# News this Week

Science  05 Aug 2005:
Vol. 309, Issue 5736, pp. 858
1. STEM CELL POLITICS

# Frist's Support Raises Odds for Passage of Stem Cell Bill

1. Constance Holden*
1. With reporting by Jocelyn Kaiser.

Advocates of stem cell research are ecstatic about their new friend, Senator Bill Frist (R-TN). After failing all month to hold a promised vote on stem cell legislation, the Senate majority leader dropped a bombshell on 29 July, the last day before a 5-week recess: He announced that he supports expanding the number of embryonic stem (ES) cell lines eligible for federal funding. That puts Frist at odds with the policy laid down by President George W. Bush in August 2001 and on the side of those who hope the Senate will throw its weight behind a measure similar to one passed by the House of Representatives in May.

Scientists and even National Institutes of Health (NIH) officials have increasingly been chafing against Bush's policy as it has become clear that only 22 of the 78 cell lines he originally named are actually available for federally funded research. Many of these lines are aging and developing genetic abnormalities; all were derived with the aid of mouse feeder cells, which makes their clinical use problematic. A flurry of bills are vying for attention as senators who oppose the use of human embryos to derive stem cells offer alternative proposals to show that they're on the stem cell bandwagon. Now sponsors of S. 471, the Senate version of H.R. 810 that passed the House, are expressing confidence that the measure will sweep the Senate when it reconvenes in September—and possibly even garner the 67 votes necessary to override a presidential veto.

In a Senate speech, Frist said “the limitations put in place in 2001 will, over time, slow our ability to bring potential new treatments for certain diseases. Therefore, I believe the president's policy should be modified”—that is, federally funded scientists should be allowed to work with ES cells derived after the presidential cutoff date of 9 August 2001. Frist added that ES cells “meet … medical needs that simply cannot be met today by adult stem cells.”

His changed stance delighted stem cell supporters. “We had no idea he was going to make the switch,” said Representative Mike Castle (R-DE), a sponsor of the House bill (Science, 3 June, p. 1388). Senator Arlen Specter (R-PA), a dogged promoter of the Senate version, called Frist's action a political “earthquake.” Now others who follow his lead have “cover” and are far less likely to suffer political repercussions, Specter noted at a 29 July press conference.

In his remarks, Frist said that he's not entirely happy with H.R. 810. Although the bill is “fundamentally consistent” with principles he laid down 4 years ago, he said it lacks adequate ethical safeguards—in particular, the need to prohibit giving financial incentives to fertility clinics that could influence couples' decisions to donate “spare” embryos. A Frist spokesperson confirmed, however, that he is ready to support the bill in its present form. Senator Tom Harkin (D-IA) said that Frist's objections can be addressed in regulations that the Department of Health and Human Services (HHS) would issue after the bill is signed into law.

Scientists showered Frist with praise after his speech. “He is to be applauded,” says Stanford University stem cell researcher Irving Weissman, who says he had a phone conversation with Frist 2 days before the announcement in which the senator quizzed him extensively about stem cells. Weissman pushed hard on the need to allow research cloning, or somatic cell nuclear transfer experiments, before the two “agreed there were some areas where we'd always disagree.”

Much remains to be settled before S. 471 comes to a vote. Opponents of the bill have come up with at least six other measures that senators may be asked to vote on at the same time:

· S. 681, a bill already passed by the House, would authorize funding for a national cord blood stem cell network.

