of oxygen from the blood. To get around this problem, these fish have a special Root-effect hemoglobin, a form of the protein that releases its oxygen cargo even when concentrations of the gas are high. This new hemoglobin evolved before the swim bladder's capillary network, according to Berenbrink, a comparative animal physiologist. He and his Liverpool colleague Andrew Cossins reconstructed the history of the self-contained swim bladder by looking for its prerequisite components, such as the hemoglobin. The researchers studied species, ranging from sharks to dolphinfish, that represented the different stages of fish evolution. According to the new study, the Root-effect hemoglobin evolved once in primitive fish. Although the molecules function at high oxygen concentrations in sharks, lungfishes, and even tetrapods, they are most efficient at releasing oxygen in those conditions in codfish and other modern fish. Next came a capillary network that supplied oxygen to fish eyes, allowing them to see better. This also evolved just once, about 250 million years ago, and depended upon the Root-effect hemoglobin. From that point, the hemoglobin was essential to fish. About 100 million years later, a similar capillary network, this one supplying oxygen to the swim bladder, finally began showing up. This network arose four times in different fish groups, the researchers found. “It's one of the few examples of our understanding of the evolution of a complex organ from simpler parts,” says Albert Bennett, an evolutionary physiologist at the University of California, Irvine. “They have done an excellent job of teasing apart what happened when.” Over millions of years, the swim bladder's capillary network came and went in various species, adds Berenbrink. In those species in which the network disappeared, the Root-effect hemoglobins became less essential, he says. The development of a self-contained swim bladder enabled fish to invade new waters and diversify, according to the researchers. As evidence, Berenbrink contrasts the 198 species of elephant fishes, all with the complex swim bladder, with a close relative that lacks this swim bladder and has just eight species. Some remain skeptical, however. “To postulate that oxygen secretion is the reason for the diversity of fish … that might be an overstatement,” says Axel Meyer, an evolutionary biologist at the University of Konstanz in Germany. The hypothesis rests on the questionable accuracy of the fish family tree, adds John H. Postlethwait of the University of Oregon, Eugene. Still, he and others are impressed by the new study's breadth. “The paper nicely demonstrates the power of an integrated approach,” says Pelster. “I am convinced this paper will stimulate scientists from other areas.” 5. GENETICALLY MODIFIED CROPS # Safety Research Falls Foul of German Politics 1. Gretchen Vogel BERLIN—Researchers at two government-funded labs in Germany have had to withdraw from projects involving the safety of genetically modified (GM) plants after their bosses, officials in the agriculture ministry, said the work was inappropriate. The ban came despite the fact that the projects won funding from another government department—the ministry of research and education—in a nationwide competition for projects studying GM plant safety. The showdown is the latest example of political hostility toward GM research in Germany, says Jörg Hacker of the University of Würzburg, a vice president of the federal research agency DFG. Even so, he says, the cancellation of specific projects is unprecedented: “To my knowledge, it's the first time such a thing has happened.” The projects involved “one of the core concerns of the ministry,” he adds, to improve the safety of GM plants. Agriculture and consumer protection minister Renate Künast, a Green Party member of the left-leaning governing coalition and the researchers' ultimate boss, is openly skeptical of gene technology. Last year, her ministry proposed a law that holds anyone who plants GM crops financially liable if neighboring fields are contaminated with genetically altered pollen. Scientists have complained that the law, which received final approval from the Bundestag in December, essentially prevents all field research with GM plants (Science, 25 June 2004, p. 1887). The researchers leading the projects, Joachim Schiemann of the Institute for Plant Virology, Microbiology, and Biosafety in Braunschweig and Reinhardt Töpfer of the Federal Center for Cultivated Plant Breeding Research in Siebeldingen, hoped to optimize a method for removing antibiotic-resistance genes from GM plants. During the genetic alteration process, antibiotic-resistance genes are commonly introduced as markers. Their presence in GM plants is often cited by opponents of the technology as a potential danger to consumers and the environment. A spokesperson for the agricultural ministry says the projects could lead to products that would later need to be evaluated by the institutes in question, and the ministry acted to prevent potential conflicts of interest. The researchers were not available for comment, but a member of Schiemann's consortium, Inge Broer of the University of Rostock, says the research will go on. Her group will take over the project, she says, “but we have enough other work to do. It would be better if the [agriculture ministry] researchers did it themselves.” If the government hopes to properly assess the safety of GM crops, she says, they will need qualified experts in the field. 6. GRADUATE SCHOOLS # Drop in Foreign Applications Slows 1. Yudhijit Bhattacharjee The number of foreign students applying for graduate studies in the United States has declined for the second year in a row, according to a survey released last week by the Council of Graduate Schools (CGS). But after a 28% fall last year that was widely attributed to a tightening of U.S. visa policies, this year's drop of 5%—combined with a similar pattern in the United Kingdom—has some university administrators looking at external factors as the primary cause. CGS's survey of 450 U.S. institutions shows that applications from the two biggest sources of students, China and India, are down 13% and 9%, respectively. But a 6% rise from the Middle East undermines the theory that the fight against terrorism has tarnished America's reputation as a welcoming country. That finding also “counters the concern that visa changes (geared toward individuals from predominantly Muslim nations) would disproportionately discourage students from these countries,” says Heath Brown, co-author of the study. The Asian numbers point to increasing domestic opportunities in the region, says Peggy Blumenthal, president of the Institute for International Education in New York City. “A U.S. degree is not the only guarantee of a good job and successful career,” she says. Her analysis is bolstered by numbers from the U.K. Universities and Colleges Admissions Service, which last month reported a 26% drop in Chinese applications as part of a 5% decline in undergraduate applications this year from non-E.U. countries. The same trend is reflected in the number of Asian students who enrolled at U.K. institutions in fall 2004. A survey by Universities UK found that some campuses reported a drop of more than 50% in enrollments by Chinese students compared with 2003 figures. No matter what the short-term figures show, “there's no denying that U.S. universities face increasing global competition for the best students, particularly in the sciences and engineering,” says CGS president Debra Stewart. In response, the council wants U.S. graduate schools to step up efforts to attract both international and domestic applicants. Stewart warns that “we will never return to the day when the top 1% of every country's students will want to come to the United States.” 7. MARINE GEOLOGY # Pursued for 40 Years, the Moho Evades Ocean Drillers Once Again 1. Richard A. Kerr Hopes were running high early last month that geophysicists had finally come within striking distance of a decades-old goal. Drillers aboard the JOIDES Resolution in the mid-North Atlantic were making steady progress down through hundreds of meters of rocky ocean crust toward the legendary Mohorovicic discontinuity, or simply the Moho, the boundary between the thin veneer of Earth's crust and the 2900-kilometer-thick mantle. But as drilling proceeded with unparalleled ease through 700 meters of crust, then 1000 meters, and even 1400 meters, the Moho was a no-show. Seismic probing had put it at a depth of 1 kilometer or less just off the Mid-Atlantic Ridge, but drilling cores never showed any sign of the predicted fresh mantle rock. It seems Earth is more complicated than the best geophysical tools had suggested, says Jay Miller, the onboard project manager during the 4 months of drilling. But he and colleagues are still game to return to the hunt. Ambitions of reaching the Moho drove the first scientific deep-sea drilling effort, Project Mohole, in the early 1960s. Funded by the U.S. National Science Foundation (NSF), oceanographers eventually tested a system for drilling to the Moho where it is closest to the surface, in the deep sea. Croatian geophysicist Andrija Mohorovicic (1857–1936) had found that seismic waves moved faster below a depth of about 35 kilometers beneath the European continent than they did above, presumably reflecting the iron-rich mineralogy of mantle rock. But beneath the oceans, where the crust is thinner, the Moho lies less than 10 kilometers beneath unsedimented sea, Mohole researchers pointed out. That might put the mantle—the sole source of the magmas that form the crust—within reach of drilling. Project Mohole ended in a bureaucratic and fiscal fiasco, but by the late 1960s, NSF had launched a broadly based ocean drilling program that continues in the international Integrated Ocean Drilling Program (IODP) (Science, 18 April 