News this Week

Science  04 Nov 2005:
Vol. 310, Issue 5749, pp. 754
1. EVOLUTION

Groups Wield Copyright Power to Delay Kansas Standards

1. Yudhijit Bhattacharjee

For the second time in 6 years, two U.S. scientific organizations have thrown a wrench into plans by Kansas school officials to adopt new science standards that would promote the teaching of alternatives to evolutionary theory. Observers say the move, which prevents Kansas from incorporating copyrighted materials into the state's revised standards, could indefinitely delay their adoption by forcing officials to craft substitute language.

“That could take them several months,” says Steven Case, a biologist at the University of Kansas in Lawrence and chair of the science standards writing committee, which has been fighting the 10-member board. “The more we can push back the implementation of the standards, the less damage they can do.” Case and others see the board's proposed standards as an attempt to introduce intelligent design (ID) into school curricula.

When drafting new education standards, state officials typically borrow liberally from the National Academy of Sciences' (NAS's) National Science Education Standards (NSES) and the National Science Teachers Association's (NSTA's) Pathways to Science Standards. But the two organizations said in a 27 October statement that the set of standards proposed by the Kansas board “inappropriately singles out evolution as a controversial theory despite … its acceptance by an overwhelming majority of scientists,” and that its definition of science “[blurs] the line between scientific and other ways of understanding.” As a result, the two organizations denied Kansas the right to incorporate any of their materials into its new standards.

For example, in a section specifying what students between grades 8 and 12 need to understand about evolution, the draft reproduces the concepts listed under the same section in the NSES. But it also contains insertions such as “in many cases the fossil record is not consistent with gradual, unbroken sequences postulated by biological evolution.” Similarly, a section on “science as inquiry” looks identical to the corresponding section in the NSES except for one additional statement: “[The student] understands methods used to test hypotheses about the cause of a remote past event (historical hypothesis) that cannot be confirmed by experiment.” The modification seems to be aimed at “open[ing] the door for various kinds of explanations that may not be scientifically based,” say NAS's Jay Labov and Barbara Schaal, who reviewed the Kansas standards.

Observers say the decision is unlikely to stop the board from adopting the standards when it meets on 8 November. But the absence of copyright permission means that the board will have to rewrite the 123-page document. Kansas education officials are working “to remove any material that would violate any copyright provisions,” says Kathy Martin, one of a six-member bloc that is pushing the change. She predicts that a new version will be ready by December. “How long can we keep beating an old horse to death?” she asks.

But John Staver, a science education professor at Kansas State University in Manhattan who serves on the standards writing committee, doubts that the board will be able to complete its task so quickly. He says a similar move in 1999 by NAS, NSTA, and AAAS (publisher of Science) delayed implementation of new standards in Kansas by more than a year, and that the ruling majority was booted out in the meantime. “We're hoping for the same thing to happen again,” says Staver. Conservatives hold four of the five board seats up for election in November 2006.

2. CHEMISTRY

'Grandfather of Nanotech' Dies at 62

1. Robert F. Service

Nanotechnology pioneer Richard Smalley, who shared the 1996 Nobel Prize in chemistry for work that launched the nanotechnology industry, died 28 October after a long battle with cancer. He was 62.

Smalley, a chemistry professor at Rice University in Houston, Texas, co-discovered carbon-60, a soccer ball-shaped form of carbon also known as buckminsterfullerene or “buckyballs.” He helped persuade Congress to create the National Nanotechnology Initiative, a $1-billion-a-year federal effort that he predicted could lead to a new generation of nanotech-based drugs capable of wiping out many forms of cancer, such as the non-Hodgkin's lymphoma from which he suffered. “I may not live to see it. But, with your help, I am confident it will happen,” Smalley testified in 1999. “Richard was truly the grandfather of the entire field of nanotechnology,” says Anna Barker, deputy director of the National Cancer Institute in Bethesda, Maryland. Jim Heath, a nanotechnology expert at the California Institute of Technology in Pasadena and a former graduate student in Smalley's lab, called him “a Moses” leading the field to the promised land. In recent years, Smalley had also been a tireless campaigner for increased spending on new sources of energy, warning audiences that “energy is the single most important problem facing humanity today.” 3. BIODEFENSE Critics Question Proposed Countermeasures Agency 1. Jocelyn Kaiser Spurred by worries about avian influenza, a Senate panel has come up with an idea to speed the development of new drugs and vaccines against urgent public health threats such as pandemic flu and bioterror weapons. But its solution—a new research agency within the Department of Health and Human Services (HHS)—has put scientific groups on alert. They worry that its work would be secret and could duplicate existing efforts at HHS. “The creation of a new agency raises many issues,” says Janet Shoemaker, public affairs director of the American Society for Microbiology in Washington, D.C. The proposal is part of S. 1873, a bill passed on 18 October by the Senate Committee on Health, Education, Labor, and Pensions. Sponsored by Senator Richard Burr (R-NC), the legislation is in part meant to address gaps in the BioShield law passed in 2004 that provides$5.6 billion to drug companies over 10 years for procurement of biodefense drugs and vaccines. Few companies have applied for BioShield funding partly because of concerns about liability. S. 1873, which some are calling BioShield II, would protect companies from lawsuits and also offers sweeteners such as exclusive markets for countermeasures.