· S. 1557, introduced on 29 July by Senator Tom Coburn (R-OK), mirrors a House bill that would give NIH $15 million to fund research on “alternative” ways of deriving pluripotent (ES-cell-like) cells. · Senator Kay Bailey Hutchison (R-TX) plans to introduce a compromise of sorts between Bush's policy and S. 471. The measure would allow federally funded research on additional stem cell lines, but only those derived from frozen embryos currently held at fertility clinics. · Senator Sam Brownback (R-KS) wants votes on two bills. One, S. 658, is a ban on all cloning, including research cloning—a measure that the House has already passed twice. The other bill (S. 1373) would ban the creation of what Brownback calls human-animal “chimeras.” · Senator Dianne Feinstein (D-CA) on 27 July introduced a bill (S. 1520) aimed at banning just reproductive human cloning. Frist has said he will introduce all the stem cell bills for up-or-down votes—that is, no amendments—but has not specified the timing. If Specter and Harkin don't get a clean vote on S. 471, they are prepared to play hardball by inserting the measure into the HHS 2006 appropriations bill, which Specter will be managing as chair of the relevant subcommittee. 2. PLANETARY SCIENCE # Cassini Catches Mysterious Hot Spot on Icy-Cold Enceladus 1. Richard A. Kerr Since the Voyager flybys of the saturnian system in the early 1980s, planetary scientists have known there was something weird about the ice-covered moon Enceladus. Now, with Cassini's close flyby on 14 July, they understand the weirdness better. They can see places where the surface has recently been cracked and contorted. Some of those fractures near the south pole are so hot, by saturnian standards, that water vapor is spewing off the surface to form a tenuous atmosphere. However, the close-up encounter has only deepened the mystery of how a body as small as Enceladus can come up with enough energy for such an active geologic life. Cassini unveiled the icy hot spot by bringing most of its instruments to bear on Enceladus during an exceptionally close 175-kilometer pass. The camera captured the most detailed images yet of the surface, revealing a network of cracks that look fresh enough to have formed in the geologically recent past. The infrared mapping spectrometer found a broad “hot” spot near the south pole that registered 85 K and reaches 110 K or above in places. “That's pretty spectacular for a body that should have temperatures of 60 K to 70 K,” says Cassini science team member Torrence Johnson of the Jet Propulsion Laboratory in Pasadena, California. The infrared spectrometer placed at least one tiny hot spot right on one of the cracks that the camera found near the south pole (see figure, left). The hot spots of Enceladus are giving off more than heat. Three instruments independently detected an invisible plume of gas above the polar hot spot. The mass spectrometer detected water as Cassini passed the moon. The magnetometer found Saturn's magnetic field draped over an obstacle above the surface, presumably ionized water. And when a star passed behind Enceladus, the ultraviolet imaging spectrometer detected the absorption of its light by water. All three found the most water over the warm spot, not evenly distributed around the moon. “The presumption is that we're looking at icy hot spots” near the south pole, says Johnson. Strictly speaking, Enceladus is not volcanically active, he notes. There's no sign of ice lavas having flowed across the surface or even of geysers spewing the water. But somehow cracks are being opened and heated enough from below—perhaps by rising slush “magma”—that water molecules can escape to space from the relatively warm surface. Contrary to expectations (Science, 14 January, p. 202), this geologic activity seems to have nothing to do with creating the diffuse E ring of Saturn. (Cassini's dust detector did find a cloud of dust around Enceladus, presumably chipped off the moon by micrometeorite impacts, which might feed the E ring.) Why Enceladus should be driving off its water from a south-pole hot spot remains a mystery. Neither of the usual sources of planetary heat—lingering decay of radioactive elements in deep rock, or tidal kneading by orbital interaction with Saturn and other moons—seems great enough, says planetary physicist David Stevenson of the California Institute of Technology in Pasadena. Tidal heating is the more promising explanation, he says, but it heats other moons at least as much as Enceladus with no sign of a hot spot. So, appealing to tidal heating would require that “Enceladus is somehow special,” says Stevenson. “That's uncomfortable.” Theoreticians will have to redouble their efforts to hammer out a moon they can live with. 3. PLANETARY SCIENCE # Newfound 'Tenth Planet' Puts Pluto Behind the Eight Ball 1. Richard A. Kerr The discovery of a distant object larger than Pluto orbiting the sun seems secure enough. How to pigeonhole it, though, is completely up in the air. Is it the 10th planet, the first one discovered since Pluto in 1930? Or is it, with Pluto, just another Kuiper belt object (KBO), one of the thousands of icy chunks of debris left from the solar system's formation? Three astronomers—Michael Brown of the California Institute of Technology in Pasadena, Chadwick Trujillo of the Gemini Observatory in Hilo, Hawaii, and David Rabinowitz of Yale University—first photographed the cosmic bone of contention almost 2 years ago. This January, they noticed that the object, temporarily designated 2003 UB313, was moving against background stars. They calculate that it is at the most distant point of its orbit—97 times as far from the sun as Earth is on average (97 astronomical units, or AU)—and that its steeply inclined 650-year orbit will carry it as close as 36 AU from the sun. Pluto also follows an inclined orbit, between 30 and 50 AU. The new object is so bright that it must be larger than 2390-kilometer-wide Pluto, the group reports. Because the orbiting infrared Spitzer Space Telescope cannot detect the new object, it must be smaller than 3200 kilometers. Brown and colleagues are calling 2003 UB313 “the 10th planet.” Some astronomers agree. “If it's larger than Pluto,” says minor-planet astronomer David Tholen of the University of Hawaii, Manoa, “I'd call it the 10th planet, because Pluto is the ninth planet by historical precedent.” But theoretical astrophysicist Alan Boss of the Carnegie Institution of Washington's Department of Terrestrial Magnetism thinks that would be a bad move. When the first asteroid, 946-kilometer Ceres, was discovered in 1801, he notes, astronomers called it a planet, too. But they demoted it to minor-planet status after other asteroids started showing up between Mars and Jupiter. The new object, Pluto, and several slightly smaller KBOs discovered recently “are all part of one population of objects,” Boss argues—no one of which has enough mass and gravity to dominate its region of space the way the first eight planets do. The International Astronomical Union in Paris, France, has been studying Pluto's status for 6 months, with no resolution in sight. Brown, who expects a few more larger-than-Pluto objects to turn up, is rooting for Pluto. “People love Pluto,” he says. “Saying Pluto is not a planet will never be popular.” 4. AIDS RESEARCH # Male Circumcision Thwarts HIV Infection 1. Jon Cohen A study in South Africa has shown for the first time that circumcising adult men can dramatically lower their risk of becoming infected by HIV through heterosexual sex. “It is a major advance in HIV-prevention studies,” said Catherine Hankins, an associate director at the Joint United Nations Programme on HIV/AIDS (UNAIDS). For nearly 20 years, observational studies have suggested that circumcision protects men from HIV infection, but until now, there was no prospective evidence to support that conclusion. The new study, led by clinician Bertran Auvert of the University of Versailles in Saint-Quentin, France, began in August 2003 with more than 3000 uncircumcised men between 18 and 24 years old from the Orange Farm Township near Johannesburg. Half the participants were circumcised at the trial's outset. As Auvert reported last week at an international AIDS meeting in Rio de Janeiro, the study was stopped early, in November 2004, after an interim analysis showed that “the protection effect of male circumcision was so high that it would have been unethical to continue.” The study, performed in collaboration with Adrian Puren of South Africa's National Institute for Communicable Diseases and funded by France's Agence Nationale de Recherches sur le SIDA (ANRS), suggests that circumcision can offer 65% protection from infection. Only 18 men in the circumcised group acquired new HIV infections, as opposed to 51 in the uncircumcised group. Further bolstering the results, men in the circumcised group reported 18% more sexual contacts than controls. “It's extremely exciting,” says King Holmes, an expert in sexually transmitted diseases at the University of Washington, Seattle. “It's essentially an anatomic vaccine for life.” Circumcision could profoundly curtail the spread of HIV in sub-Saharan Africa. Circumcision practices vary greatly from country to country, and studies have shown that the regions with the worst AIDS epidemics have the lowest circumcision rates. But Auvert cautioned against rushing to integrate circumcision into public health policies. Not only are results from one location difficult to generalize, he said at the meeting, but the Orange Farm study also did not address whether circumcision reduces the ability of HIV-infected men to transmit the virus. That question is being explored in a Ugandan trial—one of three adult circumcision studies now under way. Charles Gilks, who directs the HIV prevention and treatment program for the World Health Organization, emphasized another caveat. Adult circumcision carries serious risks, especially when performed by traditional healers who do not have proper training. And because circumcision does not provide complete protection, it could backfire if it encouraged men to have more unprotected sex—which would also greatly raise risks for women. “We do need to make sure that we're not hurting more than we're helping,” said UNAIDS's Hankins. Even so, Helene Gayle, president of the International AIDS Society, which sponsored the conference, stressed that circumcision could be an important part of a comprehensive prevention strategy. “Obviously, there is no magic bullet,” says Gayle, who directs the HIV program at the Bill and Melinda Gates Foundation. “Prevention really is a combination approach where we need to put together all the things that we know can make a difference.” Although the results from the new study have been eagerly awaited by AIDS researchers, The Lancet rejected a paper describing them for “reasons unrelated to the data and scientific content,” The Wall Street Journal reported last month. At issue, Auvert and Puren told Science, is an ethical disagreement that involves how participants learned their HIV status and the counseling they received. The Lancet's rejection stunned the researchers. “We were taken aback,” says Puren. The U.S. Public Health Service requires that when research it supports involves testing people for HIV, the participants must be informed of their results. Other funders, including ANRS, do not have this requirement. The Orange Farm study, which was approved by the ethics committee of South Africa's Medical Research Council, provided counseling and also advised everyone to learn their status and receive more intensive counseling, but on a voluntary basis. Auvert and Puren strongly defend the study. The researchers made these conditions voluntary because of concerns about the intense stigma that HIV-infected people often face in South Africa. “Many of these people prefer to be dead than rejected by their community,” says Auvert. Lancet Editor Richard Horton declined to comment. But Ronald Gray, a reproductive epidemiologist at Johns Hopkins University in Baltimore, Maryland, thinks the journal reacted too harshly. “If there was an ethical lapse, I don't think it was so egregious,” he says. 5. PALEOANTHROPOLOGY # U.S. Government Shifts Stance on Claims to Ancient Remains 1. Constance Holden In an about-face, the U.S. government has sided with scientists fighting a proposal that would make it harder for them to investigate ancient human remains like those of Kennewick Man. At the same time, some scientific groups are supporting Native Americans in pushing for the proposal. At a Senate hearing last week, Interior Department official Paul Hoffman spoke against a proposed broadening of the definition of “Native American” in the Native American Graves Protection and Repatriation Act (NAGPRA). The amendment, sponsored by Senator John McCain (R-AZ), would enable tribes to claim ancient human remains even if no genetic or cultural connections with living groups could be established. Native American groups began lobbying for the new definition after the 9th U.S. Circuit Court of Appeals in San Francisco, California, ruled in February that the 9400-year-old Kennewick bones, discovered in 1996, aren't covered by NAGPRA because they show no connection with any existing human group. NAGPRA defines Native American as “of, or relating to, a tribe, people, or culture that is indigenous to the United States” (indigenous meaning pre-Columbus). Indians and their supporters want to add the words “or was” after “is.” The seemingly small change would label bones such as those of Kennewick Man as “Native American” and might enable tribes to rebury them without allowing scientists to examine them. Last week's hearing came after scientists complained that the Senate Committee on Indian Affairs endorsed McCain's amendment, part of a package of changes to Indian-related laws (S. 536), without any public input. The Bush Administration inherited the Kennewick case, in which the government, as the defendant in a case brought by a group of scientists, argued that the remains were covered by NAGPRA. But Hoffman indicated that the department, after 8 years of siding with the Indians, had changed its mind. “We believe that NAGPRA should protect the sensibilities of currently existing tribes … while balancing the need to learn about past cultures,” he testified. “[W]here remains are not significantly related to any existing tribe, … they should be available for … scientific analysis.” Hoffman later told Science that “we thought [the appeals court] made a good argument.” In addition to making the bones available to scientists, the appellate court ordered the NAGPRA grants program to pay the plaintiffs$680,000 in attorneys' fees, Hoffman said.

