# News this Week

Science  31 Mar 2006:
Vol. 311, Issue 5769, pp. 1844
1. DISASTER RELIEF

# Too Late, Earth Scans Reveal the Power of a Killer Landslide

1. Richard Stone

MANILA—New insights into the physics of the landslide that entombed a mountain village in the southern Philippines last month offer a bleak epilogue to the tragedy. Five days after a massive landslide buried Barangay Guinsaugon, in Southern Leyte Province, on 17 February, geologists and physicists dispatched to the scene came to a disturbing conclusion: Search teams were probing for survivors in the wrong place. The village, the scientists discovered, had been swept, en masse, downhill. “The rescuers were stunned,” says Mark Lapus, a geologist with Manila-based Earth Probe Inc., whose ground-penetrating radar equipment was used to survey the site. “One shouted at me, ‘When did you learn of this!’ He thought I was withholding information.”

This wasn't the only grim revelation in the disaster's aftermath. Ongoing analyses may explain why the rain-drenched scarp gave way, whether there were warning signs of an imminent landslide, and how rescuers might have been better guided to victims in air pockets. Although studies are still under way, one lesson is inescapable. “More scientists and more instruments should have been there from day one,” says Alfredo Mahar Lagmay, a volcano-tectonic specialist at the University of the Philippines, Diliman.

At about 10:30 a.m. on Friday, 17 February, a cliff face of a ridge straddling the Philippine fault, a tectonic zone running the length of the archipelago, disintegrated. Residents of Barangay Guinsaugon had no chance to escape: An estimated 15 million to 20 million cubic meters of rock and soil hurtled down the slope, reaching a top speed pegged at 140 kilometers per hour. Within 3 or 4 minutes, the landslide had rumbled to a halt, and the village was gone.

Rescuers were confronted with a moonscape dotted with hummocks, later determined to be debris-covered boulders. Miraculously, nearly two dozen people were pulled alive from just under the surface of the viscous debris. Meanwhile, victims trapped in air pockets were firing off cell phone text messages that grew more frantic as the hours passed. One sent on Sunday, 19 February, said simply, “Hurry, the waters are rising.”

That day, the governor of Southern Leyte called Lagmay, asking if his team could carry out a ground-penetrating radar survey. Lagmay, Lapus, and colleagues at the University of the Philippines and Ateneo de Manila University flew down and started work on the morning of Tuesday, 21 February. By then, no survivors had been found or text messages received for more than 24 hours.

Initial news reports failed to capture the enormity of what had transpired, Lagmay says: “We didn't know the scale of the landslide until we got there. The whole side of the mountain had collapsed.” His team set to work conducting radar scans and creating an inventory map of where victims and belongings had been found. By the end of the day, the researchers had concluded that the rubble was 30 meters thick and that the water table lay 14 meters below the surface—dashing hopes of finding deeply buried survivors. Radar readings coupled with the debris inventory map suggested that Barangay Guinsaugon had been displaced 550 to 600 meters southeast of its original location. Many buildings were largely intact, and neighboring houses remained adjacent to each other, Lagmay's team reported in the 21 March issue of Eos.

Lagmay briefed the leader of the rescue operation, a Philippine army general, on the evening of 21 February. At first, Lagmay says, “he resisted the idea” that the search had been off target, citing insufficient evidence. The researchers redoubled their efforts the next day. “We took new measurements and plotted everything to demonstrate that the town did indeed move,” he says. Their findings persuaded the general to search in several priority areas the team had identified. It rained all day, though, and an aerial survey using Chinook helicopters lent by the U.S. military revealed that the water table at the foot of the slide, near where the village now lay, had risen to the surface of the muddy debris. That made rescue efforts more treacherous and suggested that any air pockets had been submerged. The rains continued, and by the evening of 24 February, the governor called off the search. The rescuers had saved 20 people—all in the 48 hours following the disaster—and recovered 122 bodies; more than 1300 villagers are listed as missing. An embankment is being built around the foot of the slide to preserve it as a mass grave.

Precisely what triggered the deadly landslide remains a mystery. At first, researchers fingered an earthquake that occurred 25 kilometers west of Barangay Guinsaugon around the time of the slide. But time records of victims' cell phone calls have since confirmed that the magnitude-2.6 temblor struck several minutes after the landslide. Any other faint tremor registered that day “alone would not be enough to trigger the landslide,” says Renato Solidum Jr., director of the Philippine Institute of Volcanology and Seismology (PHIVOLCS). Kyoji Sassa of the University of Kyoto's Disaster Prevention Research Institute, who led a Japanese-Philippine team that carried out geophysical measurements last week at the site, including ground-based laser scanning of the topography, believes that a small earthquake, if near enough, could have been sufficient if the hill was primed to fall.

A precipitating factor, experts agree, is that the scarp had been saturated by 10 days of heavy rain in the Leyte region in early February. To test the rainfall-earthquake scenario, Sassa is putting debris through the rigors of a new simulator of landslide shearing forces that his group has developed, accompanied by computer modeling. Preliminary results should be available in April, he says. Intriguingly, survivors from Barangay Guinsaugon told Lagmay's team that a river between the base of the scarp and the village dried up 2 days before the landslide. (Solidum calls the observation of the lost river “unverified.”) And mountain dwellers “reported having felt an earthquake 2 months prior to the disaster and noticed cracks in the ground,” Lagmay's team reported in Eos. River water and rain “may have seeped into these fractures and lubricated the slip planes,” they wrote.

SOURCE: ADAPTED FROM A. M. LAGMAY ET AL. EOS

View this table:

Lubrication, coupled with the type of landslide that occurred—a deep-seated rockslide-debris avalanche that is “less turbulent” than shallower kinds of slides—explains how a whole village could be transported down the slope, Lagmay says. The Philippine disaster is the deadliest debris avalanche since the Nevados Huascarán event in Peru that killed 18,000 in 1970 (see table).

The Leyte disaster's consequences are still sinking in. Lagmay notes that it's impossible to say whether rescuers, even if they had known exactly where to dig from the get-go, could have reached victims who initially survived before succumbing to rising water levels. Thus much of the scientific postmortem has shifted to what can be done to prevent future such disasters. A key task is refining risk models of rare, deep-seated landslides. “We need to evaluate this better,” Solidum says.

Lagmay and others hope that more-precise hazard maps and better community outreach—for instance, prompting people to quickly report potential warning signs, such as rivers suddenly drying up—will enable officials to react more nimbly to disasters and perhaps even prevent casualties. And there's one message that governments around the world should heed. In the event of a future calamity, Lagmay says, any rescue operation “should be scientific from the start.”

2. U.S. HIGHER EDUCATION

# Foreign Grad Students Show Renewed Interest

1. Katherine Unger

Foreign students flooded U.S. graduate schools with applications this winter, reversing a 2-year decline and allaying fears that U.S. government policies were turning off talented Asian students.

The latest results from an annual survey by the Council of Graduate Schools (CGS) released last week found that international graduate applications for the 2006-'07 academic year rose by 11% over the previous year, with particularly significant upticks in Chinese and Indian applicants. All fields enjoyed a boost, although life sciences and engineering led the way with 16% and 17% increases, respectively (see graph). Although only one-third of the 450 universities queried responded to the survey, they included 80% of the 25 institutions with the largest international student enrollments.

Applications are the first of three points along the matriculation route for prospective students, and the other two metrics—admissions and enrollments—have presented a brighter picture. In fact, enrollments actually increased by 1% last year for the first time since 2001 (Science, 11 November 2005, p. 957). Peggy Blumenthal, executive vice president of the Institute of International Education, says the rise in applications suggests “we've turned the corner.” The renewed interest among Chinese and Indian students is especially welcome because those countries have consistently provided the two largest pools of international students for U.S. universities.

University administrators have blamed the 2003-'05 downturn in large part on tighter immigration policies following the September 2001 terrorist attacks and perceptions that the United States was less welcoming of foreigners. CGS President Debra Stewart believes that the government's willingness to address those concerns, including speeding up the visa application process, has helped remove those obstacles. Interestingly, applications from Middle Eastern students, arguably the most likely to be deterred by post-9/11 policies, have risen steadily for the past 3 years, by 4%, 7%, and 4%.

Many institutions have also strengthened their recruiting efforts. Washington State University (WSU) in Pullman, for example, has held focus groups among its international students to find out “things that they were drawn to, things we could play up” in recruiting, says associate graduate dean Lori Wiest. WSU now provides potential applicants from abroad with information specifically geared to their needs, she says. The approach seems to be paying off: Applications from foreign graduate students were up 37%, outpacing the national average.

3. HIGHER EDUCATION

# $200 Million Gift for Ancient World Institute Triggers Backlash 1. Michael Balter When New York University (NYU) officials announced last week the creation of the Institute for the Study of the Ancient World, it was widely seen as a major coup. The new Ph.D.-granting research institute, devoted to the art, archaeology, history, literature, and geography of ancient societies, was made possible by a private gift of$200 million in cash and real estate, one of the largest donations the university has ever landed. Yet some NYU faculty members, along with outside archaeologists, are aghast that the school accepted the money. One leading NYU archaeologist has already resigned from the university's existing ancient studies center to protest the decision.