Perhaps the most controversial part of the legislation is its creation of the Biomedical Advanced Research and Development Agency (BARDA). Burr says the agency is modeled on the Defense Advanced Research Projects Agency, which acts quickly to fund high-risk, high-payoff research that might not pass peer review at other agencies. BARDA's focus, however, would mainly be on providing funding and coordination to reduce the time between basic research and final product.

BARDA would fund research and development on countermeasures for bioterror agents, chemical and nuclear agents, and infectious diseases that could cause natural outbreaks. In addition, it would coordinate research on biodefense and infectious disease countermeasures across the federal government—a role that no agency now f ills. Although Burr's staff says BARDA's budget is still being worked out, the bill stipulates it would start out with $1 billion in 2006 from unspent BioShield 2004 funds. The legislation also calls for the National Institutes of Health to fund animal models for countermeasures research and for NIH to absorb some parts of the Armed Forces Institute of Pathology, which is to be disbanded as part of the latest defense base closings (Science, 2 September, p. 1472). Scientific groups are worried about where BARDA's funding would come from at a time when research budgets are already being squeezed. The Federation of American Societies for Experimental Biology wrote Burr that it is “troubled” that the bill doesn't clarify how BARDA would differ from biodefense and infectious disease programs at NIH's National Institute of Allergy and Infectious Diseases (NIAID) and at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. It's not clear whether the bill “will help” develop drugs and vaccines or “just adds a layer of complexity,” adds Shoemaker. Observers also note that the bill does not spell out how research proposals would be reviewed or what the necessary expertise for BARDA's presidentially appointed director would be. Another concern, say scientific and other groups, is that BARDA and a new oversight board would be exempt from the Freedom of Information Act and open-meetings laws. “Transparency is both appropriate and necessary,” particularly for developing infectious-disease countermeasures, writes the Center for Arms Control and Non-Proliferation in a letter recommending that information be withheld only in cases of a threat to national security. Burr's press secretary Doug Heye says BARDA would have “a much different role” from that of NIAID which focuses on basic research and that its reports would be public except in certain situations. Security expert Gerald Epstein of the Center for Strategic and International Studies, who testified at two hearings earlier this year on the bill, says scientists'” almost allergic reaction” to secrecy doesn't make sense in a world in which “there are folks looking at this stuff to kill us rather than help us.” BARDA's overseers “can't guarantee that they'll never have to” withhold information about, say, devices to detect bioterror agents, he suggests. An NIAID spokesperson said the institute could not comment on pending legislation. Burr, who was still revising the bill, hoped it would reach the Senate floor for a vote as early as next week. It's not clear how soon the House will take up the measure. It's also possible that the bill will be merged with measures focused on pandemic influenza, such as a provision passed last week by the Senate that would give CDC nearly$8 billion in 2006 for pandemic preparedness and President George W. Bush's new pandemic flu plan (see ScienceScope, p. 759).

4. NUCLEAR PHYSICS

Dueling Experiments Close In on Source of Proton's Spin

When searching for something, it can help to know where the thing isn't. So physicists are cheering results that eliminate one of three possible explanations of how the proton gets its spin. “This is a huge step,” says particle physicist Zein-Eddine Meziani of Temple University in Philadelphia, Pennsylvania. “It's just a matter of waiting for more data until they nail it down.”

For 70 years, physicists have known that the proton acts like a tiny top and possesses exactly half a fundamental smidgen of spin. But they don't know precisely where that spin comes from. The proton consists of three fundamental particles called “quarks” and a gaggle of others called “gluons.” Each quark carries half a unit of spin, and theorists once thought the quarks were aligned, or “polarized,” enough to give the proton most of its spin. But in the 1980s, experiments showed that the spin of the quarks accounted for only about 20% of the total.

That “spin crisis” has three possible explanations. The gluons, which also have spin, might be polarized just enough to make up the missing 80%. Or it could arise from the “orbital” motion of the quarks and gluons swirling around one another. Finally, some theorists argue that both the quarks and the gluons are polarized but swirl in a way that counteracts some of the resulting rotation. Researchers measured the spin of the quarks by bouncing particles called muons off the quarks. But a gluon can split into a quark and an antiquark, and the muon can bounce off one of them. If the gluons are highly polarized, that interaction can obscure the polarization of the quarks.

Now, two teams have measured the gluon polarization. And the results, presented at a conference* in Santa Fe, New Mexico, suggest that it's small.

With help from colleagues at the Japanese research agency RIKEN, researchers at Brookhaven National Laboratory (BNL) in Upton, New York, collided beams of protons polarized to spin along like little American footballs thrown using either the right or left hand. Experimenters studied the resulting spray of particles using the PHENIX particle detector. As they switched the relative polarizations, they tracked changes in the number of particles called pions to deduce the gluon polarization, says BNL's Gerry Bunce. The results rule out a large gluon polarization that masks the quark polarization, he says, but don't yet reveal whether the gluons provide the missing spin.