2003, p. 410). Since Mohole, oceanographers looking to reach the deep crust or the Moho have taken their drills to places where the crust is particularly thin. One such thin spot lies at the intersection of the Mid-Atlantic Ridge—where new crust forms—and the Atlantis Fracture Zone at about 30°N. The stress and strain of moving tectonic plates has sliced through the upper ocean crust and dragged it off to expose the lower crust. Seismometers placed on the sea floor above the thinned spot picked up waves from explosive charges set off near the ocean bottom. The waves sped up to mantlelike velocities whenever they passed much below a depth of 700 meters. “My interpretation was they would reach fresh [mantle rock], certainly by a kilometer,” says seismologist John Collins of the Woods Hole Oceanographic Institution in Massachusetts (WHOI). After running through a dozen drill bits in 54 days of drilling through 1415 meters of solid rock, however, scientists onboard Resolution had recovered nothing that looked like the underlying mantle. “I'm surprised,” says Collins. Possibly, he says, his vertical, two-dimensional seismic picture missed an unexpected deepening of the Moho off to one side: “Perhaps they were unfortunate in where they drilled.” WHOI colleague and seismologist Robert Detrick adds that identifying deep rock “is a hard call to make based on seismic velocity alone.” Rocks of different compositions can have the same seismic velocity, he notes: “It's a problem that plagues seismology.” Undaunted, oceanographers are ready to try again. The latest drilling shows that “we now have the technology to deliver deep holes,” says Miller, who is with IODP at Texas A&M University in College Station. For that matter, the new hole “is just sitting there waiting” to be reentered. 8. AIDS CLINICAL TRIALS # More Woes for Novel HIV Prevention Approach 1. Jon Cohen Clinical trials of a promising new AIDS prevention strategy, already derailed in Cambodia and Cameroon, suffered two more setbacks last week. The studies aim to test whether the drug tenofovir can thwart HIV if people at high risk of becoming infected take one pill every day. Tenofovir, an anti-HIV drug on the market since 2001, has relatively few side effects and stays in the body for an unusually long time. Citing ethical concerns, Cambodia stopped a tenofovir prophylaxis study in sex workers in August 2004; Cameroon halted a similar trial in February. Then on 11 March, Family Health International (FHI), the North Carolina-based nonprofit that organized the Cameroon trial, announced that it was pulling the plug on a Nigerian study of sex workers, this time citing technical, not ethical, concerns. Just a day earlier, critics of a study in Thailand involving injecting drug users (IDUs) held a press conference to attack a pending tenofovir study there, charging that the trial, funded by the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, “ignores international ethical standards.” FHI determined that the research team running the Nigerian trial, which started enrolling participants in September 2004, “is not at this point able to comply with all of the standards that have been established for conducting this study.” The study team had problems with record-keeping and other technical issues, says Ward Cates of FHI, which decided to cut its losses. “The juice wasn't worth the squeeze,” Cates says. (The Bill and Melinda Gates Foundation funded FHI to conduct its tenofovir prophylaxis trials, two of which are still under way in Ghana and Malawi.) In Thailand, the Thai Drug Users' Network and other AIDS advocates blasted several aspects of the study. Approved by both U.S. and Thai authorities and run by Thai researchers, the study plans to enroll 1600 uninfected IDUs who visit 17 different methadone clinics. Critics insist that drug users who participate should receive clean needles and syringes to help prevent HIV infection. They also allege that it's “coercion” to recruit people at methadone clinics, as some fear they must join the study to receive the heroin substitute. They further worry that IDUs who test positive for HIV either during the screening process or the trial itself will not receive AIDS drugs from government programs, which they claim discriminate against them. Jordan Tappero, head of the CDC program in Bangkok, notes that both U.S. and Thai law prohibit providing sterile injection equipment, but that Thai pharmacies and convenience stores sell needles and syringes without a prescription at low cost. He also disputes the charge that Thailand does not provide anti-HIV drugs to infected drug users. “That's just a misunderstanding,” he says. As for coercion, social workers, not clinic staff, will recruit people to the study, he says. Tappero and co-workers are continuing discussions with the critics, and he hopes the study can start as planned within the next 2 months. “This community needs a prevention intervention, and tenofovir could be a great tool,” says Tappero. “The only way to evaluate it is a clinical trial.” 9. GENETICS # Mutterings From the Silenced X Chromosome 1. Elizabeth Pennisi A large-scale survey of the X chromosome has revealed that genes once thought to be silenced in women are sometimes expressed—and that their degree of expression varies from woman to woman. Researchers are now scrambling to figure out whether this previously unknown source of genetic individuality accounts for any significant differences among women. The X and Y chromosomes define the human sexes, with males having one of each and females having two X's. During a woman's development, a murky process called X inactivation almost completely shuts down the second X chromosome to ensure that men and women have the same relative degree of genetic activity. Five years ago, however, geneticists Laura Carrel, now at Pennsylvania State University Colleg of Medicine in Hershey, Huntington Willard, now at Duke University in Durham, North Carolina, and colleagues showed that about 25% of the genes they analyzed on the “inactivated” X actually escaped deactivation to some degree. The new work extends that finding to the full repertoire of genes on that X chromosome. An estimated 250 genes are not turned off, says Willard. What's more, for about 10% of these escapees, the level of gene expression differs among women, he and his colleagues report in the 17 March issue of Nature. He and Carrel measured the activity of 94 X chromosome genes in skin cells from 40 women. Depending on the woman, a gene that had escaped inactivation might function at anywhere between 10% and 75% capacity, they found. “Females are walking around with variability in their [X chromosome gene] expression,” says Evan Eichler of the University of Washington, Seattle. “This will have some impact on how we think about disease.” Carrel and Willard relied in part on the sequence of the X chromosome, which was described in full in the same issue of Nature by Mark Ross of the Wellcome Trust Sanger Institute in Cambridge, United Kingdom, and 250 colleagues. The 155 million bases contain 1098 genes and unusually large numbers of repetitive sequences called LINE1 elements, which seem to play a role in the X-inactivation process. “Now that we've got the sequence of both sex chromosomes, we can do a very detailed comparison [to] really ask the differences between male and female,” says Ross. 10. NASA # Nominee Wins Quick Praise for His Technical Expertise 1. Andrew Lawler President George W. Bush has tapped an aerospace engineer with an undergraduate physics degree to lead NASA. His choice of Michael Griffin, announced on 11 March, won immediate plaudits from both Democrats and Republicans, signaling a likely swift confirmation by the Senate. That will be the easy part: Once he is on the job, Griffin will immediately face a host of pressing budgetary and programmatic decisions. Griffin's chief asset is his technical expertise. That contrasts with his predecessor, Sean O'Keefe, whose strength was his political prowess. With a Ph.D. in aerospace engineering and an undergraduate textbook on the discipline, Griffin has earned a reputation as a low-key and methodical thinker who's done stints in government, industry, and academia. Although he lacks the high-level connections of O'Keefe, who was a protégé of Vice President Dick Cheney, Griffin, who heads the space department at Johns Hopkins's Applied Physics Laboratory (APL) in Laurel, Maryland, is thoroughly familiar with many components of NASA. “I am pleased President Bush is sending us a nominee with a strong technical background,” says Senator Kay Bailey Hutchison (R-TX), who chairs the space and science panel on the Commerce Committee. “I look forward to … having a smooth nomination process through our committee.” Other lawmakers and many scientists also praised the 55-year-old Griffin. “This is good news,” says Stamatios Krimigis, the APL department head emeritus. “Mike has always expressed his support for the science mission of NASA.” APL's space work focuses on solar physics and outer solar system exploration, two areas facing cuts in the president's 2006 budget request (Science, 11 February, p. 832). Griffin is well suited to carrying out the vision that President Bush spelled out in January 2004. He was a chief of exploration at NASA during the agency's aborted attempt in the early 1990s to get a similar effort off the ground, and he has been skeptical of the space station and space shuttle—two programs the White House is eager to finish and close down by the next decade in order to proceed with the lunar and Mars missions. “It is beyond reason to believe that [the space station] can help to fulfill any objective, or set of objectives, for space exploration that would be worth the$60 billion remaining to be invested in the program,” he told the House Science Committee last year. (Griffin could not be reached for comment for this article.)