The fracas stems from the source of the new institute's funds: The Leon Levy Foundation, named after the late Wall Street investor and philanthropist. Levy and his widow Shelby White, the foundation's trustee, have for years been at the center of controversies surrounding their antiquities collection, which some archaeologists believe includes objects that had been looted and illicitly traded. Indeed, several institutions, including Bryn Mawr College in Pennsylvania and the University of Cincinnati in Ohio, have adopted explicit policies against accepting funds from the foundation. “If we or our students accepted these kinds of funds, it would simply be giving credibility to the longstanding Levy-White practice of buying objects of questionable provenance,” says James Wright, chair of Bryn Mawr's department of classical and Near Eastern archaeology. Archaeologist Colin Renfrew of Cambridge University in the United Kingdom is more outspoken: “I wouldn't touch a gift from Shelby White with a barge pole,” he says.

But other scholars argue that the Levy Foundation has been a positive force, spending millions for archaeological digs, such as a major excavation at the Philistine site of Ashkelon in Israel (Science, 2 July 1999, p. 36). It also funds a program based at Harvard University that supports the publication of archaeological findings. “The foundation has done a power of good,” says Baruch Halpern, an expert in ancient history at Pennsylvania State University in State College. And Christopher Ratté, a classical archaeologist at NYU, whose publications have received Levy-White support, says that “it is very difficult to argue with this kind of generosity.” Ratté adds that the

Levy-White collection “is not coming to NYU, and there will be no direct association between the collection and the university.” Levy and White have generated debate among many archaeologists since at least 1990, when the Metropolitan Museum of Art in New York City mounted a major exhibition of some 200 of their artifacts from the Near East, Greece, and Rome. A study published later in the American Journal of Archaeology concluded that more than 90% of those artifacts had no known provenance.

More recently, publications including The New York Times and The New York Observer have reported accusations by Italian authorities that objects in the Levy-White collection, including some that are still on view at the Metropolitan Museum, can be traced to illicit trade. White takes strong issue with these criticisms. “We have been involved in the field of archaeology for many years,” she told Science, referring to herself and her late husband. “We have always collected in good faith, and we have always exhibited our collection publicly.” White adds that the items in the collection were not purchased in “obscure places” but at public auctions and from leading dealers: “If it turns out that there are objects that I should not have bought, then I will deal with them.”

Some NYU faculty members began questioning the wisdom of accepting the donation in January, when Matthew Santirocco, director of the university's existing Center for Ancient Studies, called a meeting of the center's advisory committee—the first of three committee meetings devoted to discussing the proposed institute. At least five of 13 members of the center's advisory committee expressed varying degrees of concern about accepting money from the foundation during the meetings. Some members also worried that White would have considerable input into the naming of the institute's director and faculty. “We wanted to be sure that NYU administrators were aware of concerns in the archaeological community about the problem of safeguarding cultural property,” says NYU classicist and advisory committee member Laura Slatkin.

Members of the committee say the decision was very close to being finalized by the time they were consulted. “The people in the administration and [Shelby] White had gone a long way down the road,” says Michael Peachin, chair of the university's classics department. Another member, who asked not to be identified, agrees: “It was a fait accompli.” Santirocco counters that the committee “was not at all opposed to pursuing this opportunity” and that there was a “majority consensus” in favor of accepting the donation.

Santirocco adds that the funds to create an interdisciplinary institute are a “truly transformative gift” that will “lead to a more holistic understanding of the ancient world.” University officials also say that although White will be on the search committee for the new institute's director, NYU's provost and president will have the final say.

But those assurances did not satisfy archaeologist Randall White. In a letter last week to Santirocco, White resigned his membership in the school's ancient studies center, arguing that accepting money from the Levy Foundation could have negative consequences for NYU scholars. Countries victimized by antiquities looters could shut down digs associated with the new institute, he suggests. “The gift will promote suspicion that objects would be ripped from their archaeological context by looters,” Randall White says.

Most opponents of the donation assume, however, that the institute will go ahead. Says NYU archaeologist and center member Rita Wright: “It remains to be seen whether this donation, and the institute it will create, will be in the best interests of research into ancient cultures.”

4. DNA TESTING

# Genetic Screen Misses Mutations in Women at High Risk of Breast Cancer

For women trying to learn more about their risk of developing breast or ovarian cancer, genetic tests can have a cruel twist. The bad news—that a woman carries a mutation known to raise the odds of such cancers—is definitive. But for some women, the good news that they don't have such a mutation doesn't remove the worry. That's because the only commercially available test in the United States doesn't detect many mutations that can occur in the two genes most frequently associated with breast cancer risk, BRCA1 and BRCA2.

Now a study, published in the 22/29 March issue of the Journal of the American Medical Association, has measured the frequency of such false negatives for women with a particularly high risk of breast cancer. The number “is not trivial,” says Stephen Gruber of the University of Michigan, Ann Arbor. “People who have a very high risk of having a mutation should be offered the chance to have [more complete] testing.” Critics charge that Myriad Genetics's broad patent has slowed research into alternative tests, a claim Myriad denies.

But Brown's rearranging of the science funding furniture has met with a mixed response. For example, he outlined a scheme to take the funding of the Medical Research Council and the research managed by the Department of Health and merge it into a single fund of “at least” $1.74 billion per year. This tidying-up effort is “good news,” according to a statement by Mark Walport, director of the giant biomedical foundation the Wellcome Trust. But Walport is “concerned that the figure mentioned … is considerably less” than the current total of the two agencies' research budgets. A Treasury Department spokesperson says this number isn't meant to be a cap but a general indicator of size, and that scientists will have a chance to debate it all before a decision is made later this year. University of Edinburgh physicist Ian Halliday, president of the European Science Foundation, says he sees in this proposed merger a hint of the “British disease: Let's take something that works and see if we can't make it better.” It might be wiser to follow an American adage, he suggests: “If it ain't broke, don't fix it.” For the same reason, Halliday is wary of another proposal that would split the Particle Physics and Astronomy Research Council—a body he formerly headed—and merge the parts with two other councils. The aim is to give one research council responsibility for all spending on big research facilities, such as telescopes, particle accelerators, and neutron sources. University leaders, however, seem delighted with another announcement—Brown's promise to overhaul the Research Assessment Exercise (RAE), a process that ranks departments by merit every 4 to 5 years and allocates funding for overhead costs of research. Critics say it has concentrated wealth in elite universities and destroyed some good departments elsewhere (Science, 4 February 2005, p. 668). Peter Cotgreave, head of the advocacy group Campaign for Science and Engineering in the U.K., says, “abolishing the RAE is the best thing they could do.” Brown hasn't provided details of what might replace the RAE. But few will mourn its demise. 6. PROFESSIONAL SOCIETIES # Physics Institute Settles Suit, Takes Steps to Increase Diversity 1. Adrian Cho “This book is stolen. Written in part on stolen time, that is.” When science journalist Jeff Schmidt penned those words, he inadvertently began a 6-year legal tale that even he didn't see coming. The yarn ended last month, as Schmidt settled a lawsuit against his former employer, the American Institute of Physics (AIP), which represents 10 professional societies. In the suit, Schmidt claimed that AIP, based in College Park, Maryland, fired him in 2000 for protesting the lack of racial diversity on the editorial staff of AIP's magazine Physics Today. AIP says it was responding to his claim that he used company time to write his book Disciplined Minds: A Critical Look at Salaried Professionals and the Soul-Battering System That Shapes Their Lives. The book's first line says as much, although Schmidt says he was engaging in hyperbole. Under the settlement, most of which is public, AIP admits no wrongdoing. Schmidt, who was an editor at Physics Today for 19 years, receives compensation for lost wages and benefits, pain and suffering, and legal fees. He also got his job back—just long enough to resign—and a recommendation that says his work consistently met or exceeded requirements. “Getting any one of these terms would have surprised me,” Schmidt says. “Getting all of them is amazing.” The Washington Lawyers Committee for Civil Rights and Urban Affairs, which helped represent Schmidt, reports in a press release that AIP also agreed in the settlement to support efforts by the National Society of Black Physicists (NSBP) and the National Society of Hispanic Physicists (NSHP) to become nonvoting members. If invited, AIP will also conduct a science writing course at the next NSBP annual conference, according to the release. AIP would not comment on the settlement. “Historically, AIP has always worked with the NSBP and NSHP to promote diversity,” says Marc Brodsky, AIP executive director and CEO. Brodsky says Physics Today now has at least one minority editor but that he doesn't generally ask employees about their ethnicity. As the dispute wore on, Schmidt, 59, became a minor cause célèbre among some physicists. Hundreds signed a statement accusing AIP of squelching free expression. Jean Kumagai, an editor at Physics Today from 1989 to 1999, says she and Schmidt raised the issue of workplace diversity with higher-ups. “We suggested that they actually practice what they had on paper as a policy,” says Kumagai, now an editor at IEEE Spectrum magazine. “And that didn't go over too well.” However, Graham Collins, an editor at Scientific American who worked at Physics Today from 1991 to 1998, says Schmidt deserves some of the blame for the conflict. “There were serious problems at the magazine, but he was one who tended to exacerbate the situation.” Schmidt, who has not been employed since he was fired, credits researchers for speaking out. “I think physicists protested my firing because it made the institution of physics look as political as other fields,” he says. But, he adds, few voiced concern about racial diversity. 7. ITALY # CNR Reform Moves Ahead, But Critics Cry Foul 1. Susan Biggin* 1. Susan Biggin is a writer in Trieste, Italy. TRIESTE, ITALY—Italy has begun to reform its National Research Council (CNR). But some scientists are worried that the changes are damaging and unlikely to improve the productivity of its 110 national institutes. One goal is to make the institutes more attuned to national needs. By managing its projects and allocating funding through 11 new departments, says CNR governing board member and former president Luigi Rossi-Bernardi, the council will be transformed “from a traditional disciplinary structure to a mission-oriented organization, similar to that of the French CNRS and the Max Plank Society.” Earlier this month, CNR President Fabio Pistella nominated directors for the new departments and announced that 67 existing institutes satisfy criteria of size and funds and will now move on to be scientifically assessed. But the selection of the first batch of institutes has been criticized by scientists, including some members of Pistella's own scientific council. In an open letter to Pistella, 39 of Italy's top scientists called for greater transparency and consultation in the selection process, which took no account of scientific achievement. Some scientists see Pistella's move as an attempt to push through CNR reform before the country's general elections in early April. Pistella defended his actions and their timing, saying that he is adhering to a reform plan whereby institutes with adequate “concentration of resources” and “critical mass” move forward for assessment of activities. But Luciano Pietronero, head of the Complex Systems Institute in Rome, says that directors' internal evaluations were ignored in the selection, wasting 2 years of reporting to management. Under the new structure, the funds from the research ministry are earmarked for particular departments: for example, 19% for the new materials and devices department, 5% for energy and transport. Then institutes apply to work on 76 projects run by the departments, through some 700 parcels of work known as commesse. However, the value of the commesse barely covers fixed costs, says Franco Miglietta, research manager at CNR's Biometeorology Institute in Florence, and institutes must find cash for research elsewhere. The restructuring follows the CNR reform law passed by the Italian parliament in 2003 and will transform the$1.2-billion-a-year council into a resource “for the social and economic development of the country,” says Pistella. Although 15% of the budget will be allocated to “curiosity-driven research,” Pistella suggests that CNR's role is not basic science. “Universities are the place for research not directly targeting goals of competitiveness in manufacturing or meeting individual and collective needs,” he told Science.