Some scientists who testified at the hearing were sympathetic to the proposed word change. Keith W. Kintigh of the Society for American Archaeology in Washington, D.C., said that requiring a demonstration of ties only to existing tribes is “inconsistent with a commonsense understanding” of the term Native American and might exclude “historically documented Indian tribes that have no present-day descendants.” Patricia M. Lambert of the American Association of Physical Anthropologists agreed with Kintigh that every-one who inhabited America prior to the advent of Europeans should be treated as a “Native American.”

In contrast, Portland, Oregon, lawyer Paula Barran, speaing for the Kennewick plaintiffs, cautioned that the proposed language would “stamp people from ancient cultures all as Native American as we know them.” Any newly found human remains, she warned, would be “automatically turned over … only to people calling themselves Native Americans.” Such handovers have already been made under the current law, notes Douglas Owsley, a forensic anthropologist at the Smithsonian Institution, citing a set of 7800-year-old bones that the Minnesota Science Museum yielded up for reburial in 1994.

Owsley says that the vast majority of what are called “unidentifiable remains” are obviously Native American. But a few, like Kennewick Man, are what he calls “paleoamericans,” far older than and racially distinct from Native Americans. “Many critically important skeletons will be forever lost if this bill becomes law,” says Barran.

6. BIOCHEMISTRY

# Cut-Rate Genomes on the Horizon?

1. Elizabeth Pennisi

Given the exorbitant cost of deciphering genomes, most labs have given up sequencing and left that job to the big sequencing centers. But now, two groups have published methods that may be much cheaper and faster, promising small labs a chance to do more of their own sequencing. “These are the first described techniques having the potential of replacing conventional [approaches],” says Mostafa Ronaghi, a biochemist at Stanford University in Palo Alto, California. And more are in the works, he adds.

In a paper published online by Science this week (www.sciencemag.org/cgi/content/abstract/1117389), George Church, a computational biochemical engineer at Harvard Medical School in Boston, and his colleagues introduce a do-it-yourself sequencer that uses a microscope and other off-the-shelf equipment. With this technology, his team sequenced a strain of Escherichia coli and was able to detect easy-to-miss single-base-pair changes from an almost identical E. coli genome. The approach reduces sequencing costs by 90%, Church says. Jonathan Rothberg, founder of 454 Life Sciences Corp. in Branford, Connecticut, has demonstrated the power of another cost-cutting technology he calls “454.” He describes 454's success in sequencing Mycoplasma genitalium online in Nature this week.

Researchers all over the world still depend on a sequencing method introduced decades ago by Fred Sanger of the Laboratory of Molecular Biology in Cambridge, U.K. It uses bacteria to amplify the DNA and expensive reagents to label bases for identification. The cost has dropped since the mid-1990s from more than $1 to less than a 10th of a cent per base. But it's still high for many projects, including medical uses such as checking the genomes of individuals. Both groups save money by eliminating the need for bacteria and miniaturizing the process wherever possible. In lieu of bacteria, they attach DNA to aqueous beads encased in oil where chemical reactions copy the DNA to make the necessary amount. That change alone could reduce by two-thirds the costs associated with space and personnel, says Edward Rubin, director of the U.S. Department of Energy Joint Genome Institute in Walnut Creek, California. Moreover, both perform many thousands of these sequencing reactions at once in miniature “reactors,” decreasing the need for pricey chemicals. Once the DNA is ready, the two technologies diverge: The 454 technique puts the beads on a fiber-optic chip and uses flashes of white light to identify the bases. Rothberg washes the chip surface with one base at a time, creating four light patterns that a computer puts together as a sequence. Church's technique uses bursts of different fluorescent colors, one each to a particular base, to distinguish the bases. Both use high-speed charge-coupled device cameras to record the labeled bases. Neither method is up to speed yet. The accuracy of both “should be improved by at least one order of magnitude,” says Ronaghi. Also, to sequence mammalian genomes, the length of sequence generated, the “read,” should be about 700 bases, but reads reported from these new approaches are hovering between 26 and 110 bases. Rothberg's company has sold its$500,000 machines to a dozen sequencing centers. Church's technology costs $140,000 and is in use at three of those centers. However, says Rubin, there are still kinks in the build-it-yourself version. But, he adds, in time, it “may improve efficiencies and throughput even further [than the 454].” Whatever their limitations, the two reports signal the dawn of a new era in genome sequencing and detecting changes in individual genomes. Last year, the U.S. National Human Genome Research Institute in Bethesda, Maryland, began a program aimed at decreasing the cost of sequencing mammalian genomes to$100,000 in 5 years and to $1000 5 years later. That's what many think it will take for sequencing to become affordable in small labs. 7. CLONING # The Perfect Pedigree 1. Gretchen Vogel Afghan hound Snuppy (right) is the world's first canine clone, carrying the same DNA as his older twin Tai (left). Dogs have been difficult to clone, but Woo Suk Hwang of Seoul National University and his colleagues report in the 4 August issue of Nature that a new method of collecting oocytes—and persistence—paid off. Hwang and his colleagues removed the DNA from more than 1000 canine ooctyes, fused each with a skin cell from Tai's ear, and prompted the fused cells to begin dividing. They implanted 1095 resulting embryos into 123 surrogate mothers but detected only three pregnancies. One fetus miscarried, and two full-term puppies were born by caesarean section. The second dog died of aspiration pneumonia after being tube fed, Hwang says. Although Hwang says Tai was chosen in part because of his “gentle and docile pedigree,” he isn't interested in cloning friendly pets. Cloned dogs might help researchers find genes involved in hypertension or breast cancer, he says. And if scientists could grow embryonic stem cells from cloned canine embryos, the animals could serve as models for therapeutic cloning, in which genetically matched ES cells would be used to develop cells to replace those damaged by disease or injury. 8. ENERGY POLICY # U.S. Energy Bill Promises Some Boosts for Research 1. Eli Kintisch After a 4-year effort, Congress passed a landmark energy bill last week, setting out goals and incentives that could shape federal energy policy for the next decade. The 1724-page bill includes$14.6 billion in tax breaks—mostly to encourage domestic energy production from conventional sources—new efficiency standards for appliances, and renewed legal protections for nuclear power plant operators. It also contains provisions that aim to bolster federal spending on basic research, including an increase in the budget of the Department of Energy's (DOE's) Office of Science from $3.6 billion in 2005 to$5.3 billion by 2009; backs applied research efforts aimed at burning fossil fuel more cleanly; and calls for studies on combustion and carbon sequestration. But these commitments are far from assured: The bill simply authorizes spending that must later be approved by spending committees.

“The bill largely codifies the existing energy research programs,” says a spokesperson for House Science Committee Chair Sherwood Boehlert (R-NY). While Boehlert helped craft the research provisions of the bill, he voted against it because it lacks government mandates that would boost energy production from renewables—such as wind and solar power—and raise fuel efficiency for automobiles.

For research, the bill lays out ambitious funding goals. If appropriations committees follow its lead—a big if—by 2009, fossil fuel research would rise by 23% and funding for renewables would more than double. The bill also sets a 2008 date for the construction of the Rare Isotope Accelerator, long sought by nuclear physicists to study exotic nuclei. Calling the R&D provisions “pretty good,” William Fulkerson, former energy manager at Oak Ridge National Laboratory in Tennessee, says research projects on advanced coal plants and a plan to build a hydrogen-producing nuclear plant in Idaho should eventually help cut carbon emissions. President George W. Bush is expected to sign it shortly.

But critics say the bill fails to address basic questions about the direction of U.S. energy research. “The entire energy [bill] is really based on wishful thinking, that if you throw enough money at different technologies, one of them will one day take over the market and solve our problems,” says Joseph Romm, director of the Center for Energy and Climate Solutions in Arlington, Virginia. He argues that only mandates will force companies to develop better energy technology. New York University physicist Martin Hoffert, while praising the proposed increases, says the bill “lacks focus” and calls for a national debate on which energy research areas most deserve federal investment. Judy Biggert (R-IL), chair of the House Science Committee's energy subcommittee, defends the bill's multifaceted vision. “We can't rely on just one area of research,” she says.