Yet Griffin is also a strong proponent of robotic space science. In 2003, he told the same panel that “scientific research devoted to using space assets to improve our understanding of Earth's environment, our solar system, and the cosmos beyond will always, and should always, receive due attention in the allocation of resources.” He went on to praise the Hubble Space Telescope, noting that as a young engineer he was involved in the project. “Certain unmanned space systems having little connection with human space flight will be supported—as they are today—because of their inherent scientific or utilitarian value,” he added. “There is no inherent conflict between manned and unmanned space programs, save that deliberately promulgated by those seeking to play a difficult and ugly zero-sum game.”

A test of that position will come soon enough, given O'Keefe's decision not to send the shuttle again to service the telescope. The same day that the White House announced Griffin's nomination, the National Academies released its final report on Hubble calling for a shuttle flight to upgrade the instruments.

Griffin also will be forced to take a stand on more earthly matters, including a proposal to cut 15% of NASA's workforce in coming years. That plan has upset many lawmakers, some with large NASA facilities in their districts. So although Griffin's technical expertise may go far, his ability to lead the $16 billion space agency will rest ultimately on his political acumen. 11. PLANETARY SCIENCE # Enceladus, a Work in Progress 1. Richard A. Kerr As the Cassini spacecraft orbiting Saturn looped by the icy 500-kilometer moon Enceladus again last week, it found yet more terrains beaten up by still-mysterious tectonic processes. This time Cassini focused on a side of Enceladus still bearing the pockmarks of ancient impacts; elsewhere, the surface has been wiped clean of craters by cracking, ridging, and smoothing. Now it's obvious that even recognizably old terrain has been reworked repeatedly. In places, “it looks like someone had applied an egg slicer to it,” says Cassini imaging team member Torrence Johnson of the Jet Propulsion Laboratory in Pasadena, California. Apparently, says Johnson, again and again over great spans of time Enceladus had the internal energy to rework at least parts of its surface. Such a small body should have cooled to a state of geologic stupor long ago. Planetary scientists will be searching for the source of its evident energy. 12. DIABETES RESEARCH # Researchers Puzzle Over Possible Effect of Gleevec 1. Jennifer Couzin Can a targeted cancer drug help treat diabetes? That's a question two independent teams of Italians are asking after giving leukemia patients the drug Gleevec and watching their preexisting diabetes regress. One 70-year-old woman improved so dramatically that she could no longer be classified as a type 2 diabetic, three physicians reported last week in the New England Journal of Medicine. “We don't know exactly what's going on,” says Enzo Bonora, the endocrinologist at the University of Verona who treats her. Similar observations popped up in the November 2004 Journal of Clinical Oncology. There, Italian doctors at the University of Rome “La Sapienza” described seven patients with type 2 diabetes and chronic myelogenous leukemia (CML), a cancer susceptible to Gleevec (and the same disease afflicting Bonora's patient). Six experienced enough improvement in diabetes to reduce medications or insulin dosages. The only patient whose diabetes didn't ease, the team says, was also the only one whose leukemia didn't respond to Gleevec. Since his first patient, Bonora has treated two others whose diabetes also improved. The cohort is tiny, Bonora stresses, and should be viewed cautiously. And some physicians can't corroborate the results. Brian Druker of Oregon Health and Science University in Portland, a leukemia specialist who helped develop Gleevec, says three or four diabetics with CML have been treated in his center, although he doesn't recall any change in their diabetes while on the drug. “But it's hard to ignore what other people have seen just because we haven't seen it,” says Druker, who hopes that physicians will “track down” what's happened in the patients who improved. Gleevec was designed to disable a defect specific to CML, in a protein called a tyrosine kinase, although it affects other protein kinases as well. Among those kinases are some that help control insulin signaling and how responsive the body is to insulin secreted by the pancreas—both common defects in type 2 diabetes. But the Italians can't say whether an effect on insulin signaling is behind the unusual observations. Gleevec also hits a protein kinase called platelet-derived growth factor, which some doctors suspect may spur conditions, such as atherosclerosis, that are common complications of diabetes. Two recent mouse studies by Mark Cooper and colleagues at the Baker Heart Research Institute in Melbourne, Australia, showed that Gleevec helped animals with diabetes-induced atherosclerosis and diabetes-induced kidney disease. Cooper theorized that Gleevec's effects on platelet-derived growth factor might explain the results, although he couldn't say for sure. Bonora plans to ask Novartis, the Basel, Switzerland, company that manufactures Gleevec, whether it might test its drug in type 2 diabetes patients. Although Novartis finds the results “very intriguing,” wrote Novartis spokesperson Kim Fox in an e-mail, “we do not have any studies in Gleevec in type 2 diabetes, and are not planning any at this time.” 13. FRENCH SCIENCE # INSERM Doubts Criminality in Growth Hormone Case 1. Barbara Casassus* 1. Barbara Casassus is a writer in Paris. PARIS—An expert report that came to light last week questions whether it makes sense to prosecute 12 French scientists and doctors as criminals because they treated children in the mid-1980s with contaminated human growth hormone. The French medical research agency INSERM prepared the report and submitted it last year to a drawn-out investigation. It argues that criminal charges are not justified because doctors and lab personnel were not negligent, even though they used material from human brains infected with Creutzfeldt-Jakob disease (CJD), the human form of mad cow disease. The report was made public by the aggrieved families of CJD victims, who suggest that the medical establishment quietly works against them. The report concludes, “it is not reasonable to expect the players involved in the production of growth hormone to have guessed there was a possible risk of CJD from a treatment used since the 1960s” without a single incidence of disease. It alleges a lack of “good laboratory practice”—not just in France but also in the United States and the United Kingdom. Before 1985, pediatric endocrinologists and prion experts rarely got together, it says. The first mention of a transmission risk was a letter sent by Alan Dickinson, an expert on scrapie, the sheep form of the disease, to the British health ministry in 1977: It “never left the office to which it was addressed,” the report claims. A total of 968 children were treated in France with high-risk batches of human growth hormone