The fate of the rest of the CNR institutes will be decided within 3 months “after further considerations,” says Rossi-Bernardi. CNR may be planning some clustering and networking of institutes, according to documents circulated last month.

Many researchers believe that much of the change is simply adding unnecessary bureaucracy, and doubters have their eyes set on next month's general elections. Molecular biologist Arturo Falaschi of the Scuola Normale university center in Pisa says that only a change of government will allow the creation of “a CNR on a par with organizations like the German Max Planck Society or the U.K. research councils.”

8. APPLIED PHYSICS

# Nanocolumns Give YBCO Wires a Big Boost

1. Robert F. Service

As high-temperature superconducting wires inch ever closer to market, a couple of shortcomings have continued to hold them back. Now, on page 1911, researchers at Oak Ridge National Laboratory in Tennessee report that they have surmounted those hurdles, at least for short lengths of wire made in the lab. If the work can be scaled up to make kilometers of wire, the advances could finally propel high-temperature superconducting wire into the myriad applications technologists have dreamed of ever since “high-Tc” materials were discovered 2 decades ago.

“It's very promising,” says David Larbalestier, a superconductivity expert at the University of Wisconsin, Madison. “It puts a mark in the sand that is well ahead of where we are now.”

At present, the performance of high-Tc wires—those that carry electricity without resistance at temperatures well above absolute zero (although still hundreds of degrees below room temperature)—is decidedly mixed. Companies have already commercialized high-current-carrying wires made from a mix of bismuth, strontium, calcium, copper, and oxygen. But the market for such wires is limited because they are expensive and lose their superconducting capabilities in the presence of strong magnetic fields, such as those routinely generated in motors and power-transmission cables. The ability to withstand such fields is considered a sine qua non for a wide range of practical applications.

A second generation of more field-resistant wires made from yttrium, barium, copper, and oxygen (YBCO) has been making steady progress in recent years (Science, 15 April 2005, p. 348). But it has been difficult to grow the superconductors in these wires thick enough to carry enough resistance-free current for applications. Typically, when YBCO is grown more than 1.5 micrometers thick, imperfections creep into the lattice and destroy its superconducting abilities. YBCO wires also aren't completely immune to magnetic fields; very strong fields cause tiny whirlpools of magnetic flux to move through the superconductors, snuffing out their ability to carry current without resistance.

Other teams have made some progress on both fronts. Fifteen years ago, for example, a group from the United States showed that by shooting heavy ions through a hightemperature superconductor, they could riddle the crystalline lattice of YBCO with defects that snagged passing magnetic vortices, allowing the material to superconduct in higher magnetic fields. More recently, researchers at Los Alamos National Laboratory in New Mexico discovered a way to increase the effective thickness and currentcarrying capacity by laying down several 1-micrometer-thick layers of YBCO separated by thin layers of cerium oxide. Unfortunately, both advances require complex, expensive synthetic procedures that limit their usefulness, says Oak Ridge materials scientist Amit Goyal.

So Goyal and colleagues led by postdoctoral assistant Sukill Kang decided to seek other approaches. The Oak Ridge team has long used a technique called pulsed laser deposition (PLD) to lay down YBCO atop a metal substrate. And Goyal says there was no one trick in particular in getting the technique to lay down thick superconducting films successfully. Rather, he says it was just a matter of systematically testing a wide range of deposition conditions until they found a combination that did the job.

The group did turn a new page, however, when it came to halting or “pinning” the magnetic vortices. They crushed a ceramic called barium zirconate (BZO) into nanometer-sized bits and then mixed it in with their YBCO starting material. As the researchers laid down their films, they bombarded a YBCO-BZO “target” with pulses from a laser. Under fire, the group reports, YBCO vaporized and condensed atop the metal substrate, while nanosized dots of BZO fell alongside. But because BZO has a somewhat larger spacing in its crystalline lattice than YBCO does, the two materials were energetically unhappy next to one another, creating a strain where their lattices met. The researchers found that the lattices minimized that strain by layering successive BZO nanodots right on top of one another. The result was BZO columns that ran vertically through YBCO and efficiently pinned magnetic vortices, thereby dramatically increasing the ability of the YBCO wires to withstand high magnetic fields.

The performance of the new wires is so good, in fact, that for the first time it surpasses the requirements for a wide range of electrical applications, including motors, high-field magnets, and power cables. So far, the wires are only 1.5 centimeters long. Two Japanese companies, however, are working on making long YBCO wires using PLD, while companies in the United States are racing to commercialize cheaper synthetic approaches in hopes of being the first to toe the latest line in the sand.

9. STEM CELLS

# Versatile Sperm Cells May Offer Alternative to Embryos

1. Constance Holden

Scientists in Germany reported last week that, in mice, they have succeeded in turning sperm precursor cells into cells with many of the characteristics of embryonic stem (ES) cells. If the same feat can be done with human sperm precursors, scientists say the technique could offer a much-sought alternative to human ES cells. ES cells are highly prized for their ability to differentiate into any type of bodily tissue.

Researchers have long suspected that spermatogonial stem cells, which males need for continuous sperm production, might have further potential. But only in 2004 did scientists finally succeed in growing such cells in culture from mice.

Now a team led by heart researcher Gerd Hasenfuss and Wolfgang Engel of Georg August University of Göttingen in Germany has taken the next step. After experimenting with various culture conditions, the researchers produced cell colonies that exhibit markers like those of ES cells. The cells, which the scientists labeled multipotent adult germ line stem cells (maGSC), differentiated into many types of body cells in all three germ layers: ectoderm (such as nerve cells), mesoderm (muscle and blood vessel cells), and endoderm (liver cells).

To see if the precursor cells would differentiate in live animals, the researchers injected maGSCs into mice whose immune systems had been knocked out. The mice produced teratomas, a kind of tumor that grows from germ line cells and that contains many types of tissues. The scientists also injected dye-tagged cells into blastocysts, very early embryos, that they inserted into female mice. When the embryos developed, the introduced cells contributed to multiple tissues in the offspring, the team reported online 24 March in Nature.

“I would consider this a major breakthrough,” says David Garbers of the University of Texas Southwestern Medical Center in Dallas, who has been working on obtaining pluripotent cells from both murine and human testes. “If one can obtain ES-like cells from adult mice, then no doubt it will be possible in the human as well.”

Other researchers are not as certain. Stephen Minger of King's College London notes that the success “doesn't necessarily mean it will also work in people.” But Hasenfuss is optimistic. “Right now, we are looking at [human] testicular biopsies and trying to adapt culturing conditions,” he says.

Meanwhile, California biotech company PrimeGen in Irvine this week claimed success at deriving pluripotent cells from both mouse and human testes, but the work has not been published.