The bill's generous tax incentives represent a significant victory for the energy industries, although the final legislation did not keep protections sought by producers of gasoline additive methyl tertiary- butyl ether—contested provisions that caused previous versions of the gargantuan legislation to fail. But utilities succeeded at keeping out a requirement that they draw 10% of their power from renewables. Jason Grumet of the National Commission on Energy Policy in Washington, D.C., says he fears that the only way to pay for the bill's hefty research increases is to generate income-producing measures such as auctioned carbon credits associated with a cap-and-trade system—a provision successfully blocked by energy firms.

Although environmentalists have railed against the bill, science lobbyists are cheering the creation of a new Under Secretary of Science position at DOE on the same level as the existing undersecretaries for defense and nondefense energy work, which should give researchers more influence in tough budget times.

9. NEUROSCIENCE

# Preventing Alzheimer's: A Lifelong Commitment?

1. Jean Marx

Recent research suggests that keeping mentally and physically active when young and middle-aged can help stave off the brain degeneration of Alzheimer's

A sweating man feverishly pumping an exercise bicycle may not seem to have much in common with a chess player coolly contemplating her next move. Yet both may be protecting their brains from the ravages of Alzheimer's disease. Recent results, some from epidemiological studies and others from investigations of animal models of Alzheimer's disease, suggest that exercise—both physical and mental—can help the brain combat the pathological changes that cause the illness.

If so, then people who engage in physical exercise and intellectual activities such as reading, solving crossword puzzles, and playing cards or chess may be able to slow down the development of Alzheimer's disease, perhaps delaying it long enough that incapacitating symptoms won't appear during a person's lifetime. “The brain is an organ that, like any other organ, ages depending on how it's used,” says neurologist Robert Friedland of Case Western Reserve University School of Medicine in Cleveland, Ohio.

Yet parts of the story may not be that simple. Researchers are debating, for example, whether intellectual activities are actually protective or whether people who participate in them are more resistant to Alzheimer's disease, possibly because of the way their brains developed.

## Building a cognitive reserve

Parents who warn their children that they will regret not going to college could be correct—but in an unexpected way. Over the years, several studies have shown that formal education seems to protect against Alzheimer's disease. For example, a 1997 study of 642 elderly people, conducted by Denis Evans of Rush Presbyterian-St. Luke's Medical Center in Chicago and his colleagues, found that each year of education reduces a person's risk of Alzheimer's disease by 17%.

As suggested in the late 1980s by Robert Katzman of the University of California, San Diego (UCSD), education might protect against Alzheimer's disease by increasing the number and strength of neuronal connections in the brain, thus improving an individual's so-called cognitive reserve. According to this theory, later in life when Alzheimer's pathology begins to eat away at the brain's neurons, people with larger reserves would be better able to cope with the onslaught.

One recent study supporting Katzman's idea came 2 years ago from a Rush Presbyterian-St. Luke's team led by David Bennett and Robert Wilson. Since the mid-1990s, these researchers have been following a group of older Catholic priests, nuns, and brothers who had agreed to donate their brains after they died.

Analysis of the brains available in 2003, 130 in all, showed no correlation between education and the formation of plaques and tangles, the abnormal brain deposits that characterize Alzheimer's disease. But a battery of 19 tests performed periodically in the years before the donors died revealed that people with high levels of education better maintained their cognitive abilities. Wilson says that the highly educated participants didn't develop Alzheimer's disease until they had about five times as many plaques and tangles as the less educated participants. “This suggests that education or cognitive activities achieve their effects by helping the brain tolerate the pathology,” he says.

Not everyone finds support for the cognitive reserve theory, however. The so-called Nun Study points to a different conclusion: Early variations in how the brain develops makes some brains more resistant to developing Alzheimer's pathology than others.

David Snowdon started the Nun Study more than 15 years ago, when he was at the University of Minnesota, St. Paul. It originally included 678 members of the School Sisters of Notre Dame, all of whom were born before 1917. Snowdon, now at the University of Kentucky in Lexington, reasoned that studying nuns would help him identify factors that influence Alzheimer's development because they all have similar lifestyles and medical care. This eliminates some variables, such as smoking, that might skew the results.

As in other studies, Snowdon and his colleagues found that high education levels seem to protect against Alzheimer's disease. The researchers originally thought that this supported the idea that more education leads to a higher cognitive reserve. But analysis of biographical essays the sisters had written when they entered the convent, usually in their early 20s, pointed in a different direction. The early writings, Snowdon says, were an even better predictor of who would get Alzheimer's disease than education level. “Those who had the lowest linguistic skills at age 22 had a very high risk of Alzheimer's,” Snowdon says. Indeed, most of the cases occurred in the nuns whose essays put them in the bottom third on the linguistic ability scale.

When Snowdon, neuropathologist William Markesbery, also at the University of Kentucky, and their colleagues examined the brains of nuns who had died, they found that those of lower linguistic ability were also much more likely to have signs of Alzheimer's disease such as brain shrinkage and tangles, although not plaques. That finding took Snowdon by surprise. He points out that if the lower risk of Alzheimer's disease in the high-linguistic-ability group was solely due to their having a better cognitive reserve, the pathology ought to be similar in all the nuns. Instead, it appeared as if the brains of the sisters with higher linguistic ability were somehow more resistant to developing the pathology in the first place. This, Snowdon suggests, might reflect differences in how the brain develops before birth and in early life. “Ultimately, it gets down to brain wiring and the biological mechanisms that defend the brain from disease,” he says.

That doesn't mean, however, that there's nothing we can do to decrease our likelihood of getting Alzheimer's disease. “Genes are the driving force, but it's highly likely that diet and lifestyle influence Alzheimer's risk,” Snowdon says. One indication of this comes from Margaret Gatz of the University of Southern California in Los Angeles.

In work she described at the International Conference on Prevention of Dementia held 2 months ago in Washington, D.C., she and her colleagues identified 109 pairs of identical twins in the Swedish Twin Registry in which one had been diagnosed with dementia and the other had not. “We do find that there is a difference in education. The twin with dementia had significantly less,” Gatz says. So even in these genetically identical individuals, education apparently pays off in lowered Alzheimer's risk.

Several additional studies by teams including Friedland's, the Rush Presbyterian group, and Herman Buschke and his colleagues at the Albert Einstein College of Medicine in New York City suggest that a lifelong commitment to intellectual activities may aid in—indeed, may even be necessary for—maintaining any protection against Alzheimer's disease accrued in early life. “All forms of leisure activities requiring mental activity—reading, puzzles, cards, board games, crafts—are protective,” Friedland says. “I believe they all involve learning in some way.”

Conversely, Friedland and his colleagues found that one leisure activity that is arguably not intellectually demanding—watching television—was associated with an increased likelihood of developing Alzheimer's disease. Using questionnaires, they surveyed 331 normal controls and also the close associates, primarily spouses and children, of 135 Alzheimer's patients to find out what activities they participated in during midlife. As reported in the July issue of Brain and Cognition, the patients had watched more television; each additional hour of watching per day increased the Alzheimer's risk by a factor of 1.3. That doesn't necessarily mean that heavy television watching rots the brain. Rather, Friedland says, it may be a marker for an intellectually inactive lifestyle.

These epidemiological studies all suffer from the same complicating factor, however: Much evidence—including the Nun Study and a meta-analysis of 47 studies reported in the 31 July issue of Neuropsychology by a team led by Lars Bäckman of the Karolinska Institute in Stockholm, Sweden—indicates that Alzheimer's disease develops slowly over many years before failing memory and other symptoms become apparent. Although researchers have conducted long-term prospective studies that try to exclude people already showing Alzheimer's symptoms, it is hard to eliminate the possibility that low participation in cognitively demanding activities may be an early symptom of the disease rather than a cause.

## More reason to exercise

Pursuing an intellectual life may not be the only tack that people can take to ward off Alzheimer's disease. Some recent research indicates that physical exercise can be as good for the mind as for the body, although the literature on this issue has been mixed, with not every study showing a benefit.