between December 1983 and June 1985. So far, 101 have died from CJD and several others are infected, says Jeanne Goerrian, president of the Association of Growth Hormone Victims. In 1991, magistrate Marie-Odile Bertella-Geffroy began a criminal investigation, which should be completed this year. Former health minister Bernard Kouchner asked INSERM in 2002 for data on the CJD problem in France since 1980. But the report INSERM submitted digressed, charges Bernard Fau, lawyer for the victims. “Not only was INSERM doing the examining magistrate's job, but it cleared the 12 of all responsibility,” Fau says. The accused 12 include Fernand Dray, who was in charge of purifying the material at the Pasteur Institute, and pediatrician Jean-Claude Job, formerly of the St. Vincent de Paul Hospital in Paris. INSERM chief Christian Bréchot rejects the accusation of meddling as “unjustified.” The report, which INSERM submitted to Bertella-Geffroy and the government last April, was prepared by an international committee of experts that included U.S. experts Stanley Prusiner, who won the Nobel Prize for his work on the CJD prion, and Paul Brown, formerly of the U.S. National Institutes of Health in Bethesda, Maryland. In 2003, the French courts threw out a similar criminal case involving the use of HIV-tainted blood (Science, 27 June 2003, p. 2019). “But we are now sure [the growth hormone case] will come to trial and will be the first public health case to do so,” says Fau. The proceedings could start in early 2006 and would last several months. 14. DRUG DISCOVERY # Magnificent Obsession 1. Jennifer Couzin Converting an idea for a new MS drug into the real thing turns out to be much harder than a pair of Dartmouth researchers ever imagined—but they refuse to let it go LEBANON, NEW HAMPSHIRE—Near the Vermont-New Hampshire border, where highway signs warn of occasional moose crossings, the Dartmouth-Hitchcock Medical Center looms like a mountain behind a wall of fir trees. It offers, among other services, up-to-date therapy for about 1200 New Englanders who suffer from the autoimmune disease multiple sclerosis (MS). The man who directs the MS clinic, a motorcycle enthusiast and painter named Lloyd Kasper, is a veteran of academic medicine and a pioneer in an enterprise that the federal government is pushing strongly these days: “translational research,” which aims to move basic findings into clinical practice. Kasper and a Dartmouth colleague, Randolph Noelle, set out in the 1990s to invent a new drug. Their experience on the frontier between research and business illustrates just how difficult and frustrating negotiating this alien territory can be. The Dartmouth researchers thought they had found a way to block the biochemistry that spurs MS. The disease relentlessly attacks nerve tissues, slowly robbing many patients of the ability to walk, see, speak, or even think. Today's drugs can slow its course but cannot halt it. In his Dartmouth lab, Noelle discovered a way to block contact between certain T cells and other immune cells using an antibody called anti-CD154. An immunologist at Columbia University, Seth Lederman, independently made this discovery at the same time. Over the next several years, Noelle, Lederman, and others found that CD154 was overexpressed in a number of autoimmune diseases, and that blocking it in animals eased symptoms remarkably. A better MS drug seemed tantalizingly close. But neither Noelle nor Kasper had an inkling, when they became captivated by this immunologic pathway, of how their dream of turning it into a medicine would consume them. Today, 14 years after Noelle began this work, his drug, anti-CD154, is in limbo. After years of stop-and-go clinical work, concerns about the safety of anti-CD154 left the company with which they partnered jittery. Kasper and Noelle had little choice but to defer to business decisions. They are all too aware that once a company buys a discovery, “you lose control,” says Noelle. The Dartmouth pair, still convinced their discovery can transform the lives of MS patients, are beside themselves with frustration. “This is enough to put you on psychotropic drugs,” says Noelle, reclining in a duct-taped leather chair in his seventh-floor office, swinging a black loafer on and off his foot. But not enough, it seems, to prompt either Noelle or his friend of 20 years to capitulate, even as their options for reviving the drug dwindle. Noelle and Kasper are just two of the thousands of scientists being urged by the government to translate lab work into medical therapies. The 1980 Bayh-Dole Act encouraged university involvement in commercialization; in 2003, National Institutes of Health Director Elias Zerhouni formalized NIH's effort with an R&D “roadmap” that places a premium on translational research. Academics are increasingly eager to develop marketed products. A survey from the Association of University Technology Managers (AUTM) in Northbrook, Illinois, counted almost 8000 new patent applications filed in the fiscal year 2003 by academic scientists and nearly 4000 patents issued. ## Thrill of discovery In 1991, Noelle discovered a way to disable a recently discovered molecule that helps orchestrate the dance between helper T cells and various other immune cells. The molecule, called a ligand, binds to a specific receptor on the cell's surface—in this case, CD40. When Noelle used an antibody to block the expression of CD40 ligand, he disrupted the interaction between T cells and immune cells expressing CD40. That seemed to prevent immune cells from proliferating and producing inflammation and antibodies that may attack the body's own tissues. Noelle soon learned that he was running neck-and-neck with other scientists, including one who beat him to the patent office. Lederman had identified CD40 ligand and designed an antibody that dampened its effects, the fruition of what he calls “one of the most fascinating and exhilarating experiences” of his life. (A Seattle company, Immunex, now owned by Amgen in Thousand Oaks, California, was involved in some of the early discoveries as well but didn't pursue the antibodies commercially.) Interest in the therapeutic potential of the antibody, alternatively called anti-CD40 ligand or anti-CD154, increased in part because it fit neatly with observations in medicine. Doctors had noticed that CD154 is overexpressed in autoimmune diseases such as lupus and MS. They also suspected that it was involved in attacks launched by a healthy immune system against a transplanted organ. Convinced that the CD154 findings could have commercial value, Lederman filed for a patent, followed 3 months later by Noelle. Both scientists also began hunting for companies to help finance the work. Lederman hooked up with Biogen, a biotechnology company in Cambridge, Massachusetts, and Noelle, with Idec Pharmaceuticals in San Diego, California. After obtaining exclusive licenses, the companies followed up with big investments. The first task was to convert the mouse antibodies that had been used in test-tube studies into a human form that would be accepted by the human immune system. Humanizing the antibodies cost more than$1 million. In the mid-1990s, animal testing began.