John Gearhart, a stem cell researcher at Johns Hopkins University in Baltimore, Maryland, says the German study “appears to be the best so far” at offering a potential alternative source of cells that would bypass the ethical dilemmas surrounding human ES cells, as no embryo would be involved. And for the male half of the population, they raise the possibility of treatment with genetically matched tissues cultivated with cells from a simple testicular biopsy, without resort to the controversial procedure of therapeutic cloning.

10. NEUROSCIENCE

# The Thick and Thin of Brainpower: Developmental Timing Linked to IQ

1. Greg Miller

Having a big brain probably won't ensure your eligibility for Mensa, but many studies have found modest correlations between the size of a person's brain and various measures of mental ability. Now, a study in the 30 March issue of Nature suggests that how the brain develops may be even more important to one's intellect than its final dimensions.

Using magnetic resonance imaging, Philip Shaw, a psychiatrist at the National Institute of Mental Health (NIMH) in Bethesda, Maryland, and colleagues scanned the brains of more than 300 healthy children at different ages and gave them standard IQ tests. They found that the highest-scoring children had a delayed but prolonged growth spurt in the cerebral cortex. “The idea that we can study the development of the brain and relate it to intelligence is really striking and gives us lots of ideas for future research,” says Richard Haier, a neuroscientist at the University of California, Irvine.

Previous work by Haier and others has identified size variations in certain brain regions that seem to correlate with IQ test performance, but most of this work has been done in adults. To investigate how such size variations might come about during development, Shaw, along with colleagues at NIMH and McGill University in Montreal, Canada, scanned subjects between the ages of 5 and 18 and used a computer program to estimate the thickness of the cortex, the thin sheet of tissue on the surface of the brain. Most children were scanned two or more times, typically separated by 2 years. The researchers divided the children into three groups based on their IQ scores: average (83 to 108), high (109 to 120), and superior (121 or higher) intelligence.

The overall sequence of cortical development was similar in all three groups, Shaw says. “The cortex gets thicker during childhood and reaches a peak and then gets thinner.” But the timing of these events was dramatically different in the “superior” group. Surprisingly, Shaw says, the cortex in these children started out thinner, on average, than in the other groups. Then it grew rapidly, starting around age 7, and peaked in thickness around 11 before falling off. Cortical thickness peaked between 7 and 8 years of age in the average-IQ group, and a year or two later in the high-IQ group. By early adulthood, the cortex in all three groups was roughly the same thickness.

The most pronounced disparity in cortical development between the superior-IQ group and the two lower-scoring groups occurred near the front of the brain. “The regions where the differences were most striking were in prefrontal cortex, which is interesting because that's the seat of the most complex and uniquely human activities like planning and abstract thought,” Shaw says.

The nature of intelligence and how to measure it is still a controversial topic, notes John Gabrieli, a cognitive neuroscientist at the Massachusetts Institute of Technology in Cambridge. Even so, he says, Shaw and his team has made an interesting observation and don't overinterpret their data. “The exciting thing they suggest is that prolonged maturation is a good thing for intellectual development,” Gabrieli says. Whether that extended process in the highest IQ children is determined by genetics or is susceptible to environmental influences—parenting or teaching styles, for example—is an open question, says Richard Passingham, a cognitive neuroscientist at Oxford University in the U.K.

Another fascinating question raised by the study is what cellular events cause the cortex to swell and shrink, says Haier. He speculates that the changes may reflect the growth and subsequent pruning of connections between neurons. If these two processes are well-timed, the adult brain may be more efficient, he suggests.

11. BIOMEDICAL RESEARCH

# A Cure for Medicine's Ailments?

1. Jocelyn Kaiser

Under pressure to deliver the goods after a period of lavish support, health agency leaders have an answer—“translational research”

Twelve years ago, when immunologist Elizabeth Jaffee was developing vaccines that could shrink tumors in mice, she decided to pursue a bold experiment: testing the new vaccines on patients with pancreatic cancer. This disease, which had killed a beloved uncle at age 51, is notoriously hard to treat and usually fatal within a year.

The project was risky, and so was her career move: from bench science to clinical medicine. While co-workers in the lab kept churning out papers, Jaffee's publications lagged. It took her 3 years to negotiate procedural hurdles and secure approvals to launch an initial human safety study. She also had to learn how to write a human trial protocol on her own. “There was nothing available to help you,” she says.

In the end, says the Johns Hopkins University physician-researcher, “I was lucky. Things went well.” Indeed, 8 years after her first trial with higher doses began, three of 14 patients are still alive, and 38 of 60 people in a second trial have survived 2 years compared to less than half of a control group. A bigger study of 600 patients is planned.

Jaffee's efforts to move a basic discovery into patients are a success story for “translational research,” the new buzzword in biomedicine. This kind of research has suffered, she and others say, because few young investigators are attracted to the field. “We don't get as much respect for what we do,” says Jaffee. People tend to dismiss it as “not as basic, as creative.” But that may be changing.

Public and congressional pressure on the National Institutes of Health is growing to find “cures” after a 5-year doubling of the NIH budget that ended in 2003. Translational research is being offered as the way to move basic findings from the bench to the clinic. And it is hot: Everywhere you look, academic health centers are naming deans of translational research and creating centers that bring basic and clinical researchers together. NIH Director Elias Zerhouni has made speeding basic discoveries into diagnostics and treatments one of his top priorities, and to this end he is urging universities to create administrative “homes” to nurture investigators like Jaffee. Translational research “is an intellectual discipline in itself now,” Zerhouni says.

This declaration pleases some. “Without sounding pollyannaish about it, I am very optimistic” that new programs will rejuvenate the field, says Alan Schechter, an NIH intramural researcher and longtime champion of clinical research. Even some basic researchers who have never given a thought to applying their discoveries to patients are beginning to change their thinking. But others worry that if the objectives aren't defined carefully, translational medicine could be perceived as little more than a new label for familiar work. Worse, in a time of budget cutbacks, it could be seen as a threat to basic science programs funded from the same NIH pot.

Whether the available funding will be enough to build this new discipline—and spur the culture change that many say is needed—isn't yet clear. The “signals are good, but it's going to require quite a lot of thought from the government and institutions,” says Bert Vogelstein of Johns Hopkins. “It's definitely a change from how research has been done.”

## In the trenches

People on the front lines attest to how hard it is to do the kind of work NIH now calls “translational.” One frustration, says M.D. microbiologist Jane Koehler of the University of California (UC), San Francisco, is that reviewers tend to find applied grant proposals less compelling. Koehler has spent nearly 15 years studying the natural history and pathogenesis of diseases from bacteria called Bartonella. The microbes cause devastating lesions in AIDS patients as well as trench fever and cat scratch disease. Koehler has published her work in high-profile journals such as The New England Journal of Medicine (NEJM), but sometimes has found it difficult to convince grant reviewers in the basic sciences that work directly relevant to patient care is as important as mechanistic studies, she says.

Especially daunting, many say, is moving a basic discovery into early clinical trials. Jaffee ticks off a list of obstacles to her pancreatic cancer vaccine trials: obtaining grant support, problems with having a small biotech company produce clinical-grade vaccine (“they screwed up each time”), and moving her protocols through five university committees and two federal reviews. “Getting all that to happen at the same time is not simple,” she says.

Although she still does lab work and mentors students, Jaffee and the clinician she now works with, Daniel Laheru, spend much of their time in meetings with data managers and nurses, hashing out glitches and paperwork that come with even a small trial. “This is translation,” she whispers in a meeting at which the topic is what to do about a drop in blood pressure in one patient—probably unrelated to the trial—and the discovery that a solvent used to make the vaccine was 6 months past its expiration date.

New York University M.D.-Ph.D. immunologist Nina Bhardwaj, who has developed dendritic cell vaccines for patients with HIV or melanoma, tells of similar struggles to get her first trials under way and build a translational team. “It's a lot of groundwork and paperwork,” she says. “There aren't many people who want to do this. It's not lucrative, it's not supported, and there's a culture that looks down on it.”

Cutting your teeth on phase I trials is a tough way to advance in research because it's hard to accumulate high-impact publications. Early trials are building on a basic discovery, so they don't make it into journals such as Science, Nature, or Cell. Working with very sick cancer patients is difficult for many reasons; not only will most of them not be helped by the treatment, but the low probability of success means “you're not going to publish that in the [NEJM],” says NIH cancer immunologist Francesco Marincola, editor of the 3-year-old Journal of Translational Medicine. Plus, the pace is much slower than basic research: It might take 4 years to get enough test drug to begin treatment, accrue patients, write a paper, and get published in that specialty journal, notes Lee Nadler, who headsexperimental medicine at the Dana-Farber Cancer Institute in Boston. “What happens if it didn't work? You're out of a job,” says Nadler.

These challenges come on top of other deterrents to a career in clinical research: meager salaries compared to practicing medicine; growing medical school debts; lowered chances of NIH funding (see graph); and demands on medical centers for clinical income, leaving them unable to give budding physician-scientists sufficient “protected time” for research. Various panels have tried to address these issues, from a clinical research panel that reported to then-NIH director Harold Varmus in 1997, to an Institute of Medicine roundtable that met for the past 5 years.