A few years ago, Arthur Kramer of the University of Illinois, Urbana-Champaign (UIUC), and his colleagues performed a meta-analysis of 18 trials involving adults between the ages of 55 and 80 that explored the effects of physical exercise on performance of various cognitive tasks. They concluded that the answer to the question, “Does aerobic exercise enhance cognition?” was an “unequivocal yes.”

Since then, additional studies have borne out that conclusion. These include two large prospective epidemiological studies that focused on women. In one, Kristine Yaffe and her colleagues at UC San Francisco, followed for 6 to 8 years nearly 6000 women over age 65 who did not show signs of Alzheimer's disease at the time they were recruited into the trial. The other trial comes from Francine Grodstine of the Harvard School of Public Health and her colleagues, whose study group included 18,766 women aged 70 to 81 from the Nurses' Health Study. Both studies reached the same conclusion: Women who got the most exercise, mainly walking, showed less cognitive decline over the years than women at the low end of the activity scale.

Varying one's exercise routine may also have mental benefits beyond relieving boredom. Constantine Lyketsos of the Johns Hopkins Medical Institutions in Baltimore, Maryland, and his colleagues have looked at the effects of physical activity on mental abilities in more than 3000 men and women in the Cardiovascular Health Cognition Study. “What mattered wasn't the absolute energy expenditure but the number of activities,” Lyketsos says.

As reported in the April issue of the American Journal of Epidemiology, study members who engaged in four or more physical activities, which could be anything from gardening to jogging or biking, had about half the risk of dementia as that of participants who engaged in one or none. The effect was primarily seen, however, in persons who did not carry a gene variant called ApoE4 that's known to increase Alzheimer's risk. In the ApoE4-endowed population at least, genetics seems to trump activity.

The exercise studies all have the same potential downfall as the ones focusing on education and mental activities: the possibility that low activity levels are an early sign of Alzheimer's disease rather than a cause. But the exercise conclusions receive additional support both from imaging studies of human brains and from investigation of animal models of Alzheimer's disease.

Neurobiologists have known for some time that the human brain shrinks with age. Between ages 30 and 90, the losses range from 15% to 25% of brain matter, with the shrinkage particularly severe in areas such as the frontal and temporal cortex that are involved in memory and learning. About 2 years ago, Kramer and his colleagues confirmed such cortical shrinkage by using magnetic resonance imaging (MRI) to observe the brains of 55 older adults. But they also found that those losses were much reduced in the most physically fit individuals (assessed by performance on a treadmill).

In a second set of experiments, Kramer and his colleagues used functional MRI to assess brain activity in subjects performing a cognitive task. The more physically fit individuals not only performed better on the task than the less fit participants, but their brains also showed higher activity in the areas associated with the task. “Fitness training improves neuronal efficiency and performance,” Kramer says. “Older brains are a lot more flexible and plastic than we have been led to believe.”

## Lessons from rodents

How physical exercise enhances brain maintenance and function is unclear, but work with rodents points to several possibilities. One is that it improves cerebral blood flow, thus providing better nourishment to the neurons. For example, William Greenough and colleagues at UIUC have shown that exercise increases blood flow to rat brains, at least partly by stimulating the growth of the capillary vessels feeding the cortex.

Another possibility is that exercise turns up production of proteins that stimulate neuronal growth. About 10 years ago, Carl Cotman's team at UC Irvine, found that the brains of rats who ran voluntarily on a wheel show increases in one such factor, BDNF (for brain-derived neurotrophic factor). The increase was particularly strong in the hippocampus, an area involved in learning and memory that's hard-hit by Alzheimer's disease.

Consistent with that finding, researchers including Greenough and Fred Gage at UCSD, have shown that exercise or so-called enriched environments in which animals live in cages equipped with exercise wheels and other toys can increase formation of brain neurons and lead to other changes that should strengthen neuronal connections.

For example, the numbers of dendrites, the tiny projections of nerve cells that receive incoming signals, normally decline with age. But Greenough's team found that keeping rats in an enriched environment could counteract that decline. All but the oldest animals kept in such an environment showed increases in dendrite numbers, and even those very old rats maintained their dendrites better than control rats kept in standard lab cages equipped with nothing more than food, water, and bedding. “At the younger ages, use it [the brain] and gain,” Greenough says. “And at the older ages, use it or lose it.”

Exercise may even prevent formation of the amyloid typical of Alzheimer's disease, although the evidence, derived from animal models, is far from clear. Sam Sisodia's team at the University of Chicago in Illinois has been studying mice genetically modified to overproduce a protein called β amyloid, a major plaque constituent. As the researchers report in the 11 March issue of Cell, mice kept in an enriched environment produced much less of the protein and had fewer plaques than did animals kept in standard cages (also see Science, 11 March, p. 1547). The effect was especially pronounced in those animals who spent the most time on the running wheels, Sisodia says.

The Sisodia team didn't determine whether the enriched environment improved the animals' learning abilities, but in a similar experiment, Cotman and his colleagues did. The Irvine group found that voluntary exercise, again running on a wheel, not only decreased the number of plaques in the hippocampus and cortex of mouse brains but also improved a rodent's performance on a cognitive task, learning to find a hidden platform in a water maze. (The results appeared in the 4 May Journal of Neuroscience.)

But not everyone has found that an enriched environment results in decreased plaque formation in Alzheimer's mice. In 2003, Joanna Jankowsky of the California Institute of Technology in Pasadena, David Borchelt of Johns Hopkins University School of Medicine in Baltimore, and their colleagues reported just the opposite: that it can lead to increased plaque formation. That experiment has been criticized on the basis that the animals were under stress. Jankowsky disputes that, noting that her team has since done additional experiments with a different genetically altered mouse strain. Again, they found that β-amyloid and plaque deposition increased when compared to control animals kept in standard cages. “Not only have we found the same result, but we found it in another strain of mice,” Jankowsky says.

Even so, the experiment sounds a hopeful note about the effects of enrichment. All the animals kept in the enriched environment showed improved performance on three different cognitive tests, although the mice with high β-amyloid production fared less well than animals with lower levels.

The reason for the discrepancy between the various groups' plaque findings are unclear, although it might be due to differences in the strains of mice used. Still, Cotman describes the recent results as “cool.” He points out that, taken together, they indicate that it may be possible to prevent or slow the mental decline of Alzheimer's disease with or without decreases in plaque formation.

Researchers warn, though, that people need to act before they get old. “If you're going to do something to ward off Alzheimer's, you have to do it before memory problems develop,” Snowdon says. On the bright side, the interventions to prevent Alzheimer's disease are looking pretty much like the same ones recommended to prevent obesity and cardiovascular disease. Yaffe, who runs a memory clinic, notes that she tells her patients that exercise is “inexpensive, has very few side effects, and if worst comes to worst, it's good for your body.”

10. PROTEIN STRUCTURE

# A New Portrait Puts Potassium Pore in a Fresh Light

1. Robert F. Service

An atomic structure of a potassium channel, which is central to the firing of neurons, may settle some debates over how this critical protein operates

Two years ago, Roderick MacKinnon and colleagues at Rockefeller University in New York City unveiled an atomic map of an ion- channel protein that rocked the small community of researchers working to unravel the details of how nerves and other cells conduct electrical impulses. Solving that structure was a tour de force of chemistry. It required getting copies of the protein, which is normally embedded in the bacterial cell membrane, to arrange in an ordered crystal. But the map showed parts of the molecule to be in positions that were not what other experts had come to expect. Now, in a pair of papers on pages 897 and 903, MacKinnon and colleagues reveal the structure of a closely related eukaryotic ion channel protein that has other experts breathing much easier. “This is a terrific structure,” says Richard Horn, a physiologist at Jefferson Medical College in Philadelphia, Pennsylvania.