Meanwhile, as in earlier experiments, researchers with the COMPASS experiment at the European particle physics laboratory CERN near Geneva, Switzerland, smashed polarized muons into a target containing polarized protons. This time they used judicious data “cuts” to identify collisions in which a gluon splits into a quark and an antiquark—the same ones that may have muddled measurements of the quark polarization. That trick enabled the physicists to measure the polarization of the gluons. It accounts for no more than 10% of the proton spin, says particle physicist Jan Nassalski of the Soltan Institute for Nuclear Studies in Warsaw, Poland.

Researchers debate which result is more definitive. The PHENIX experimenters use the unknown structure of one proton to probe the structure of the other, says CERN experimenter Gerhard Mallot, “and I think that's a disadvantage because you have unknown squared.” But Werner Vogelsang, a theorist at BNL, says the COMPASS measurements rely on shakier theoretical assumptions and apply only to gluons moving with a particular momentum within the proton.

All agree that the two experiments are complementary and that the uncertainties will shrink with more data. Within a few years, most expect to know at last what's whirling within the proton.

• * Particles and Nuclei International Conference, 24-28 October 2005, Santa Fe, New Mexico.

5. SCIENTIFIC MISCONDUCT

MIT Terminates Researcher Over Data Fabrication

1. Jennifer Couzin

A rising star at the Massachusetts Institute of Technology (MIT) in the hot field of RNA interference (RNAi) was dismissed last week after admitting that he had fabricated and falsified data in grant applications, submitted manuscripts, and one published paper, the university reported in a statement. The California Institute of Technology (Caltech) in Pasadena has now begun reviewing two papers published by the researcher, Luk van Parijs, 35, when he was a postdoc there. Harvard Medical School and Brigham and Women's Hospital, where Van Parijs was a graduate student, is also scrutinizing his early work.

“I thought Luk was an excellent scientist and truly cannot understand why he would fake anything,” wrote Caltech president David Baltimore in an e-mail message to Science. Van Parijs was a postdoc in Baltimore's lab in the late 1990s. Van Parijs did not reply to an e-mail message seeking comment.

Graduate students and postdocs in Van Parijs's lab first approached MIT administrators in August 2004 with allegations of research misconduct, says Alice Gast, MIT's associate provost and vice president for research. “There were data that they could not verify the origins of,” says Gast. The university launched an investigation, put Van Parijs on paid leave, pulled his lab Web site off the MIT server, and reassigned his lab members to other faculty. A copy of Van Parijs's home page from 2003 shows that his lab had 17 members.

Gast oversaw the investigation, which was conducted by investigators whose names have not been made public. She declines to say which of 22 papers Van Parijs co-authored during his 5 years at MIT contains allegedly falsified information, nor would she quantify the number of grants or manuscripts at issue. MIT, she says, is working with the co-authors to retract the suspect published paper.

Van Parijs, a prominent and prolific young researcher in RNAi, was trying to use the method, which can alter gene expression, as a tool for studying normal physiology and disease. The applied nature of his work may have made it more difficult to detect problems, because it was less likely to match other research exactly, says Thomas Tuschl, a basic RNA biologist at Rockefeller University in New York City. “If somebody picks a gene and turns it off, it's only the people who already have a knockout who can say [if] that's the wrong thing,” he says.

MIT's findings have put many of the top journals in which Van Parijs published on alert. Immunity, which ran seven articles by him, “will be looking into these cases in detail,” said Lynne Herndon, the president and CEO of Immunity's publisher Cell Press, in a statement. Staffers at both Immunity and the Journal of Immunology say they learned of the misconduct case from reporters.

MIT hasn't yet returned any of Van Parijs's grant money to the National Institutes of Health (NIH). But the university is now beginning to weigh that possibility. “That's definitely one of the next steps,” says MIT spokesperson Denise Brehm.

Since fiscal year 2001, Van Parijs had won NIH grants totaling at least $1.2 million. But two of his three grants expired in August 2004, and the third would have expired in August 2006. 6. SCIENCE AND THE LAW Thomas Butler Loses Appeal, Vows to Fight On 1. Martin Enserink Texas physician and microbiologist Thomas Butler suffered another defeat last week in a legal battle that has already cost him his freedom, his career, and more than$1 million in legal fees. Last week, a three-judge panel on the U.S. Court of Appeals for the Fifth Circuit in New Orleans—operating temporarily from Houston—unanimously upheld Butler's conviction and 2-year prison sentence for illegally shipping bacteria to Tanzania and defrauding his former employer, Texas Tech University Health Sciences Center in Lubbock.

Although “very disappointed,” Butler is “determined to continue his appeal” and restore his honor, says his lead attorney, George Washington University law professor Jonathan Turley. Meanwhile, supporters are trying to help the 64-year-old researcher find a job once he is released from federal prison on 2 January.