Varmus responded by creating new training and early-career grants for clinical research; NIH later added debt-relief programs. Foundations have also stepped into the breach: The Doris Duke Charitable Foundation and Bur roughs Wellcome Fund have supported early and midcareer translational researchers since 1998, and the Howard Hughes Medical Institute (HHMI) selected for its 2002 class of investigators only patient-oriented researchers. Such support can be crucial, say recipients. “It enabled me to do trailing-edge science,” says HHMI geneticist Matthew Warman of Case Western Reserve University in Cleveland, Ohio, of his Burroughs grant, which he used to develop a mouse model for an inherited skeletal disease that affects only 200 people in the world.

These programs appear to be attracting more young physicians to research, according to an analysis of indicators last September in the Journal of the American Medical Association. An annual survey by the Association of American Medical Colleges has found that growing numbers of medical students say they're interested in research, for example, and applications are rising for NIH clinical support grants.

Some institutions have revived an old educational practice, introducing Ph.D. students and postdocs to disease research. Varmus, now at the Memorial Sloan-Kettering Cancer Center in New York City, has started a graduate program in cancer biology that will include exposure to clinical research; Stanford just announced a master's program in medicine for Ph.D. students; and HHMI last month announced $10 million in awards for similar programs at 13 institutions. Brian Druker of Oregon Health & Science University in Portland, an M.D. who spent a dozen years in the lab before conducting clinical trials with Gleevec, the widely heralded new drug for chronic myeloid leukemia, is all for it: “We need to bring Ph.D.s to clinical trials,” he says. ## Boom times But focusing on individuals is not enough, some argue; they think more resources must go to building teams. Many observers agree that a single physician-scientist can no longer carry the burden of bridging basic and clinical research: “You can't do both well at the same time,” says Druker. While some NIH institutes have been funding translational centers or collaborations such as the Immune Tolerance Network, a new crop of projects has taken root in the last few years funded by NIH, foundations, and others. At Yale University, for example, pathologist and immunologist Jordan Pober realized 6 years ago that his group's cell and mouse studies on the role of inflammation in cardiovascular disease had reached the point at which they needed to see whether the same mechanisms were relevant in human disease. After much “cajoling,” he raised seed money from Yale and later an industry sponsor, Boehringer Ingelheim, and started a translational program in vascular biology and transplantation. Now 35 faculty members are involved, including cardiologists and surgeons, and some are conducting observational trials. And basic researchers will “no longer have to read about someone else seeing if what works in the mouse is relevant in humans,” Pober says. A similar desire to bring together a critical mass of researchers inspired pharmacologist Garret FitzGerald to create the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania. FitzGerald says he was concerned that “the intellectual resource was fragmented” at Penn. Taking a page from the drug company GlaxoSmithKline, which has reorganized its scientific staff into teams focused on a single disease, FitzGerald's 1-year-old center brings together three teams focused on neurotherapeutics, targeted drug delivery, and systems biology. He is assembling vast resources: 2140 square meters of dedicated lab space; study coordinators and research nurses; a “freezer farm” for biological samples; a drug-screening component; seed grants of up to$150,000; and links with Pennsylvania companies. He aims to train grad students and postdocs as well. “Growing your own is where we are with the bulk of staff,” he says.

Comparable efforts are under way across the country. The University of Minnesota last year opened an 8825-square-meter building devoted to translational research on stem cells, orphan drugs, and infectious diseases. UC San Diego has a new “clinical investigation” institute that will focus partly on early drug trials. The University of Cincinnati in Ohio created an Office of Translational Research 5 years ago that offers seed grants for gathering preliminary data and helps investigators work up protocols and get them through Food and Drug Administration approval. The off ice has spurred 26 patient studies, including 15 new drug investigations and three gene-therapy trials, researchers there report.

Even basic labs are getting interested in applying discoveries. Vogelstein, a pioneering cancer genetics researcher, for example, says about half of his 20-person lab is now working on translational projects, compared to none a decade ago. The projects include developing cancer diagnostics based on detecting abnormal DNA in blood and stool samples, drug discovery, and engineering anaerobic bacteria to treat tumors. These applied projects attract a different kind of student or postdoc, Vogelstein says—often someone who had cancer in their family or even survived it herself or himself. “They are driven to do something,” he says, even though they recognize that it may be harder than it would be for a basic researcher to get a faculty position down the road.

New translational programs at NIH institutes are also encouraging basic researchers to add applied projects. “A lot of these investigators say, ‘I want to make a difference, I really want to develop a therapy before I retire,’” says Thomas Miller, who heads one such program at the National Institute of Neurological Disorders and Stroke.

## Inertia

Zerhouni is trying to spur such changes across all of U.S. academic medicine, but he faces some challenges along the way. Persuading academic centers to buy into his plan to create campuswide “homes” for translational researchers could be tricky. Leading academics are anxious about the numbers they see in a new program, called Clinical and Translational Science Awards, that is part of Zerhouni's “Roadmap” of trans-NIH initiatives. Institutes that now have one of NIH's blue-ribbon general clinical research centers will have to compete for one of the new awards, which requires putting all clinical research and training under one administrative roof (Science, 21 October 2005, p. 422). This should give all clinical research the prestige now enjoyed by studies conducted by the National Cancer Institute's cancer centers, says Schechter. But there's a catch: Whereas there are 78 general clinical research centers today, Zerhouni's plan calls for only 60 of the new clinical and translational research awards.

Some researchers, including Jaffee, also worry that the new awards won't be large enough both to pay salaries and fund new translational studies. Druker would like to see NIH set aside more money for quick turnaround, early-stage clinical trials.

Another challenge will be getting institutions to create a clear promotion path for translational researchers. Because much of this work is done by teams, “measuring individual contributions will be fuzzy wuzzy,” FitzGerald says. Counting publications as a measure of achievement is also a problem because translational researchers publish fewer papers in high-profile journals. Pober says Yale is talking about giving credit for designing successful protocols, not just publications.

Perhaps the biggest concern is that the translational research push could be coming at the wrong moment. Growth in NIH's budget is being held down, basic research may be headed for a funding slump, and grant success rates are in decline. “I think there's beginning to be a backlash to this” from basic researchers who feel their funding is threatened, says Pober. He cites a recent editorial by Gerald Weissman, editor-in-chief of the FASEB Journal, arguing that biomedical breakthroughs come from “childish curiosity” and not an “empire of translational research centers.”

Whether NIH sticks to its plan to bolster bench-to-bedside research may also depend on how long Zerhouni, who has now been at NIH 4 years, stays in the job, researchers say. Richard Rettig, a former RAND researcher and longtime NIH observer, says, “The next director could shut it down or turn the spigot slowly.” Yet if there's anything translational research needs, it's a sense that the field has a stable future.

12. BIOMEDICAL PATENTS

# Broad Patent Faces Narrow Odds in Court Battle

1. Ken Garber*
1. Ken Garber is a science writer in Ann Arbor, Michigan.

Upstream biotech patents face a crucial test in April in a trial with implications for future drug development

This year marks the 20th anniversary of the discovery of NF-κB, arguably one of the most prolific molecules in biology. But celebration is overshadowed by litigation, as a high-stakes legal battle approaches its climax.

In 2002, Ariad Pharmaceuticals, Harvard University, the Massachusetts Institute of Technology (MIT), and the Whitehead Institute sued Eli Lilly & Co. for patent infringement. Because the Lilly osteoporosis drug Evista and sepsis drug Xigris work by affecting NF-κB, the plaintiffs argued, they infringe a patent issued to the three research institutions and exclusively licensed to Ariad. After years of contentious legal maneuvering, the case is scheduled to go to trial on 10 April before a Boston jury.

The lawsuit has financial and legal implications well beyond the two drugs in question. NF-κB, a powerful transcription factor, controls whether cells live or die in response to outside stresses, and its inappropriate activation has been linked to cancer, arthritis, atherosclerosis, diabetes, and stroke. The patent covers methods for reducing NF-κB activity in cells—a strategy that could prove effective against at least some of these common diseases.

In addition, many other drugs on the market, besides Lilly's, affect NF-κB and so may already infringe the patent. One recent review paper listed more than 200 compounds known to inhibit NF-κB, including aspirin and several top-selling prescription drugs. The same day it sued Lilly, Ariad sent letters to about 50 companies with products either on the market or in development that work via NF-κB, asking them to license its methods, according to The Wall Street Journal. (Ariad declined to comment for this story.) An Ariad legal victory over Lilly could force these companies—and others developing drugs that affect NF-κB—to pay royalties to Ariad. “It is a pretty broad patent that would cover a huge number of compounds,” says Arti Rai, a law professor at Duke University in Durham, North Carolina.

Patent experts worry that an Ariad victory could set a new legal precedent for patents with broad claims on biological processes far “upstream” of actual drugs. Because of their potential to discourage new drug development, “upstream patents are something to be worried about,” says Rai, who adds that “thus far the federal circuit [court] has tended not to uphold these broad claims.” Ariad, on the other hand, has argued that there's nothing unusual about the patent, and that it's similar to many Lilly itself has filed.