Both the new and earlier structures offer close-ups of proteins called potassium voltage gated ion channels. When a neuron fires, potassium ions build up inside the cell. These positively charged ions create an electrical voltage across the cell membrane that triggers the potassium channel to open, allowing the excess potassium ions to spill out and restoring the cell to its resting state, ready to fire again. Virtually all potassium channels consist of four identical subunits, each made up of six linked helical segments. Two of those helical segments from each subunit assemble to form the central pore through which ions flow, while the other segments form a cloverleaf pattern of four voltage sensors that detect voltage changes across the cell membrane and move like a lever to open and close the pore.

Getting structures of such complex proteins is no simple task. Researchers must first coax billions of copies of a protein to stack in a perfectly ordered crystal. They then fire a tight beam of x-rays at the crystal and track how those x-rays ricochet off the atoms in the crystal to work out the precise positions of each atom. That task is especially challenging with potassium ion channels, MacKinnon says, as the voltage sensors are barely connected to the pore regions and therefore are floppy and difficult to stabilize in a crystal. Two years ago, MacKinnon's group attached antibody fragments to copies of the bacterial protein to help stabilize it. But when the structure was published in Nature in 2003, the voltage sensors looked to many experts to be tilted on their sides from what they expected (Science, 27 June 2003, p. 2020). Many of the measurements that had been done on the channels over the years didn't seem to mesh with the new structure, Horn says. MacKinnon and colleagues themselves noted in the Nature paper that portions of the protein were in unexpected positions, possibly as a result of the technique used to crystallize the protein.

For their new structure, MacKinnon's team was able to do away with the antibodies. The eukaryotic channels are nearly identical to those in bacteria, but there's a key difference: Eukaryotic potassium channels contain an additional protein domain, known as T1, and another associated protein, known as β, that sit outside the cell membrane in the cytoplasm. With the help of some novel crystallization techniques that used lipids to crystallize the entire complex, MacKinnon's team found that T1 and β helped stabilize the channel protein during crystallization without requiring support from antibodies. Whether or not getting rid of the antibody fragments made the difference, the voltage sensors in the new structure are rotated upright, where other lines of evidence suggested they should be. “It was comforting to see [the position of the voltage sensors] was much more like everyone thought,” says Francisco Bezanilla, an ion channel researcher at the University of California, Los Angeles (UCLA).

Like its predecessor, the new structure offers fresh insights into how the channel works. For one, Horn says, helices that form each subunit's voltage sensor aren't adjacent to those that help make up the pore. Rather, those domains from the different subunits interlace around one another. Gary Yellen, a neuroscientist at Harvard University adds that the new structure shows for the first time how the voltage sensor links to the pore, which, he says, “is a pretty neat thing to see.”

Controversies remain. For example, ion-channel experts have long known that four positively charged arginine amino acids sit atop each of the voltage sensors that surround the pore. These charged arginines move in response to changes in the voltage across the cell membrane, pressing up and down on the lever that opens and closes the pore. But just how this movement takes place remains at issue.

MacKinnon's team has suggested that two of the helices that help make up the voltage sensor are part of a “paddle” that moves through the membrane and pushes on the lever. That view, he suggests, was supported by a study 2 years ago that showed that positively charged arginine amino acids that are part of this paddle move a considerable distance—15 or so angstroms—through the membrane, from the extracellular to the intracellular portion, as the pore moves from its open to its closed configuration. David Clapham of Harvard University says the new structure is consistent with this model. But not everyone is convinced. Bezanilla points out that two 1999 studies, by his group and Ehud Isacoff's group at UC Berkeley, used fluorescence tracking techniques to show that a key helix in the sensor that presses on the lever, known as S4, does not change its depth in the membrane by more than 3 angstroms.

MacKinnon points out that this debate can't be settled by the new crystal structure because it's a static view of the potassium channel in the open position. He says he and his colleagues are already working to get a structure for the protein in its closed form, which together with the current structure should reveal how the protein moves. In solving this debate, MacKinnon says, “there is nothing like data.”

11. RENCONTRE ASSYRIOLOGIQUE INTERNATIONALE MEETING

# Alas, Babylon: Tracing the Last King's Desert Exile

1. Andrew Lawler

CHICAGO, ILLINOIS—More than 300 Mesopotamian scholars gathered at the University of Chicago's Oriental Institute from 17 to 23 July.

Mid-6th century B.C.E. was a dark time for the empire of Babylonia. Persians and Medes were threatening in the east, and the king mysteriously abandoned his famed capital of Babylon for a remote oasis in the western Arabian desert. Contemporary texts portray King Nabonidus as mentally unstable and complain that he forsook the prime Babylonian deity, virile Marduk, for the mystical cult of the moon god Sin, often portrayed as an old man with a long beard.

Those texts, written by Nabonidus's clerical enemies, have been the only evidence of his claimed exile. Now archaeologists have found the first concrete signs that Nabonidus indeed lived in the oasis of Tayma, more than 1000 kilometers to the west of today's Iraq, and they hope also to uncover why this obscure oasis played such a pivotal role in history. Academics familiar with the Middle East say that the Tayma dig itself, in sparsely settled northwestern Saudi Arabia, is a triumph of science over politics, given the difficulty of winning permits from the Saudi government for excavations by foreign teams.

Three years ago, Saudi researchers working near Tayma found rock inscriptions that mention an army of Nabonidus that battled local Bedouin. Then in December, a joint Saudi-German team found a piece of badly weathered stele, a stone slab inscribed with writing, which closely resembles other slabs associated with Nabonidus's reign.

The slab originally would have stood for passersby to read, but the team's fragment—60 centimeters (cm) wide, 50 cm high, and 11 cm thick—was later reused in building a wall. Only about a dozen lines of the stele are legible, but they indicate that Nabonidus made offerings to Babylonian deities—including Marduk—in the form of carnelian, lapis lazuli, and censers of gold, according to a translation by Assyriologist Hanspeter Schaudig of the University of Heidelberg in Germany. The find “is very valuable for our knowledge of history,” says philologist David Weisberg of Hebrew Union College in Cincinnati, Ohio. But he adds that the inscription “is quite damaged, and many lines are illegible,” so it will require more study.

The find is part of a larger effort to understand the complex trade routes that linked the ancient Middle East. Tayma lies at a critical juncture of the frankincense trade flowing north from Yemen and other routes to the Persian Gulf and Mesopotamia, and for millennia it offered travelers a respite from the desert. At the time of Nabonidus, the oasis included a city with a vast wall some 14 kilometers in circumference and a well 18 meters across, one of the largest on the notoriously dry Arabian Peninsula. The team, led by Ricardo Eichmann of Berlin's German Archaeological Institute and Said al-Said, a professor at King Fahd University, has found 13 successive layers of occupation from the mid-3rd millennium to the early centuries of the modern era, showing a surprising continuity in urban desert life.

Although Babylonian texts mention that Nabonidus built a palace at the site, Eichmann says none has yet been found, but the team will keep looking when it returns to Saudi Arabia in November. Textual evidence found elsewhere indicates that Nabonidus was ill when he left Babylon and recovered during his decade in the desert. But German excavation director Arnulf Hausleiter speculates that his real motives could have been economic: By asserting control over an important trade city, Nabonidus may have been attempting to bolster Babylon's flagging treasury. If so, the gambit failed. The texts say that the king returned to Babylon in 542 B.C.E. after a decade in exile, only to be overthrown by the Persian King Cyrus the Great 3 years later. Thus Mesopotamians lost control over their own rich territory—a control that was not fully regained until 2500 years later in the 20th century.

12. RENCONTRE ASSYRIOLOGIQUE INTERNATIONALE MEETING

# Ur's Xena: A Warrior Princess for Sumeria?

1. Andrew Lawler

CHICAGO, ILLINOIS—More than 300 Mesopotamian scholars gathered at the University of Chicago's Oriental Institute from 17 to 23 July.

One of the most spectacular archaeological discoveries in history was Leonard Woolley's excavation of the royal tombs of Ur in the late 1920s. The 16 graves included a “death pit” with sacrificed retainers and animals. Woolley believed the tombs were those of kings and their consorts, including the famous Queen Puabi, buried with a magnificent crown and other jewelry.