Butler's troubles began in January 2003, when he reported that 30 vials of plague bacteria were missing from his lab. His statements triggered a massive FBI operation and a nationally televised bioterror scare in Lubbock, a college town in western Texas. Butler was eventually charged with lying to investigators, mishandling plague samples, defrauding Texas Tech, and tax evasion. Although a jury acquitted him on most of the plague-related charges, he was convicted of 47 offenses and received a 2-year sentence (Science, 19 March 2004, p. 1743).

Butler's lawyers argued that lumping the charges related to plague with allegations on financial wrongdoing may have prejudiced the jury, that Butler should have had the right to subpoena internal e-mails and take depositions from four witnesses in Tanzania, and that prosecutors offered no evidence that Butler willfully violated export rules when he sent plague cultures to Tanzania via FedEx.

Turley says he's “frankly astonished” by the ruling from what is generally considered one of the most conservative appeals courts in the country. But he expects Butler, now in prison in the Federal Medical Center in Fort Worth, Texas, to continue the fight, to the Supreme Court if necessary.

Last week, members of the National Academy of Sciences's Committee on Human Rights, chaired by Duke University's Peter Agre, a Nobel laureate and ardent supporter of Butler, discussed ways to help him rebuild his ruined career. But as a convicted felon who gave up his medical license, Butler faces an uphill battle, Agre says.

Stanford microbiologist Stanley Falkow, another prominent Butler defender, says his efforts to find Butler a job have failed to bear fruit. “Short of him leaving the country, it's going to be very difficult,” Falkow says. Butler “really wants to work again,” says his wife, Elizabeth Butler. “I think work will help him heal.”

7. NEUROSCIENCE

Genes That Guide Brain Development Linked to Dyslexia

1. Greg Miller

Genetic variations that cause miscues in brain development may play an important role in reading disabilities such as dyslexia, according to research presented last week at a meeting of the American Society of Human Genetics in Salt Lake City, Utah.

“Before these studies, no one has really known what's going on” in the brain to cause dyslexia, says Juha Kere, a molecular geneticist at the Karolinska Institute in Stockholm, Sweden, and leader of one of the studies. Taken together, Kere says, the new work strongly suggests that dyslexia results from faulty neural connections formed early in life.

People with dyslexia have reading impairments despite normal intelligence. The problem affects up to 17% of the population and tends to run in families, pointing to a strong genetic component. Geneticists have recently implicated several genes, but little has been known about how they might contribute to the disorder.

In one new study, a collaboration of 20 researchers led by Haiying Meng and Jeffrey Gruen of Yale University School of Medicine homed in on a region of chromosome 6 that had been fingered previously. Using DNA from 536 people with a dyslexic in their families, the researchers tracked 147 single-nucleotide polymorphisms (SNPs), spots where the genetic code differs by one letter among individuals. Searching for SNPs that tend to have one “spelling” in people with reading impairments and another spelling in normal readers, the researchers found a disproportionate number of such SNPs in a gene called DCDC2. They also found that about 17% of dyslexics were missing a short stretch of DNA within DCDC2. Everyone who had this deletion had dyslexia, Gruen says.

Analyses of cadaver brains revealed high levels of DCDC2 expression in brain regions used during reading. And when the researchers used a technique called RNA interference to dampen DCDC2 activity in fetal rats, newly born neurons didn't migrate to their proper positions in the cerebral cortex, the team reported at the meeting and online this week in the Proceedings of the National Academy of Sciences. This suggests that certain variations of the DCDC2 gene may damage development of the neural circuits normally used for reading, says Gruen. People who inherit those variations probably compensate by using less efficient circuits for reading, he says.

Also at the meeting and in a paper published on 28 October in PLoS Genetics, Kere and colleagues reported evidence linking a gene on chromosome 3 called ROBO1 to dyslexia. In one man with dyslexia, the team found that the ROBO1 gene had been disrupted by a freak genetic accident: a piece of chromosome 8 wedging itself into chromosome 3. Kere's team also found reduced ROBO1 activity in 21 dyslexic individuals from a large Finnish family. The fruit fly version of ROBO1 helps shape neural connections between the two sides of the brain during development, and Kere says such connections may be impaired in people with dyslexia.

A third candidate dyslexia gene called KIAA0319, first described by Julie Williams of Cardiff University, U.K., and colleagues in February in the American Journal of Human Genetics, may also play a role in brain development, according to work presented by Anthony Monaco at the Wellcome Trust Centre for Human Genetics in Oxford, U.K., and colleagues.

Gruen predicts that the new work will quickly lead to genetic tests for dyslexia susceptibility. “If we can identify kids early, we can get them into [classes] tailored to their problem,” he says. But others aren't so sure. Monaco and Williams, for example, say they've failed to find an association between DCDC2 and dyslexia in their British populations. Kere, on the other hand, has a paper in press at the American Journal of Human Genetics replicating the DCDC2 link in a German population. Everyone agrees that more work is needed to resolve the discrepancies. One possibility, Gruen says, is that different genes are more important for dyslexia susceptibility in different populations.