Hopes for CD154-based therapy soared further when a series of experiments at the University of Wisconsin, Madison, strongly hinted that the drug might prevent rejection of a transplanted organ. At first, “nobody was thinking [anti-CD154] would be all that promising” in transplant patients, says David Harlan, who with his youthful, slightly freckled colleague Allan Kirk conducted the monkey studies. They were funded by the U.S. Navy. (Both Kirk and Harlan are now at NIDDK, the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland.) Monkeys given anti-CD154 after a kidney transplant were able to retain the kidney without traditional immunosuppression, even after anti-CD154 was withdrawn. One animal experienced a rejection episode and spontaneously recovered, something “we'd never seen,” says Harlan.

All the monkeys eventually rejected their new kidneys, but in some cases only after several years. Still, keeping a kidney transplant without standard immunosuppression was unprecedented. The news spurred NIH to form a $144 million clinical trials network, the Immune Tolerance Network, in 1999, to test similar drugs in people. As clinical trials of anti-CD154 took shape, Idec grew concerned that Lederman's patent, awarded in 1995, conflicted with the application from Noelle and Dartmouth, which the U.S. Patent and Trademark Office hadn't yet ruled on. The patent office apparently agreed. In 1999, unable to sort out who owned what regarding anti-CD154, it declared an “interference” between the two claims. Noelle lost the initial case, and Idec appealed on his behalf, defending Noelle's priority based on his lab notes. Years of court battles ensued, costing tens of millions of dollars in legal fees. In March 2004, a federal appeals court ruled in favor of Biogen and Columbia, which owns Lederman's patent. They can claim royalties on any anti-CD154 antibody to human cells, including Noelle's, should it reach the market. Before the patent battle reached its climax, both companies had set up clinical trials to test anti-CD154 in neglected diseases such as lupus. Biogen and Idec “did something that took courage, … which is to devote some scientific attention and meaningful resources to a disease that's usually ignored,” says David Wofsy, a lupus specialist at the University of California, San Francisco, who led lupus trials of the Idec-Dartmouth drug. “It is precisely fear of the unexpected problems that develop when you go into these areas that keeps companies from doing it.” Idec and Biogen had another factor to consider: With similar antibodies in hand, they were in a flat-out race. Idec, which lagged slightly behind, “knew that if Biogen finished their development program and got their drug approved before Idec got to the [U.S. Food and Drug Administration] FDA, Idec would have nothing,” says Wofsy. “Time was of the essence.” ## A punishing setback The Dartmouth group initially saw no showstoppers. Kasper began enrolling the first of 15 MS patients for a trial in 1999. In four sessions spaced weeks apart, each volunteer received an hourlong infusion of anti-CD154. At the same time, Biogen and Idec were running trials of their drugs in lupus and the platelet disorder immune thrombocytopenic purpura; Biogen was also testing its antibody in kidney transplant patients. Then, months after the MS trial began, disaster struck. Two volunteers in a 28- person Biogen lupus trial suffered heart attacks. In the Biogen transplant trials, which included seven patients, an obese, bedridden woman died of a pulmonary embolism. In all, roughly 10 of the 100 patients taking the Biogen drug experienced clotting, says Akshay Vaishnaw, the company's senior director for medical research. What caused the excess clotting remains a mystery. One theory is that, in addition to binding to certain T cells, the Biogen drug also binds to and activates platelets, which help blood to clot. But “we extensively studied that” after the trials “and could not prove” that platelet binding was the culprit, says Burt Adelman, Biogen's executive vice president for research and development. FDA immediately halted trials with both the Biogen and Idec antibodies. But 9 months later, the agency concluded that the Idec drug seemed safe, and those trials resumed, including the one at Dartmouth. After extensive, failed efforts in animals to understand the side effects of its antibody, Biogen decided to abandon it. Kasper completed his phase I MS trial in June 2001. The only significant possible side effect occurred in a man who struggled for 3 weeks with the flu. He recovered. Like most early trials, the study in MS patients assessed safety, not effectiveness. But Kasper and Kathleen Ryan, a nurse who coordinated the trial, say they saw hints of great promise in the antibody. “This small cohort of people … did phenomenally well,” says Kasper, who saw “uniform stabilization” in all the patients for at least 6 months. Some went 2 years with stable magnetic resonance imaging scans and no relapses, he says. The Dartmouth team garnered nearly$7 million from NIH and the Immune Tolerance Network for a 40-person phase II trial with a placebo group. But it had only randomized one patient when trouble struck in another anti-CD154 trial. A 62-year-old woman in an Idec study of Crohn's disease developed a blood clot in her leg. She needed emergency vascular surgery. In June 2002, FDA again halted all the anti-CD154 trials.