Ariad's chances of winning, at first glance, appear small. “It's probably somewhat less than 20%,” says Philip Nadeau, a biotech analyst at investment bank Cowen & Co., which counts Ariad among its clients. “These broad patents in general seem to be tough to defend when brought to court.” But among the inventors on the NF-κB patent are David Baltimore, now president of the California Institute of Technology in Pasadena, fellow Nobel laureate Phillip Sharp of MIT, and well-known Harvard molecular biologist Thomas Maniatis. Their very presence on the patent, and possibly in court, could be decisive. “You've got very prominent scientists who are the inventors,” notes Rochelle Seide, a patent attorney with Arent Fox in New York. “That sells very well before a jury.” (These inventors have not commented publicly on the patent or lawsuit and declined to do so for this story.)

## Multitalented

Ironically, NF-κB's debut 20 years ago attracted little attention. No one then, including Baltimore, suspected that NF-κB played a wide role in biology. He found the protein while studying how the immune system's B cells make antibodies and other immunoglobulins in response to foreign invaders. (Sharp contributed the key technology.) Baltimore named the protein “nuclear factor kappa B” because it bound to the “B” site of the kappa subunit of the immunoglobulin gene and was, he thought, confined to the nucleus.

That turned out not to be the case. NF-κB, except in B cells and a few others, is kept biologically inert in the cytoplasm by an inhibitor molecule, IκB, that must be degraded for NF-κB to be activated. Baltimore first described IκB in 1988. (Preventing IκB degradation is now a promising anti-NF-κB drug strategy.) Another piece of the puzzle fell into place in 1989, when Maniatis isolated a protein that bound to the gene for interferon, which is produced by cells under viral attack. The binding protein resembled NF-κB, Baltimore recalls. “Tom and I were talking about the induction of interferon, and the factor that he was describing sounded so much like the factor we had found. I said, ‘Well, why don't we just look and see if it's the same thing?’” says Baltimore. It was. Because the interferon response is general, it was clear that NF-κB plays an important role throughout the body. Suddenly other researchers wanted to study NF-κB, and its many roles gradually emerged.

The NF-κB pathway, we now know, is amazingly multifunctional, activating or deactivating more than 175 genes in response to a wide range of substances, organisms, and conditions. “Evolution has utilized this system over and over again, in different circumstances,” says Baltimore. From its location in the cell cytoplasm, NF-κB acts as a messenger, carrying outside signals to the nucleus and orchestrating the cell's response. NF-κB, by stimulating the immune system, is central to inflammation, which in turn is an important contributor to atherosclerosis, arthritis, and cancer. By shutting off death pathways in cancer cells, NF-κB plays a key role in tumor progression. All that makes NF-κB a tempting but problematic drug target, because so many normal processes depend on it.

And given its many roles, it's not surprising that so many drugs affect NF-κB. Even before NF-κB was discovered, Lilly was developing raloxifene hydrochloride and activated protein C, the drugs later named Evista and Xigris. According to Lilly, the company made both “in the early '80s, … well before the discovery of NF-κB.” Initially, it evaluated raloxifene because it works through the estrogen receptor to prevent bone loss, and protein C for its blood-thinning properties. Only much later, in a 1996 patent application and at a 2000 scientific meeting, respectively, did Lilly report that the drugs lowered NF-κB levels. But “we do not concede that Evista and Xigris work through an effect on NF-κB,” the company writes.

The Food and Drug Administration approved Evista in 1997, and Xigris in 2001. When the NF-κB patent was issued in 2002, after a 16-year patent off ice review, Ariad sued. According to an Ariad press release, Lilly ignored Ariad's offer of a patent license. “Consequently, we were left with no option other than initiating this litigation,” the release reads. Counters Lilly: “No license is needed. … The claims in [the] suit are invalid, not infringed, and unenforceable.”

Courtroom confrontation now looms. Lilly would not comment on its defense strategy, but court records show that the company is challenging the validity of the patent on at least two grounds. Lilly argues that earlier drugs that lower NF-κB levels—antibiotics, for example—predate the patent and thus invalidate it, because one cannot patent an already-discovered method. Lilly also argues that the patent does not describe methods that “enable any person skilled in the art” to make an NF-κB inhibitor “without undue experimentation”—a key requirement of U.S. patent law.

This “enablement” clause that Lilly invokes has been used to defeat other broad patent claims. Three years ago, a New York judge denied the University of Rochester's patent claims over COX-2 inhibitors, a class of drugs that includes Pfizer's Celebrex (Science, 14 March 2003, p. 1638). The judge ruled the Rochester patent invalid because it did not show how to specifically inhibit COX-2. The same judge also concluded that the COX-2 patent did not meet the law's standard for “written description” of the invention, because the patent did not describe a COX-2 inhibitor.

## Barrier to entry?

Regardless of the lawsuit outcome, the very existence of an exclusively licensed patent on an important drug target raises questions of the greater public good. “NF-κB ought to be available to anybody who wants to make a drug against it, and the terms should not be unreasonable,” says Roger Brent, president of the Molecular Sciences Institute, a nonprofit genomics research laboratory in Berkeley, California. Brent notes that a proliferation of broadly enforced upstream patents would constitute a “barrier to entry” for smaller companies contemplating new drug projects, because of legal and financial hurdles. Faced with many such patents to identify and license separately, “you cannot even begin,” he says. “Do not bother to pick up the phone.” Instead, Brent favors compulsory, nonexclusive licensing of drug-target patents, or eliminating them altogether.

Rai points out that publicly funded research should promote innovation, not put barriers in its way. “The only reason for having patents on publicly funded information is to promote technology development, not to impede it,” she says. “If anything, this particular patent is impeding development.” Seide, though, points to a new report by the National Academy of Sciences that concludes that “access to patented inventions … rarely imposes a significant burden for biomedical researchers.” The academy report encompassed patents on the NF-κB pathway, among others.

Ariad, a research-based pharmaceutical company in Cambridge, Massachusetts, says licensing proceeds will be used to advance its cancer programs and that, as exclusive licensee, it must “create value” for the inventors and their institutions. “There's nothing unusual about this patent,” Ariad CEO Harvey Berger told the Boston Globe in 2002. Berger, in a 2002 press release, said that “Lilly has filed hundreds of patent applications on treatment methods similar to our newly issued patent on NF-κB” and that “such patents are one of the cornerstones of pharmaceutical R&D and that they represent a recognized way of rewarding innovation.” (Lilly disagrees, saying its patents are much more specific.)

Broad upstream patents like Ariad's are actually not unusual, says Chris Holman, a law professor at the University of Missouri, Kansas City. But enforcing them on marketed drugs is. “There are a lot of patents like this out there,” he says. “[But] off the top of my head, I don't know of any case where one's successfully been asserted.”

Ariad's lawsuit will directly affect the companies that Ariad contacted in 2002. Ariad has revealed only two that have so far agreed to terms. “If Ariad wins on this, there will probably be other lawsuits, or lots of settlements,” says Seide. As Science went to press, U.S. District Judge Rya Zobel was considering two Lilly motions to invalidate the patent. If she rules against Lilly and the trial proceeds, Ariad seems prepared to see it through, despite the apparently long odds.

Meanwhile, several companies are working on drugs that directly target NF-κB. Among them are Millennium Pharmaceuticals and Nereus Pharmaceuticals, both of which declined to comment for this story. Baltimore says such drugs are well worth pursuing, but their success in any given disease can't be predicted. “Anybody who's developing a drug against NF-κB would have to be very conscious of side effects … because NF-κB is involved in the whole organism,” Baltimore says. “It doesn't mean you can't develop drugs; it means that you've got to be very careful.” If Ariad defeats Lilly in court, that warning will take on new meaning.

13. LUNAR AND PLANETARY SCIENCE CONFERENCE

# New Signs of Ancient Life in Another Martian Meteorite?

1. Richard A. Kerr

LUNAR AND PLANETARY SCIENCE CONFERENCE, 13–17 MARCH 2006, HOUSTON, TEXAS

They're back. Ten years ago, astrobiologist David McKay of the Johnson Space Center (JSC) in Houston, Texas, and colleagues found potentially life-generated minerals, organic matter, and even wormy-looking relics in martian meteorite ALH84001. Now the mini-Martians have returned with a twist. At the meeting, much the same group presented new evidence of organic remains of life in another martian meteorite. And they're not alone. This week, another group published entirely independent, inorganic evidence of microbial life in the same meteorite. The combination intrigues but hardly convinces an astrobiological community still smarting from its first encounter with a martian meteorite.

McKay's 1996 Science paper (16 August 1996, p. 924) on ALH84001, written with several of the same colleagues as the new report, launched the modern field of astrobiology nearly single-handedly. In the end, their numerous critics picked apart their half-dozen lines of evidence. Intriguing minerals could have formed without the help of living organisms, they found, and the wormy shapes were purely mineralogical creations, not microfossils. But one bit of evidence—the presence of complex, high-molecular-weight organic matter somewhere in martian meteorites—stood up to criticism better than the rest.