8. PATENTS

Antibody Drug Dispute Ends in $255 Million Cash Payout 1. Eli Kintisch Developers of a new drug for arthritis last week ended a 2-year dispute over royalties, leading to one of the biggest-ever lump-sum payments on record to academic scientists. The payoff came after a U.K. biotech firm, Cambridge Antibody Technology (CAT), withdrew a suit against its giant partner Abbott in Abbott Park, Illinois. The settlement between CAT and Abbott will release a total of$255 million in royalties, to be split between the U.S. nonprofit Scripps Research Institute, the U.S. biotech firm Stratagene, and the U.K. Medical Research Council (MRC), which helped fund early studies. The deal cuts future royalties Abbott must pay on Humira, a blockbuster anti-inflammatory drug made with a process patented by Scripps and MRC scientists.

“I expect it will be one of the single largest academic licensing transactions in the United Kingdom's history and would be very high on the list of North American licensing transactions,” says Ashley Stevens, technology transfer director at Boston University. Emory University in Atlanta, Georgia, holds the record, though: In July, it sold the rights to AIDS drug Emtriva for a one-time payment of $525 million. U.S. universities in 2003 garnered$1.3 billion in licensing revenue from science discoveries, according to the Association of University Technology Managers.

At the heart of the CAT-Abbott deal is a technique to create human antibodies to order. Previously, animal cells were used to derive antibodies for medical therapies, and as a result, candidate drugs triggered an immune attack by the patients' own cells. Competing labs at MRC and Scripps published landmark papers on techniques to derive human monoclonal antibodies in 1989 (Science, 8 December 1989, p. 1275; Nature, 12 October 1989, p. 544). Nine years later, after shelving a patent dispute, the teams joined forces under the auspices of CAT. Abbott and CAT then partnered to produce Humira but eventually found themselves at odds in 2003 over profits; Abbott attempted to reduce the royalty rate to the inventors, citing contract provisions, and CAT sued. The parties settled out of court last week.

Doctors have prescribed Humira to more than 110,000 patients worldwide for rheumatoid arthritis. In addition, drugs based on the MRC-Scripps antibody technique are in clinical trials for Crohn's disease and ankylosing spondylitis.