After a year of reviewing the data, FDA concluded that the blood clot was probably not linked to the drug because the patient had preexisting risk factors for clotting. At least two other Idec patients, both in their 80s, had also suffered blood clots, but FDA couldn't definitively link them to the drug either, says Kasper. In 2003, FDA gave Idec the go-ahead.

By then, however, the dealmakers of the pharmaceutical industry had intervened. One day in late June 2003, Noelle turned on his computer and was startled to learn that Idec and Biogen had merged. The company was now based at Biogen's headquarters in Cambridge and renamed Biogen/Idec. Years of legal wrangling were rendered irrelevant, because the merger meant that Biogen/Idec now jointly controlled the intellectual property.

In November 2003, Noelle and Kasper learned that the company was halting development of Idec's anti-CD154 drug, citing safety concerns. Biogen executive Adelman says the danger signal from Idec's drug was perhaps “softer” than the one from Biogen's, but there was “still a signal.”

The Biogen and Idec drugs had been tested in 300 patients with kidney transplants, MS, lupus, Crohn's disease, psoriasis, and immune thrombocytopenic purpura. The largest trials were in lupus, but the Idec drug was not effective, says Wofsy. The Biogen lupus trial was halted early, but its leaders reported that the drug, given at double the doses in the Idec lupus trials, worked in several patients and reduced antibodies linked to lupus kidney flares. Anti-CD154 did not substantially help the seven transplant patients who tried it. Unlike marketed autoimmune and transplant drugs which must be given continuously, the new therapies were designed to be given for several months and then withdrawn. Noelle and others suspect that may have made them less appealing to business executives.

## Rescue missions

Kasper and Noelle, who have a deep personal stake in anti-CD154, aren't its only cheerleaders. Despite the lackluster response to anti-CD154 among the seven transplant patients who received it, many transplant doctors consider the therapy an extremely promising way to prevent organ rejection. It's “the most significant drug in transplant,” says Kirk, now the chief of transplants at NIDDK. Kirk's belief was bolstered, perhaps, by the experience of his cousin, who was dying of lupus-induced kidney disease before entering a Biogen trial. She's been stable ever since. “There's no way that this pathway is not important in a lot of immune responses,” says Kirk. “We just need to figure it out.”

In the months after Biogen/Idec dropped the drug, Noelle and Kasper began looking for ways to revive it. They argued that the clotting that brought down Biogen's drug shouldn't taint the Idec drug, pointing out that FDA had allowed clinical trials of Idec's therapy to proceed. Furthermore, in early 2004, Noelle and Kasper learned from published research out of Massachusetts General Hospital in Boston that combining a drug very similar to Biogen's with a powerful anti-inflammatory drug prevented asymptomatic blood clots in monkeys. Noelle and Kasper traveled to Cambridge and suggested to a group of Biogen/Idec executives that the company co-administer anti-CD154 with an anti-inflammatory drug.

Biogen/Idec executives were unwilling to take any more chances. Adelman says he believes that pharmaceutical companies must be conservative. “In drug development,” he notes, “where you know that you have a risk and you don't understand what's driving that risk, I don't know how you can go forward.” (In a sign of how volatile drug risks can be, on 28 February, Biogen/Idec and Elan Pharmaceuticals in South San Francisco, California, suspended sales of a new MS drug they had jointly developed. The drug, Tysabri, was linked to a rare and life-threatening neurological disease in two patients.)

Biogen/Idec, says Adelman, is now partnering with the U.K. subsidiary of a Belgian company, UCB, to begin the multiyear process of developing differently structured—and, he hopes, safer—anti-CD154 antibodies.

The Dartmouth pair believes Biogen/ Idec saw only the risks and not the potential enormous benefits of a drug everyone was still learning to use. “It's not a decision based upon the science,” says Noelle.

Even after the company had pulled its support, Noelle and Kasper saw a way to keep going. NIH and Idec had signed a contract that guaranteed that no matter what Idec chose to do with anti-CD154, it would supply NIH with the drug.

The researchers asked NIH to demand that Biogen/Idec live up to the promise. But they learned that even if NIH exercised this option, someone would need to indemnify the clinic in case problems arose. Dartmouth declined. NIH said it wasn't set up to provide such insurance. “Dartmouth did consider suing NIH” to get the drug but “didn't warm up to that idea,” says Noelle.

Giving up, he says, is not an option. It's a stubbornness other academics can relate to. “You never know how long to persist,” says Judah Folkman, a cancer biologist at Harvard Medical School and Children's Hospital in Boston, who has been trying to push an anticancer therapy forward for 20 years. There's a “fine line between persistence and obstinacy in research,” he says. “If you work for 10 years on something and succeed, it's highly valued. On the other hand, if by 11 years you have not yet succeeded, they say, ‘He's obstinate, … wedded to a theory, pigheaded.’”

## Looking ahead, and back

Hope in anti-CD154 is still running strong. Kirk's lab and Harlan's spent a year creating a new anti-CD154 antibody—which may have different surface markers from those of either the Biogen or Idec drug, although it still targets CD154—from scratch. They have tested it in monkeys, and it appears effective—but it also causes some blood clotting.

Now, Kirk and Harlan want to humanize their antibody and distribute it to scientists “to try and figure out the complications,” says Harlan. A third colleague, heart transplant surgeon Richard Pierson III of the University of Maryland Medical System in Baltimore, Maryland, who has studied anti-CD154 in primates, is waiting to hear whether NIH will endorse his request for \$12.5 million to create a new, humanized anti-CD154 antibody and test it further in monkeys.