But one grave, tomb 1054, left Woolley perplexed. In the shaft 4 meters above the stone burial chamber was a cylinder seal inscribed with the word “lugal,” Sumerian for “king” or “ruler,” along with a name read as Meskalamdug and traditionally translated as “hero of the land.” In the stone chamber itself were a host of weapons, including a dagger at the side of the principal occupant. But there was one hitch: Woolley determined that the remains were of a woman. Scholars had long held that ancient Mesopotamian rulers, unlike their Egyptian neighbors, were always men. “That seal cannot be hers,” Woolley concluded in a 1934 publication.

The puzzle has obsessed two generations of researchers, who have come up with a variety of theories to explain it. Now Kathleen McCaffrey, a graduate student at the University of California, Berkeley, says that the most logical answer is the simplest: The seal and weapons did indeed belong to the buried skeleton, which may have been that of a female Sumerian ruler. That claim has sparked fierce debate, however, especially because Woolley disposed of the bones shortly after discovering them.

Woolley himself suggested that the seal and weapons were gifts from the woman's husband. Another theory is that the true owner of the seal, a male, was buried in a mud-brick shaft above the stone tomb. But McCaffrey notes that the materials in that shaft are low quality and lack weapons, and that no other royal tomb is constructed of mud brick. In fact, the remains in the mud-brick shaft, identified by Woolley as male, were wrapped in women's clothing with feminine jewelry. Unfortunately, those bones also were discarded.

The principal occupant of 1054 herself reveals some curious gender anomalies, notes McCaffrey. Her skeleton was found wearing a hair ribbon, two golden wreaths, and a gold dress pin, all typical for high- status Sumerian women of the day. But she was not adorned with the usual earrings or elaborate choker, and there were no floral combs or cosmetic containers. And a gold headpiece and a dagger and whetstone at her waist were typical for Sumerian men; a gold headdress near the skeleton has a brim, a style that Woolley believed was worn mostly by men.

Also in the stone chamber were a bronze ax, dagger, and hatchet—very atypical for a woman's tomb. Other researchers attribute those weapons to the male attendants in the room, but McCaffrey notes that the attendants lack rings, weapons on their bodies, or any other sign of elite materials, suggesting that they were servants.

McCaffrey maintains that the root of the problem is translation: Sumerian grammar does not include gender distinctions, but “lugal” has always been translated as “king” rather than simply “ruler.” In the case of tomb 1054, she concludes that the woman was in fact a lugal.

But other scholars hotly disagree. University of Chicago archaeologist McGuire Gibson argues that the seal's location above the stone chamber makes it difficult to tie it to the elite occupant below. He adds that most of the bones had deteriorated so much that identifying gender was difficult. “Woolley couldn't tell the difference between a man, a woman, or a monkey,” he says. McCaffrey counters that Woolley was competent enough to identify correctly the genders of the dozen skeletons that still exist. Philologists, meanwhile, note that although “lugal” is technically a gender-free term, there is the counterpart term “eresh,” which traditionally is translated as female consort to a male ruler.

Without a skeleton, scholars may never definitively sort out the mysteries of tomb 1054. But the women of ancient Ur may have more to say in the near future: Researchers are now examining Queen Puabi's remains for clues to her genetic identity.

13. RENCONTRE ASSYRIOLOGIQUE INTERNATIONALE MEETING

# Looted Tablets Pose Scholar's Dilemma

1. Andrew Lawler

CHICAGO, ILLINOIS—More than 300 Mesopotamian scholars gathered at the University of Chicago's Oriental Institute from 17 to 23 July.

Few societies before our own were as obsessed with recording data as ancient Mesopotamia. After inventing the first script in the 4th millennium B.C.E., the Sumerian scribes used clay tablets to keep track of the most minute economic transactions as well as great myths such as The Epic of Gilgamesh that stir readers even today. The tablets have proved invaluable in understanding the hearts and minds of that lost world.

But the artifacts also have attracted collectors and antiquities dealers. Today, as many as 100,000 tablets a year are being ripped out of archaeological sites in war-torn Iraq and put on the international market, according to U.S. government estimates. By comparison, only some 300,000 to 400,000 likely existed in libraries and private collections prior to 1990, say scholars. So far, the number of stolen tablets confiscated or returned is minuscule: An FBI official said at the conference that fewer than 400 had been recovered recently by U.S. agents.

Should academics publish texts from cuneiform tablets that may have been looted? This thorny ethical question sparked the fiercest debate at the meeting and revealed a bitter split within the community. Some philologists say that given the scale of the looting, they are eager to salvage what data they can by translating and publishing texts. “You have an obligation to your science, to your data,” says Jerrold Cooper, a philologist at Johns Hopkins University in Baltimore, Maryland, who says he would work with collectors who own tablets. “It makes no sense at all to condemn all publication” of potentially looted items.

But many archaeologists see the widespread looting in Iraq as an unalloyed nightmare and any involvement with potentially stolen tablets as aiding and abetting the destruction. At the meeting, a faction led by Michael Mueller-Karpe, a specialist in ancient metals at the Roman-German Central Museum of Mainz, Germany, proposed a resolution opposing scholarly involvement with tablets that may have been looted. “Scholars … are urged to refrain from providing expertise to the antiquities market and to private collectors, unless the artifacts in question can be proved to be neither excavated illegally nor exported without permission,” states the resolution, which was signed by 130 academics at a meeting after the conference officially ended. A number of scholars, primarily philologists like Cooper, refused to sign.

The different opinions do not always track disciplinary lines. Robert Adams, a retired archaeologist and former head of the Smithsonian Institution, surprised many participants at the opening session by allowing that no discipline should be expected to ignore vast amounts of new data, however it might have been obtained. (After taking fire from colleagues, Adams later clarified that he did not mean to condone the publishing of looted material but wanted to emphasize the complexity of the problem.)

Meanwhile, several philologists draw a distinction between working on existing collections and trafficking with dealers seeking to boost the value of tablets. Cooper, for example, says he would “not be comfortable” examining tablets owned by dealers.

But a few at the meeting do read recently acquired tablets for dealers, for free or for pay—an act that archaeologists maintain can boost the tablets' value and reinforce the cycle of looting. Cooper says he hopes participants at the next conference will come up with a common ethical stance to guide scholarly actions.

14. EPIDEMIOLOGY

# Drugs, Quarantine Might Stop a Pandemic Before It Starts

1. Martin Enserink

Thirty-six years after the last influenza pandemic, researchers wonder whether they can make these global disasters a thing of the past

It might just work. With military-style planning, a big stash of pills, and a lot of luck, the world might be able to stop a nascent influenza pandemic dead in its tracks, two new modeling studies conclude.

The models, published online this week in Nature and Science (www.sciencemag.org/cgi/content/abstract/1115717), are the first attempts to estimate the power of the antiviral drug oseltamivir to quash a pandemic—an unprecedented and audacious idea. If large numbers of people in the region first hit by a pandemic virus take the drug prophylactically and comply with some quite draconian measures to limit their movements and contacts, millions of lives might be saved, the authors of both papers say—and medical history would be rewritten in the process.

But just how likely is that scenario to succeed? As experts point out, the models, both of which chose Thailand as the presumptive ground zero, are based on several untested assumptions: that the runaway virus isn't highly infectious, for instance, and that large quantities of drugs can be distributed rapidly to the right people, even in remote villages. “The models make sense, and we should seriously consider this approach,” says Harvard epidemiologist Marc Lipsitch, “but the take-home message is there's no way we can count on this.”

The researchers—one team led by Ira Longini of Emory University in Atlanta, Georgia, the other by Neil Ferguson of Imperial College London—hope their work will lead to concrete actions because until now, there's been little if any official commitment to such a plan. The World Health Organization (WHO), which the researchers say would have to lead the effort, is “interested,” says the agency's pandemic chief, Margaret Chan. Rich countries are stockpiling oseltamivir to protect their own populations, but they have no plans yet for shipping it to the cradle of a pandemic. Nor are the Asian countries affected by H5N1—the avian influenza strain most feared as the potential source of the next pandemic—on board or necessarily up to the logistics, although they were slated to discuss the idea at a meeting in Bangkok earlier this week.