“You like to see academic research ultimately go to products to help people,” says chemist Richard Lerner, a co-inventor and now president of Scripps. “Humira is a very good product,” adds co-inventor Gregory Winter, an MRC researcher at the University of Cambridge, U.K., in part because it is formulated in a way that permits patients to administer injections themselves. “I think [analysts] believe the market will go to about $1.6 billion.” MRC and Scripps are poised to receive$191 million and $34 million respectively, with roughly$45 million more in the offing. Lerner is entitled to a quarter of Scripps's take; the U.K. inventors to 10%-15% of MRC's share. None has decided how the money will be used. San Diego, California-based Stratagene will receive 24 million for related patents. 9. ITALIAN UNIVERSITIES Government Wins Fight to Modernize Academic Appointments 1. Susan Biggin* 1. Susan Biggin is a writer in Trieste, Italy. ROME—After almost 2 years of debate, Italy's Parliament approved a law last week to reform the status and recruitment of academic staff and bring the university system in line with those of other leading nations. The most dramatic change will be the elimination of the ricercatore position, a tenure-track job for young researchers, currently numbering 20,000. The law will also switch professorial appointments from a local to a national system and allow universities the autonomy to take on contract research projects and make ad hoc academic appointments. The government took action this autumn after the bill risked running aground under the weight of hundreds of amendments. On 28 September, University Minister Letizia Moratti called on the Senate to give the bill a vote of confidence. Designed to free up the bill's progress, the appeal passed the next day, with government supporters blaming the opposition for obstruction tactics. But opponents complained of a “coup,” and the college of university rectors (CRUI), an unyielding critic, declared the action an “unacceptable forcing of parliamentary practice.” When the bill returned to the Camera—Parliament's lower house—on 25 October, opposition delegates walked out in protest. The bill was passed. The position of ricercatore, which the bill will phase out by 2013, was introduced in 1980 to boost university research. In reality, many ricercatori were overloaded with teaching duties while others remained in the role for an academic lifetime. Under the new law, young researchers will be employed on 3-year contracts and can complete only two contracts before they must apply for an associate professor position. The new law will also reform the concorsi system, in which universities set up panels to vet candidates for promotion to associate or full professor. The concorsi have often been attacked for favoring in-house candidates. Moratti plans to combat this “localism” by returning to national appointment competitions abandoned in reforms 7 years ago. Successful candidates will be put on a list from which universities can choose individuals to apply to fill their posts. Another aspect of the law covers new rights for universities to draw up contracts with businesses and other bodies to fund research. And to combat brain drain, says Moratti, they will be able to directly appoint candidates from abroad—Italian nationals or otherwise—to associate and full professorships. Researchers from industry may also be named temporary professors. Although Moratti is confident that the provisions will benefit young researchers and “bring the Italian system up to that of the most advanced countries,” there remain many opponents. During the bill's progress, CRUI, for one, called for even greater university autonomy, researcher assessment to ensure a meritocratic system, better career paths for young researchers, and guarantees of adequate funding. According to CRUI President Piero Tosi, approval of the new law is unfortunate because basic questions about the future of the universities are left “unresolved.” 10. GEOLOGY Tracking Myth to Geological Reality 1. Kevin Krajick* 1. Kevin Krajick is the author of Barren Lands: An Epic Search for Diamonds in the North American Arctic. Once dismissed, myths are winning new attention from geologists who find that they may encode valuable data about earthquakes, volcanoes, tsunamis, and other stirrings of the earth SEATTLE, WASHINGTON—James Rasmussen, owner of a funky used-record store called Bud's Jazz, and Ruth Ludwin, a seismologist at the University of Washington, Seattle, make an unlikely professional team. Late last year, they were walking down the beach near the bustling Fauntleroy ferry dock, searching for a reddish sandstone boulder. Native American legends-Rasmussen belongs to the local Duwamish people-say the boulder is haunted by a'yahos, a spirit with the body of a serpent and the antlers and forelegs of a deer. Old folks used to say not to look in the direction of a'yahos because it could shake the ground or turn you to stone. “It was not at all clear to me what my granddad was talking about when he said you should be careful as you travel through here along the shore,” said Rasmussen. “Then I heard the scientific evidence, and it got me thinking about the old stories.” The evidence is this: In the 1990s, geophysical images and excavations revealed a huge, hidden fault traversing Seattle. Disturbed soils and other evidence show that 1100 years ago, it produced a quake that would level Seattle today. Scientists agree that the fault could slip again at any time, toppling buildings and elevated highways. The city's infrastructure is now being reinforced for disaster. Ludwin, Rasmussen, and others have documented at least five Seattle-area legend sites related to shaking, including the boulder, all aligned along the fault near old landslides and other signs of seismic violence. They conclude that the threat was encoded in folklore long before scientists uncovered physical signs. More and more geoscientists are willing to combine their work with such stories these days, in a budding discipline called geomythology. Volcanologist Floyd McCoy of the University of Hawaii, Manoa, says discussing myth has traditionally been “a good way to sink your own credibility”; it can put you on the list with flaky Atlantologists and other amateur zealots. But, says McCoy, “I'd be a fool to write it all off. There is a new realization that some myths have something to say.” Myths can sometimes alert researchers to previously unheeded geohazards; in other cases, where science has demonstrated the danger, legends “enrich the record” and reinforce the fact that people lie in harm's way, says paleoseismologist Brian Atwater of the U.S. Geological Survey (USGS) in Seattle, who has spearheaded many studies of seismic events in the Pacific Northwest. The trick is teasing out which myths carry kernels of truth that can be connected to hard data. Deities of flood and fire The movement traces in part to the 1980s, when scientists realized that the slow march of geologic time is sometimes punctuated by biblical-scale catastrophes, such as the giant meteorite that wiped out dinosaurs 65 million years ago. After this was accepted, some (usually those with tenure) felt freer to wonder if near-universal myths of great floods and fires implied that such disasters also have punctuated human time. In the 1990s, Columbia University marine geologists Walter Pitman and William Ryan argued that rising Mediterranean sea levels following the last deglaciation topped what is now the Bosporus Strait and roared into the Black Sea 7600 years ago, serving as the original inspiration for the biblical flood. Their work triggered sharp criticism and a torrent of research, resulting in growing acceptance of some sort of Black Sea flooding (Science, 22 September 2000, p. 2021). Whether the book of Genesis somehow grew from this is a further step, admits Ryan, who presented his latest findings at the International Geoscience Program in Istanbul, Turkey, in early October. Recent studies on more local disasters have raised the field's stock, with geoscientists connecting myths to past disasters in North America, the Mideast, Africa, Europe, and the Pacific. For example, Ludwin's study on the Seattle fault came out this year in Seismological Research Letters, along with a paper in which she discusses dozens of aboriginal stories about times when the ocean along British Columbia, Washington, and Oregon rolled up in great waves, carrying away coastal villages. Native people often described these events as a battle between a great whale and a thunderbird. Paleoseismologists have a modern explanation: Quaking along the offshore subduction zone has produced at least a dozen huge tsunamis at intervals of 200 to 1000 years, as shown by shore deposits including inland sand sheets and mud that buried native camps. The most recent wave is dated through tree rings and other evidence to January 1700; scientists agree the next can come any time. The utility of myth became clear in the Indian Ocean tsunami of 2004. While up to 300,000 people are thought to have died, the indigenous seafaring Moken people of Thailand almost all survived. Their traditions warn that when the tide recedes far and fast—as happens before tsunamis—a man-eating wave is coming, and everyone should run. They did. Patrick Nunn, a geoscientist at the University of the South Pacific in Suva, Fiji, believes such stories can be harnessed to find other hidden geohazards. He currently has a grant from the French government to collect tales that might pinpoint islands where scientists should look for warnings of earthquakes, volcanoes, or catastrophic landslides not included in written records. These include common motifs in which deities “fish up” islands from the water and sometimes throw them back. Nunn thinks such tales may encode sudden uplifts, subsidences, or flank collapses of islands, and he has already confirmed that sinking islands are not just myths. He has correlated at least a half-dozen stories with actual land masses seen by early European seafarers but which are now gone; a few were never charted but have since been located just under the waves, exactly where the stories said they were. Nunn's studies have also turned up a surprise. People on the volcanic island of Kadavu, Fiji, have a suggestive legend about a big mountain that popped up one night, and locals say they have heard rumbling from the main cone recently. In 1998, Nunn and others investigated the volcano but decided on preliminary evidence that it had not erupted for 50,000 years. The island has been inhabited for only 3000 years, so they concluded that the myth was imported. Months later, a new road cut revealed pot shards under a meter-deep layer of ash. “The myth was right, and we were wrong,” says Nunn. Myths may provide unusually precise tools in the Pacific because some are tied to royal genealogies that can be roughly dated. In Hawaii, where the genealogies go back 95 generations, archaeologist Bruce Masse of Los Alamos National Laboratory in New Mexico has compiled stories of battles between the fire deity Pele and others that seem to relate to volcanic eruptions; the reigns of kings at the time of the “battles” correlate within a few decades to radiocarbon dates of burned vegetation under lava sheets. Other tales apparently record celestial events. One, said to have taken place during the reign of King Kakuhihewa, narrates a human sacrifice at dawn interrupted by giant owls who fly across the sun. When Masse lined up the number of generations with recent NASA tables that calculate times of past events, he hit a match: A rare solar eclipse took place over Hawaii precisely at sunrise on 10 April 1679. Myth has also figured in work at Nyos, a crater lake in Cameroon that exploded and killed 1700 people in 1986. The disaster was at first a mystery, with no signs of volcanic eruption. Scientists finally figured out that carbon dioxide bubbling from deep rocks had slowly built up in the water, then burst out and suffocated all living things nearby—a phenomenon never observed by scientists. It could have been dismissed as a one-time fluke except for the fact that the region is full of stories about haunted lakes that rise, sink, or blow up. Anthropologist Eugenia Shanklin of The College of New Jersey in Trenton, who collected the stories, says many local people have taboos against living near lakes and instead dwell on high ground. Scientists now know that gas buildup affects at least one other lake in the region, Lake Monoun, as well as giant Lake Kivu in east Africa, which has 2 million people living on its shores. The myths “helped tell us it happened before, and it will happen again,” says geochemist William Evans of USGS in Menlo Park, California, who is working to remove gas now rebuilding in Nyos and Monoun. Next year, the Geological Society of London will publish Geology and Myth, a collection of papers by Shanklin, Nunn, and others. Co-editor Luigi Piccardi, a structural geologist at the National Research Council of Italy, says he hopes it will lead colleagues to take the field more seriously. Among other work, Piccardi has studied a cataclysmic 493 C.E. appearance at southern Italy's Monte Sant'Angelo by the Archangel Michael, said to have left his footprint in the rocks—code, Piccardi says, for a big, previously unauthenticated earthquake. In the late 1990s, Piccardi found ample physical evidence for the event, including a dramatic fault scarp in the floor of the popular shrine to the apparition, long hidden until it was uncovered in archaeological excavations— the apparent “footprint.” In 2001, the National Institute of Geophysics and Volcanology in Rome upgraded the area to seismic high risk. This may also be an example of how geomyths are periodically reinvented in places where disasters reoccur: The shrine was previously an oracle and supposed entry to the underworld dedicated to the Greek seer Kalchas, who is mentioned in The Iliad. Piccardi's description of the shrine is in press at Tectonophysics. Piccardi is currently studying the possibility that many ancient sites of worship and miracles are over active faults, on the theory that past rumblings and cracking have been transmuted into visits by monsters and gods. One such example is the oracle at Delphi, Greece. Here, priestesses were said to enter