Robert Goldstein, chief scientific officer of the Juvenile Diabetes Research Foundation in New York City, is another enthusiast. “This keeps hitting the list” of promising drugs, says Goldstein. His deep-pocketed advocacy group is making inquiries about anti-CD154's potential use in kidney and islet cell transplants. He's considering what might be done to revive one of the existing anti-CD154 antibodies or create a new one. But “going forward without [the company's] help may complicate life enormously,” Goldstein says. Biogen/Idec, after all, still controls the intellectual property.

Determined to prove that the Idec- Dartmouth drug is safe, Noelle is testing a theory that the Idec drug, unlike the Biogen drug, doesn't bind to platelets. He's asked a Dartmouth platelet expert to conduct a series of experiments to determine whether this is the case and expects results any day now.

Kasper still has his multimillion-dollar NIH grant for an MS clinical trial with anti-CD154. But Biogen/Idec is no longer making the antibody. Like a movie stuck midway, its characters frozen in time, the trial could continue—but, says Noelle, “for the minor detail of not having any drug.”

15. HISTORY OF MATHEMATICS

# "Amateur" Proofs Blend Religion and Scholarship in Ancient Japan

1. Dennis Normile

A 300-year-old Japanese art form presents some surprising mathematical discoveries on elegant wooden tablets

TOKYO—When Japan was isolated from the rest of the world, a unique brand of mathematics flourished in the country's shrines and temples. Amateur mathematicians crafted geometric theorems on elegant wooden tablets called sangaku (literally “mathematical tablets”) and offered them to the gods. Remarkably, some of those theorems predate by more than a century the work of Western mathematicians.

Next month the Nagoya City Science Museum will present an exhibition of 130 sangaku from Japan's Edo Period (early 17th to mid-19th centuries). Assembling the show was a labor of love by Hidetoshi Fukagawa, a high school math teacher in central Japan, who has written the definitive texts on the unusual art form. “It's a really remarkable phenomenon, showing that ordinary people of that time studied mathematics purely for enjoyment,” says Fukagawa about the sangaku, which were hung up at shrines and temples and often beautifully illustrated with miniatures of women in kimonos, teachers and pupils studying, and landscapes.

Their appeal crosses the oceans. The exhibition “is a unique occasion to see one of the great treasures of Japanese culture,” says Freeman Dyson, a mathematician at the Institute for Advanced Study in Princeton, New Jersey. “I wish I could come to Japan.”

The sangaku tradition flourished in an era when Japan was closed to outside influences and at peace both internally and with its neighbors. That calm meant that the samurai—traditionally schooled not only in swordsmanship but also literature, philosophy, sciences, and the arts—could turn their attention from martial to more intellectual matters. Adds Fukagawa, “There was no academia as we know it. So samurai, farmers, and merchants all felt free to study mathematics.”

The amateur mathematicians built upon an existing tradition of hanging wooden tablets with poetry or paintings in Shinto shrines and Buddhist temples, painting or engraving sangaku that typically give the result of a problem but not the proof. “Ostensibly, the tablets were left as gifts to the gods,” Fukagawa explains. “In reality, people were showing off and challenging others to work out the proof.”

The vast majority of the problems involve plane geometry. But some involve calculating volumes of solids and others deal with algebra-like equations. The sangaku crafters typically included their names and the dates they hung the tablets.

Once Japan ended its isolation in the mid-1800s, the government encouraged the study of the European mathematical tradition as part of its push to catch up to the West technologically and economically. The archaic Chinese characters of Japanese mathematics fell into disuse, and the sangaku tradition disappeared. The rediscovery of sangaku is due in large part to 61-year-old Fukagawa, who holds a degree in mathematics and who has spent nearly 40 years teaching high school math in Aichi Prefecture. Looking for material to enliven his classes, he stumbled upon sangaku. “At the time, no Japanese mathematician had studied sangaku in any depth,” he says.

His first step was to teach himself the archaic Chinese characters used on the tablets. The more sangaku Fukagawa deciphered, the more impressed he became with their sophistication. Japanese mathematicians were less enthralled, however, so Fukagawa started contacting geometers in other countries. His search led to a number of collaborations. In 1989 he and Daniel Pedoe of the University of Minnesota, Twin Cities, co-authored Japanese Temple Geometry Problems, which remains the most complete monograph on sangaku in any language. In 2002 he and John Rigby of Cardiff University in Wales published Traditional Japanese Mathematics Problems from the 18th and 19th Centuries.

The first book describes a number of Western geometrical theorems that were solved independently in Japan. One notable example is Soddy's hexlet, a theorem published in 1936 by Frederick Soddy, a British chemistry Nobel laureate, involving a complex construction of spheres within a sphere. Fukagawa and Pedoe found that the identical solution had been inscribed on a sangaku placed at a shrine in Kanagawa Prefecture in 1822. (The tablet is lost but is described in a written text.)

Even so, the mathematical significance of the sangaku tradition is an open question. Hikosaburo Komatsu, a mathematician at the Science University of Tokyo who studies Japan's indigenous math, agrees that their existence “shows that knowledge of math among ordinary citizens of that time was quite high.” But the tablet format limits results so that “mathematically, sangaku are not very deep,” he says. Serious Japanese mathematicians were producing much more significant theoretical work at the time, he notes. Still, Peter Wong, who grew up in Hong Kong and now teaches mathematics at Bates College in Lewiston, Maine, says the sangaku “open up all sorts of questions” about how laypeople developed sufficient mathematical skills to tackle nontrivial problems.

Fukagawa hopes further study will provide some answers. About 900 sangaku are known to remain, and dozens more that have been lost are known from written references. Only last year, during a visit to a shrine in Mie Prefecture, Wong used his knowledge of Chinese characters to point out a sangaku that Fukagawa had overlooked. Fukagawa also hopes the exhibition, which runs from 19 April to 26 June, will stimulate interest in the topic and yield additional sangaku.

16. PUBLIC HEALTH

# Provocative Study Says Obesity May Reduce U.S. Life Expectancy

1. Charles C. Mann

The rising incidence of obesity, especially among children and teenagers, is leading to a variety of diseases that could depress average life span

In the 1980s and 1990s, the late maverick economist Julian Simon infuriated environmentalists by arguing that free markets and scientific progress were constantly improving human life rather than pushing the world toward ecological ruin, social collapse, and famine. A key example was life expectancy at birth, which Simon showed had been steadily rising for centuries. Using that as a metric, he repeatedly claimed that in the 21st century, “humanity's condition will improve in just about every material way.”