McKay and colleagues now believe they can see exactly where complex organic matter is stuffed into microscopic veins and pockets in a second martian meteorite, called Nakhla. Bringing a half-dozen microanalytical techniques to bear on a transparently thin sliver of Nakhla, they find vein-filling organic matter with a carbon isotopic composition that others have also found in large bits of Nakhla. The McKay group is convinced their organic matter is not just the vein-filling epoxy used to hold such “thin section” samples together and that the organic matter entered the rock on Mars, not Earth. It may have come from an organic-rich meteorite that hit Mars, they say. Or groundwater on Mars may have carried the organic matter from organisms into rock that became the meteorite.

Even more eye-catching than what the JSC researchers think they found is where they think they found it. The putative organics are in veins whose walls are peppered by tiny tubules extending into the adjacent mineral, olivine. These tubules bear a striking resemblance to ones found in the basaltic glass of modern ocean crustal rock (Science, 23 April 2004, p. 503). Several groups have found organic matter and even DNA in these terrestrial tubules. They have argued that microbes acid-etched the tunnels in the hunt for nutrients. Similar tubules show up in ocean crustal rocks that are billions of years old.

Now, petrologist Martin Fisk of Oregon State University in Corvallis and his colleagues report in the April issue of Astrobiology that they have found the same boreholelike tubules in the mineral olivine in terrestrial basalts and in Nakhla. Fisk's Nakhla tubules are indistinguishable from McKay's organic-rich Nakhla tubules.

Could the organic matter be the remains of tubule-boring microbes? “I think they have something interesting, [but] I'm not convinced,” says astrobiologist Andrew Steele of the Carnegie Institution of Washington's Geophysical Laboratory in Washington, D.C. McKay “has so many contaminants he has to eliminate. We do know Nakhla is contaminated with a lot of organics.” They include organic matter produced by abiotic means on Mars, organisms that invaded Nakhla after it fell to Earth in Egypt in 1911 killing a dog, and organic agents used in the preparation of thin sections. Steele would take another tack: “In Nakhla, I assume it's contamination. Prove me wrong.”

14. LUNAR AND PLANETARY SCIENCE CONFERENCE

# Snapshots From the Meeting

1. Richard A. Kerr

LUNAR AND PLANETARY SCIENCE CONFERENCE, 13–17 MARCH 2006, HOUSTON, TEXAS

Dust gets in your eyes. Deep Impact scientists have figured out why they couldn't see the crater formed last July when they smashed a nearly half-ton “bullet” into comet Tempel 1. Team members compared the plumes of debris blown off Tempel 1 with ejecta from laboratory impact experiments, and they simulated debris trajectories under a comet's feeble gravity. Both approaches indicate that the dirty snowball at the heart of Tempel 1 is mostly empty space. Surface materials especially have all the heft of fluffy snow or photocopier toner. A low-angle collision into such porous material sends a cloud of fine dust straight up, blocking the view from above.

Not to worry. Planetary scientist Joseph Veverka of Cornell University announced at the meeting that he and colleagues will soon be proposing to NASA that they fly a “Stardust Next” mission. They would send the now-hibernating Stardust spacecraft—which just returned comet material to Earth (Science, 17 March, p. 1536)—on to Tempel 1 on Valentine's Day 2011. Then it could take a look at the comet's fresh and by-then-unobscured crater.

Martian ring of fire. Most Mars rover scientists have concluded that the cryptic “Home Plate” that the Spirit rover spent 3 months reaching is the remains of a little ash-spewing volcano. The 90-meter-wide, 2-meter-high platform of layered ash has a distinctive chemical composition linking it to nearby lavas on the floor of Gusev impact crater and to rocks on the adjacent Columbia Hills, says team member Harry McSween of the University of Tennessee, Knoxville. He thinks volcanism driven from beneath Gusev blanketed any lake sediments mission planners expected to find on the floor of Gusev.

Hobbled by a broken right-front drive wheel, Spirit is now on a “drive or die” mission to a nearby hillside. It must tilt its dust-laden solar panels toward the sinking sun to boost power production and survive the coming winter, or sit the winter out in hibernation.

15. LUNAR AND PLANETARY SCIENCE CONFERENCE

# Tumbling Icy Moons

1. Richard A. Kerr

LUNAR AND PLANETARY SCIENCE CONFERENCE, 13–17 MARCH 2006, HOUSTON, TEXAS

In all their excitement over a watery geyser on Saturn's little satellite Enceladus, the media overlooked a geophysical oddity. What's the geysering doing at the south pole, of all places? At the meeting, two planetary scientists suggested an answer: An imbalance in Enceladus's innards may have rolled the moon over to bring the geysering down there. If so, they may have found a solution to a 25-year mystery on Uranus as well.

Contrary to intuition, spinning planetary bodies need not spin like a perfect top forever. Move some weight around, and they can go topsy-turvy. Pile too much ice on one pole, for example, and the ice mass will drag the former pole down to the equator, the stable position for the excess mass to rotate. Robert Pappalardo of the University of Colorado, Boulder, and Francis Nimmo of the University of California, Santa Cruz, wondered if something like that might have happened to Enceladus, but in the opposite sense. What if a warmer, less dense, and therefore buoyant plume rose through an icy interior? In principle, that would roll the moon until the lower-density plume was at a pole, where it could deliver its heat to a geyser. In detailed calculations, a plume did just that, at least under favorable conditions. Those included a particularly buoyant plume rising through a thick, icy mantle overlying a liquid ocean.

If a rolling moon could explain a curiosity at Enceladus, it may resolve a deep mystery at Uranus. The planet's moon Miranda is dominated by not one but three huge “coronae” imprinted on the surface. Apparently, three rising plumes shoved the surface upward at those spots and spewed icy lavas. But one corona sits at the south pole, whereas the other two face off at east-west antipodes on the equator. Pappalardo and Nimmo suggest that three rising plumes in sequence could have repeatedly rolled the moon and formed that pattern.

Tumbling moons “is an interesting hypothesis,” says planetary physicist William McKinnon of Washington University in St. Louis, Missouri. “It's possible, but I'm waiting for more information” on the interior of Enceladus. That could be coming after June 2008, when the Cassini spacecraft orbiting Saturn may extend its mission and fly by Enceladus. A close pass would refine the picture of the saturnian moon's gravity field and therefore its internal structure.

16. LUNAR AND PLANETARY SCIENCE CONFERENCE

# Roughed Up and Far From Home

1. Richard A. Kerr

LUNAR AND PLANETARY SCIENCE CONFERENCE, 13–17 MARCH 2006, HOUSTON, TEXAS

Japan's Hayabusa spacecraft is in a sad state. Battered and drained of its life's blood, it lies 190 million kilometers from Earth, and no one knows whether it carries a precious sample of asteroid Itokawa intended for return home. But the asteroid looks to have a sadder tale to tell. Hayabusa team members reported at the meeting that half-kilometer Itokawa shows every sign of having been smashed into a zillion bits and pieces over the eons and reassembled into a bloated, misshapen version of its former self. That now appears to be the likely fate of all small asteroids.

Mission chief scientist Akira Fujiwara of the Japan Aerospace Exploration Agency (JAXA) ticked off the signs that Itokawa is nothing more than a pile of rubble: boulders protruding tens of meters everywhere; an overall low density, implying a porous interior; rounded ends; and broad facets that hint at 100-meter boulders beneath. In its most recent reassembly, a small, roundish “head” evidently merged gently with an oblong “body.” Team members have dubbed the result “the sea otter.”

Whether Hayabusa can pull itself together as well and return to Earth remains to be seen. Its most serious troubles began last November right after its second attempt to touch down on Itokawa and pick up a rock sample (Science, 2 December 2005, p. 1409). Once it sprang a leak and began gushing the chemical fuel for its attitude-control thrusters, things went downhill rapidly. Hayabusa lost its proper orientation, breaking off communications and losing solar power. It short-circuited its batteries and sank into a deep freeze. Engineers have managed to recover some control, project manager Jun'ichiro Kawaguchi of JAXA reported. They jury-rigged an attitude-control system by commandeering the xenon-gas jets of the ion-drive main engine to counter any unwanted spinning. Hayabusa still has enough main-engine fuel onboard for both attitude control and propulsion on the homeward voyage, Kawaguchi said.

If deep-frozen components still work, Hayabusa may be able to leave the vicinity of Itokawa in spring of 2007, Kawaguchi said, and return to Earth in June 2010, 3 years behind schedule. Whether it will bring any of Itokawa with it is unknown. No one is sure whether contact with the surface ever triggered the sample-collection system. The craft did make contact on its first try, however, so hope remains for some sort of sample. “It would be extraordinary” if wounded Hayabusa made it back with a sample, says asteroid specialist Clark Chapman of the Southwest Research Institute in Boulder, Colorado, “but I'm not betting against them.”

17. AMERICAN PHYSICAL SOCIETY MEETING

# Semiconductor Advance May Help Reclaim Energy From 'Lost' Heat

1. Robert F. Service

AMERICAN PHYSICAL SOCIETY MEETING, 13–17 MARCH 2006, BALTIMORE, MARYLAND

Harnessing even a fraction of the waste heat given off by engines, boilers, and other high-temperature machines could save billions of dollars a year in energy costs. Researchers are counting on thermoelectrics—semiconductor devices that turn heat into electricity—to perform that trick. First, however, these devices must do their job much more efficiently.