Given influenza's history, most experts peg the chance that the world will be hit by another pandemic at 100%. The question is when it will occur and how bad it will be; there's widespread agreement that the death toll could be in the tens of millions. Vaccines offer by far the best chance to avert that danger—at least in countries that can afford them—but these would take months to produce after a pandemic begins (Science, 15 October 2004, p. 394).

A bold new idea is to use oseltamivir to battle a potentially pandemic virus at the source, before it becomes a global threat, using an internationally run stockpile. The strategy might be the only way to prevent disaster in the majority of countries unable to afford vaccines or drugs at all, notes Arnold Monto of the University of Michigan, Ann Arbor. Oseltamivir would make those who get the flu less infectious to others, but by far its most important task would be to prevent infection in those exposed to the virus.

Now, that idea has been put to the test. Longini and his colleagues simulated an imaginary population of 500,000 people who live, work, and move about in rural Southeast Asia. Meanwhile, Ferguson and his colleagues built a model based on the 85 million people living in Thailand and a 100-kilometer-wide border zone in neighboring countries. Both then introduced a pandemic virus and looked at how well different containment strategies performed.

The cornerstone in each model was giving a 10-day prophylactic course of oseltamivir to the contacts of every suspected flu patient—either by treating everyone in their household, school, or workplace, or by simply giving it to anyone living within a certain radius. In both models, the drug regimens were supplemented by measures such as closing schools, “home quarantine,” or “area quarantine,” in which travel into and out of the hot zone is restricted.

And in both models, the more such measures were deployed, the higher the chances were that the pandemic petered out, with thousands or even millions of people taking an oseltamivir course, but only a few hundred actual flu cases. But success depended critically on a few factors.

One is the infectiousness of the pandemic virus. Epidemiologists characterize infectious agents by a factor called R0, which denotes the number of secondary infections caused by a primary case. In both studies, viruses with an R0 between 1.0 and 1.8 could usually be contained, depending on the exact set of measures; with an R0 well above 2.0, the outbreak often spiraled out of control. Estimates for R0 during past pandemics have varied; in a paper published in December, Lipsitch concluded that it was between 2 and 4 in the United States during the 1918-19 pandemic. But Ferguson estimates it was about 1.8.

Another key condition in both models is that the operation starts within a couple of weeks of the first cases. Chances of containment drop dramatically if it takes more than 2 days to reach new patients' contacts. Both conditions may be challenges, to say the least, in rural areas with poor health care.

Some infectious-disease experts put little stock in models like these. “In 30 years in public health, I've never seen any statistical modeling that had any impact on public health. And this is no exception,” says Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Twin Cities. A single SARS patient in a Hong Kong hotel triggered a worldwide outbreak in 2003, he notes; no model could have predicted that turn of events.

But to Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, the studies provide an “interesting blueprint” of what might be possible. “Even if there's only a 20% or 30% chance of success, it's worthy of the effort,” adds Frederick Hayden, an antiviral expert at the University of Virginia, Charlottesville, “given the enormous impact that a pandemic would have.”

It wouldn't be all that expensive, Hayden notes. The amount of oseltamivir needed—some 3 million courses in Ferguson's most unfavorable scenario—isn't very much; the United Kingdom alone has ordered almost 15 million 5-day courses for its own citizens. WHO already has more than 100,000 treatment courses, donated by Roche, sitting in a stockpile. And Roche may soon make another, much larger donation to WHO, says David Reddy, the company's influenza pandemic task force leader.

But although WHO welcomes any oseltamivir it can get its hands on, more studies, as well as discussions with the affected countries, are needed to find out whether the snuffing-out scenario is feasible, Chan says. The Thai government, for its part, is interested in exploring the option, says Supamit Chunsuttiwat, a senior expert for communicable diseases at the Ministry of Public Health. The two papers, he says, “give us some hope that we might be able to do this.”

But Osterholm worries that the two papers might calm fears prematurely. Even if the scheme envisioned by Ferguson and Longini were successful once, he said, it would need to be repeated as long as H5N1 is rampant in the bird population. Longini agrees. But who knows, he says, researchers might get better at it after the first time. And in any case, only a small region would be affected in every budding pandemic. “It's not like we're exposing the entire world to a fire drill every time,” Longini says.

15. EPIDEMIOLOGY

# A Drug Makes It Big--But Can It Deliver?

1. Martin Enserink

The worldwide fears triggered by the Asian outbreak of H5N1 have created one clear winner: oseltamivir, the drug that, from a quartet of candidates, is considered the best one to fight a pandemic. More than two dozen governments have placed orders for a stockpile with the producer, Roche in Switzerland; 2005 sales are expected to exceed $700 million—up from just$110 million 3 years ago—and seem poised to grow further, says Bret Holley, an analyst at CIBC World Markets in New York City.

The procurement orders may be lucrative, but it remains to be seen just how effective oseltamivir, known commercially as Tamiflu, will be during an influenza pandemic. Nor is there agreement about how big a national stockpile should be, or who should receive the drugs to maximize their impact. And in the worst-case scenario, resistance in the flu virus might render stockpiles worthless.

As a remedy against nonpandemic flu, oseltamivir has certainly failed to win many supporters since its launch in 1999. The drug, which blocks a viral enzyme called neuraminidase, can make a bout with influenza more bearable and shorten the duration of symptoms by a day or more; it has also been shown to prevent complications and hospitalizations—but not mortality. The problem is that it needs to be given within 48 hours of infection to be fully effective. And even for patients who meet that deadline, most doctors don't think the benefits warrant the \$65 cost of a prescription. (Japan, where sales have soared, is the exception.)

How well oseltamivir will perform against human infection with H5N1 is unclear. It has shown anti-H5N1 activity in test-tube and animal studies, but human cases have been so rare that experience is extremely limited.

Who should get treatment is also in question. Pandemics may sicken between 25% and 50% of the population in 3 months, but many people with milder cases can probably recover by themselves. Still, countries such as France, the United Kingdom, and Finland are amassing enough oseltamivir to treat 20% to 30% of their populations; the United States, on the other hand, currently has only 2.3 million doses for almost 300 million people. The Bush Administration was expected to announce a new order shortly—although nowhere near the 67 million to 124 million treatments that the Infectious Diseases Society of America has urged.

Recently, another potential role of oseltamivir has garnered a great deal of attention: that of preventing illness rather than treating it. Studies have shown that oseltamivir can reduce the risk of infection in people exposed to the virus by around 80%. That benefit is key in global plans to stamp out a pandemic early on (see main text); once a virus is on its worldwide rampage, national governments could similarly attempt to slow its spread within their own borders.

Last year, a study by Ira Longini's team at Emory University in Atlanta, Georgia, showed that using oseltamivir preventively could contain an outbreak in the United States, and a paper published this month by Ran Balicer of Ben Gurion University of the Negev in Be'er Sheva, Israel, suggests that stockpiling drugs for this purpose should be cost-effective if pandemics occur more often than once every 80 years. That may seem like a fairly safe bet, but it would require reserves for much more than 25% of the population—an amount few countries are considering at the moment.

For now, a more feasible and widely discussed approach may be to restrict prophylactic use to certain groups, such as health care workers, people performing “essential” jobs, or the elderly—although picking the beneficiaries might create wrenching ethical dilemmas.

Another worry is that once tens of millions of people start taking Tamiflu, the virus will become resistant. So far, resistance appears to be rare in other flu strains; during the 2003-04 flu season, when a whopping 6 million treatment courses were prescribed in Japan, only 4 of 1180 virus isolates tested there showed resistance, a group reported in April. And fortunately, mutations that confer resistance also appear to slow the virus's growth.

Tamiflu may soon face some competition, as other drugs are in the pipeline. And many researchers say they'd feel a lot better if the bullish market for flu drugs were split between a couple of rivals.