Not so, says a 10-person research team led by S. Jay Olshansky of the University of Illinois, Chicago, and David S. Ludwig of Children's Hospital in Boston, Massachusetts. In a study published in the 17 March New England Journal of Medicine, the team predicts that U.S. life expectancy “could level off or even decline” by 2050.

The culprit, though, is not environmental heedlessness but the very market-driven affluence that Simon celebrated, because it has fostered an explosive rise in obesity, and especially childhood obesity. That rise, the research team argues, has already offset increasing life expectancy “by 0.33 to 0.93 year for white males,” with similar offsets for women and other races. Assuming that current trends continue and that no big technical fixes emerge, Olshansky says, “we have strong reason to believe this number will rise rapidly in the coming decades.”

That conclusion is likely to be controversial. Critics argue that it is based on a partial reading of the evidence. “Obesity is indeed a problem,” says James Vaupel, director of the Max Planck Institute for Demographic Research in Rostock, Germany. “But on the other side there are extraordinary advances being made as a result of biomedical research.” Moreover, he says, “the United States has seen a slowdown in life expectancy, but in other countries it's going up fairly rapidly—about 3 months per year in places like France and Japan.”

To Olshansky, the continuing increases in those countries may mean only that they have not yet reached U.S. obesity levels. If the projections in the New England Journal article come true, he notes, the next generations will be the first in recorded history to die younger and sicker than their parents—a public-health catastrophe.

But there may be more immediate consequences as well. In 2004 the Social Security Administration estimated that by 2078 female and male life expectancy will jump from their current levels of, respectively, 79.9 and 74.5 years to 89.2 and 85.9 years. That rapid increase, which will increase disbursals, is one of the motors driving the current debate over the program's potential insolvency. “Those projections are made from mathematical models,” Olshansky says. “If you look at actual people now, I believe you see very quickly that this is not going to happen. The ‘benefit,’ if you can call it that, is that Social Security will be in less trouble, because fewer people will be alive to collect it.”

## What goes up …

In the 20th century, U.S. life expectancy climbed from 47 to its present height, a rise unprecedented in human history. The fastest part of the increase occurred in the first few decades of the century, as improved sanitation and nutrition dramatically reduced infant and child mortality. Because a child who avoids death from measles may go on to live for decades more, whereas an older person who avoids death from the same cause will only live a little longer, reducing childhood mortality has a disproportionately large impact on overall life expectancy.

Now, if the New England Journal authors are correct, the unprecedented rise in life expectancy will be followed by an equally unprecedented fall. In the 1999–2002 period, according to a Centers for Disease Control and Prevention (CDC) analysis last year, some 16% of U.S. children from 6 to 19—more than 1 out of 8—were overweight, a proportion that has more than tripled in the past 30 years. (Overweight is defined as a body mass index, or BMI—weight in kilograms divided by the square of height in meters—for age and gender at or above the 95th percentile of CDC's baseline growth charts.) Another 15% were at risk for becoming overweight (a BMI between the 85th and 95th percentiles of CDC's growth charts). (For adults, a BMI of 30 or above is considered “obese,” and between 25 and 30 is “overweight.”)

Because the health effects of obesity can take decades to appear and childhood obesity is a relatively new phenomenon, researchers have relatively little firsthand information on the impact that being overweight in childhood has on the incidence of disease in later life. Instead they make projections from the consequences of obesity on life expectancy for adults. “Obesity is not like running through a minefield, which kills you all at once or lets you run through it unscathed,” says David Allison, a biostatistician at the University of Alabama, Birmingham, and a co-author of the New England Journal paper. “Instead, your risk increases over time. What you die of is the accumulated effects from years of obesity.”

In a typical study, the Netherlands Epidemiology and Demography Compression of Morbidity Research Group analyzed data from the Framingham Heart Study to find in January 2003 that obesity led to declines in life expectancy of 7.1 years for 40-year-old female nonsmokers and 5.8 years for 40-year-old male nonsmokers. The next day, Allison's research team released a study arguing that life expectancy for extremely obese white 20-year-olds (BMIs of 45 or more) is 13 years lower than that for people of normal weight. “The younger you become obese, the more years of life you lose,” Allison says. “That's not at all surprising. If you become obese as a child, the impact should be even greater.”

## Conservative assumptions

For the New England Journal study, Olshansky says, “we tried to answer a simple question: What would life expectancy be like in the U.S. if obesity did not exist?” Basing their estimates on data from CDC's big National Health and Nutrition Examination Surveys, they assumed, for simplicity's sake, that all overweight or obese people had BMIs of either 30 or 35, respectively. The assumption had the additional beneficial effect of making the calculation “very conservative,” Olshansky says, because it implicitly excluded the impact of higher BMIs. “The proportion of extremely obese is rising very rapidly—things are really moving in the wrong direction—and we ultraconservatively eliminated that.” The researchers also assumed that obesity had no effect before the age of 20 or after 85, both of which “we know are not true.”

Although Olshansky stresses that the estimate is “a first-pass approximation,” he believes the effect is large enough to demonstrate “that trends in obesity in younger ages will lead to significantly higher rates of mortality in the future—we will lose 2 to 5 or more years [of life expectancy] in the coming decades” if the obesity epidemic continues unchecked. Another way of expressing this impact is to note that curing all forms of cancer would only add 3.5 years to average U.S. life expectancy. Rising obesity would more than cancel that out.

Perhaps so, says Vaupel of the Max Planck Institute. But on a global level the United States is an outlier—life expectancy is continuing to rise elsewhere. “That suggests to me that this is a localized problem that could be addressed by appropriate public-health policies,” Vaupel says. As he has argued (Science, 10 May 2002, p. 1029), demographers have repeatedly predicted that increases in life expectancy will level off. “And they've always been wrong. Olshansky himself wrote in 1990 [Science, 2 November 1990, p. 634] that life expectancy would never exceed 85 on average without major breakthroughs. Well, in 2003, Japanese female life expectancy reached 85.33.”

To team co-leader Ludwig, the New England Journal paper is a “call to action when action could still make a difference.” The explosion in obesity, he says, will occur in three phases. The first is increased prevalence. “For the first decade or so, very little occurs—you just have a lot of heavy kids.” In the second phase, the rising prevalence is “translated into actual diseases. Then, after yet another period of time, the third phase comes, when those diseases come to translate into lower life expectancy. Right now, we're at the beginning of the second phase. … The first wave of children diagnosed with type 2 diabetes in adolescence is now reaching their late 20s, and we're just starting to see [circulatory problems leading to] amputations, kidney failure requiring dialysis, and increased mortality.”