Two years ago, a group led by Mercouri Kanatzidis, a chemist at Michigan State University (MSU) in East Lansing, took a huge stride in that direction by unveiling a thermoelectric semiconductor with higher energy-conversion properties than any such bulk material ever invented. It was a so-called n-type material that conducts electrons. But to make real-world devices, researchers need to marry an n-type material with a p-type partner that conducts positive charges called holes. At the Baltimore, Maryland, meeting, Kanatzidis reported that his team had found just the thing—two of them, in fact.

“It's a really important piece of work,” says Terry Tritt, a physicist and bulk thermoelectrics expert at Clemson University in South Carolina. Having both the n-type and p-type materials opens the door to making energy conversion devices about 50% more efficient than those on the market today. Kanatzidis has already licensed the technology to a company called Tellurex that hopes to recover waste heat from diesel truck exhausts. But because turning thermoelectrics into high-efficiency devices can require complex engineering, it's still too early to say whether they will make it to market, Tritt says.

Materials that convert heat to electricity and vice versa have been known for nearly 200 years. They work because when a semiconductor spans two different temperatures, it will move heat—and typically electrical charges—from the warm side to the cold side. Researchers harness that movement of charges to create a tiny voltage difference between electrical contacts on opposite sides. To get enough current for practical purposes, however, they must wire many such devices in a series. A simple approach is to alternate devices incorporating n-type and p-type materials so that they form a continuous path for electrons to flow along.

Researchers compare thermoelectrics by measuring a property known as ZT. Today's best thermoelectrics, thin films just a few dozen atomic layers thick, have a ZT of 2.5 to 3. But such devices are costly to make and too slender to maintain the large temperature differences needed for large-scale applications, Tritt says. As a result, researchers are trying to chemically synthesize bulk quantities of thermoelectrics with high ZTs.

Kanatzidis made his record-setting n-type semiconductor from lead, antimony, silver, and tellurium; it was abbreviated LAST. That material excels thanks to a series of tiny nanosized inclusions that form during synthesis. The inclusions, Kanatzidis explains, scatter heat-carrying phonons—vibrations of the crystal lattice—as they try to pass through the material. The result is that electrons careen swiftly through while stifled phonons maintain the heat differential between the two sides of the material.

To create a p-type material, Kanatzidis and MSU colleagues Timothy Hogan and S. D. Mahanti synthesized dozens of different compounds, systematically altering the composition of silver and antimony to change the number of electrons in the mix. Doing so provided a matrix with electrical vacancies that make it p-type. And in two cases—one in which they spiked LAST with tin, and another made from silver, antimony, lead, and tellurium, which they dubbed SALT—the researchers produced thermoelectrics with ZTs of about 1.6, the highest ever for bulk p-type materials.

Kanatzidis says he and his colleagues are now trying to incorporate their n-type and p-type materials into working devices. If they and other researchers can pull it off, thermoelectrics could soon usher in a whole new scheme for increasing energy efficiency.

18. AMERICAN PHYSICAL SOCIETY MEETING

# In a Jumble of Grains, a Good Hard Shake Restores Order

AMERICAN PHYSICAL SOCIETY MEETING, 13–17 MARCH 2006, BALTIMORE, MARYLAND

Whether they're chess pieces on a board or nuts in a jar, things usually move and mix when shaken. But vibrations can cause flowing beads to “freeze” into an orderly pattern like atoms in a crystal, a pair of physicists reports. The surprising observation could lead to deeper insights into disorderly solids such as glasses, in which the atoms or molecules are locked or “jammed” into a random state because they lack the energy to reach a more orderly one.

In keeping with the second law of thermodynamics, pumping energy into something usually raises its temperature and jumbles its insides. For example, heating a crystalline solid such as ice scrambles the regular pattern of atoms or molecules within it, eventually causing it to melt into a disorganized liquid. So “if you think of shaking as raising the temperature, then [the result] creates a cognitive paradox,” says Jerry Gollub of Haverford College and the University of Pennsylvania.

But granular materials—in which grains, marbles, or other macroscopic objects play the role of the atoms or molecules—often defy common sense. For example, shaking beads in a can doesn't always mix them. If the beads vary in size and density, the shaking may drive the larger ones to the top (the so-called Brazil-nut effect) or the bottom (the reverse Brazil-nut effect) depending on the details of the shaking and the precise sizes and masses of the beads. Lacking a comprehensive theory of granular materials, physicists and engineers continue to puzzle over such phenomena, which can affect materials as diverse as sand, gravel, foods, and powdered medicines.

When Karen Daniels of North Carolina State University in Raleigh and Robert Behringer of Duke University in nearby Durham observed that shaking can freeze flowing spherical beads into an orderly pattern, the finding took them by surprise. The researchers filled a can 50 centimeters wide and 10 centimeters deep with plastic beads measuring 2.5 millimeters in diameter. The bottom of the can was spring-loaded to gently squeeze the beads, and the top of the can rotated, causing the beads near the top to flow randomly over those below. At the same time, the researchers shook the can up and down and used a high-speed camera to film the motion of the beads.

They had hoped to study the details of the flow of the beads over one another, Daniels says. But when the shaking was sufficiently vigorous, the flow stopped and the beads locked into a regular three-dimensional array like the atoms in a crystal. “My initial reaction was frustration,” Daniels says. “The thing kept freezing on me.”

Sidney Nagel of the University of Chicago in Illinois says that the extra energy of the shaking may let the jumbled grains seek out an orderly state from which they'd otherwise be cut off. Because the disorderly atoms in glass are similarly cut off from reaching a more organized arrangement, the surprisingly orderly grains could lead to insights into the puzzling physics of glass. “What's nice is the control you can have over some of these experiments” with granular materials, Nagel says.

As for the paradox that shaking causes the beads to freeze into place, the resolution may come in finding the right definition of the effective temperature of the beads, Daniels says. The actual temperature describes only how hot each grain is and reveals nothing about the organization and motion of the grains. With the right definition, Daniels says, it might turn out that shaking actually causes the effective temperature of the beads to decrease.

19. AMERICAN PHYSICAL SOCIETY MEETING

# New Trick With Silicon Film Could Herald a Bright Future for Rolled-Up Nanotubes

AMERICAN PHYSICAL SOCIETY MEETING, 13–17 MARCH 2006, BALTIMORE, MARYLAND

Rolling a carpet may not seem high-tech, but doing it on a nanoscale with a single material is quite a feat. Researchers reported at the meeting that they have coaxed a layer of silicon—the material of choice for microchips—to roll up into nanotubes, and that similar tubes can guide and generate light. The advances might lead to devices that can be built into ordinary electronic microchips.

Widespread applications may be years away, but the ease and control with which the structures can be made gives them great promise, says Max Lagally, a materials physicist at the University of Wisconsin, Madison. “The whole idea that you do this with ordinary electronics and put [the structures] where you want them is potentially paradigm-shifting,” Lagally says.

To make rolled-up nanotubes, researchers use lithography—the etching of materials that's key to making microchips—to lift the films off a surface, dissolving the underlying substrate. At the same time, they exploit the penchant of films to bow and curl when stresses build up inside them. Researchers typically start by depositing one semiconductor on top of another, such as silicon on top of germanium, in layers as thin as a single plane of atoms. In such a film, the silicon atoms are stretched a bit farther apart than normal, and the germanium atoms are slightly squeezed together. So if the underlying substrate is etched away, the silicon atoms pull together, and the germanium atoms push apart, causing the film to curl.

If done correctly, the films coil into tight rolls as narrow as a few nanometers, says physicist Victor Prinz of the Siberian Branch of the Russian Academy of Sciences in Novosibirsk, who pioneered the technique in the late 1990s. “Nobody around us thought that it would be possible to make such a thing,” Prinz says. “Our experiments disproved all these theoretical predictions.” In recent years, Prinz and colleagues have curled films into elaborate structures, including spiraling “nanodrills” and needles small enough to puncture a single cell.

Now, physicists Oliver Schmidt and Rudeesun Songmuang of the Max Planck Institute for Solid State Research in Stuttgart, Germany, and colleagues have taken the budding technology a step further. First, the researchers found a way to roll up a film of a single material. The key, Schmidt said at the meeting, is to grow the film thick enough that the atoms are stretched together or pulled apart on the bottom, but spaced normally on the top. “That's really surprising,” Lagally says. “I don't really understand how it works, and he didn't really explain it.” Still, he says, the advance opens the way to all-silicon nanotubes on silicon chips.

Schmidt also reported that nanotubes of silicon and silicon oxide can emit light when zapped with a laser. That advance is also exciting, Lagally says, because it could lead to tiny silicon lasers and all-silicon optoelectronic circuits that manipulate both electricity and light.

Those goals may be a way off, but Lagally and others say they see no fundamental problems to be overcome. Wound-up films, it seems, are nanotech on a roll.