prophetic trances by inhaling the breath of the god Apollo from a magical chasm; people came from around the ancient world to hear their words. While the oracle was indisputably real, classical scholars wrote off the chasm as an invention—until geologist Jelle de Boer of Wesleyan University in Middletown, Connecticut, and archaeologist John Hale of the University of Louisville in Kentucky published a series of papers on the oracle over the past few years. De Boer and Hale showed that the ruins of Delphi lie over the juncture of two faults that conduct up psychoactive hydrocarbon gases through a spring, exactly as described in ancient accounts. (Why some prophecies were uncannily accurate is another question.) This summer, de Boer and Hale visited the partially excavated ruins of the oracles of Apollo at Klaros and Didyma in southwest Turkey and detected hydrocarbon gases there too. From story to data The process of translating myth into geology, or vice versa, can be murky, but Elizabeth Barber, a professor of linguistics and archaeology at Occidental College in Los Angeles, California, believes it can be done scientifically. In the recent book When They Severed Earth From Sky: How the Human Mind Shapes Myth, she argues that transmutations of reality into myth take predictable courses, with natural forces often turned into supernatural beings (Science, 27 May, p. 1261). Some examples seem straightforward. A story from the Klamath people of Oregon about a battle between the chiefs of Above World and Below World is faithful in every geologic detail to the volcanic explosion of Mount Mazama and the formation of Crater Lake in its place, from the rain of burning ash and rock to many years of rainfall afterward that eventually filled in the crater—a process that started 7000 years ago. Other legends are more confusing. These include a hypothesis that the pillars of cloud and fire that guided the Hebrews from Egypt came from the 1625 B.C.E. volcanic eruption of Thera in the Mediterranean. Here, mismatches between dates of the events and problems with the Hebrews' route lead Barber to think the account is conflated from several real but distinct events. “The question is how often and in what cases you can take it back literally,” she said. Other researchers' hypotheses about events as widely varied as the destruction of Sodom and Gomorrah and the death of King Arthur (said by some to relate to a catastrophic comet impact) suffer similar problems of time and space. Efforts to connect myths with comet or meteorite impacts have met with skepticism. Repeated, undetected big impacts in human time “contradict everything we know about the rate of impacts on Earth, and the inventory of what's out there now, and their dynamics,” says David Morrison of NASA's Ames Research Center in Mountain View, California, head of the global Near Earth Object Working Group, which tracks celestial objects that might endanger Earth. The pendulum may have swung too far in favor of accepting myths, says social anthropologist Benny Peiser of Liverpool John Moores University in the U.K., who runs the Cambridge Conference Network, an Internet clearinghouse for catastrophist theories. Now that more people are willing to listen, he says, too many scientists are invoking myth “left, right, and center to explain everything.” In a paper at a late-October workshop on natural catastrophes in the ancient Mediterranean, he asserts that no major myths have yet met scientific standards, although he does credit some regional ones, such as the Pacific Northwest earthquakes. “That's not all bad,” he says. “This is all so new, you expect more speculation than hard evidence. The refinements can come later.” From his perspective as a storyteller, James Rasmussen, the record-store owner, also expresses reservations about how much myths can reveal. When he and Ludwin reached the spot where the a'yahos boulder was supposed to be, it was gone. In its place was a big wooden chair in front of someone's beach house. “Maybe it's been hauled away,” said Ludwin. “Maybe the tide buried it in the sand,” said Rasmussen. They poked around for a while among the foam cups, logs, and newspapers littering the beach and finally gave up. “Maybe some things show themselves for a while, and we get a little understanding,” said Rasmussen. “Then they go away again, and they don't want to be found.” 11. MOLECULAR BIOLOGY P-Bodies Mark the Spot for Controlling Protein Production 1. Jean Marx Serving as sites for RNA degradation and storage puts the tiny speckles at the heart of the cell's machinery for regulating protein synthesis In the past few months, tiny cellular structures with the unglamorous name P-bodies have captured cell biologists' attention. Mere specks in the cytoplasm, they have been shown to play key roles in regulating one of the cell's most important activities, protein synthesis. Efforts to understand how cells control the production of their many proteins have typically focused on the first step in the process: the reading of genes to create the messenger RNAs (mRNAs) that in turn direct the actual protein synthesis. Researchers had thought that once mRNAs had done their job, enzymes in the cytoplasm simply broke them down. About 2 years ago, however, several groups showed that much of this degradation occurs in P-bodies—or, as they are sometimes known, GW or Dcp bodies. Now, a flurry of results indicates that the particles are much more than just mRNA chop shops. They appear to play a more dynamic role, serving as routing stations that can temporarily store mRNAs before sending them out to be translated into the proteins that cells need. Still more recent evidence has linked P-bodies to another exploding area of biology, RNA interference (RNAi). In this phenomenon, which many companies are seeking to exploit to treat diseases, short segments of double-stranded RNA shut off gene expression by directing the destruction of the corresponding mRNAs. This RNA breakdown, which helps cells fight off viruses and genetic damage, may also take place in P-bodies. Given their apparently broad role in controlling mRNAs, it is perhaps not surprising that there are hints that P-bodies are involved in disease, including cancer and certain autoimmune conditions. As Paul Anderson of Harvard's Brigham and Women's Hospital in Boston, Massachusetts, points out, “regulation of mRNA translation is a very fundamental process with profound implications for cell metabolism.” P-body origins The path that led to the discovery of P-bodies began about 10 years ago when researchers were studying a key step in mRNA degradation. Before these messengers can be broken down, cells have to knock off a so-called cap, consisting of methylyated guanosine, attached to the mRNA's beginning end. In the late 1990s, Roy Parker's team at the University of Arizona in Tucson cloned the yeast genes for the decapping enzymes (Dcp 1 and -2) as well as the genes for several proteins that activate the enzymes. Several groups, including those of Bertrand Seraphin at the CNRS Center of Molecular Genetics in Gif sur Yvette, France, Michael Kiledjian at Rutgers University in Piscataway, New Jersey, and Jens Lykke-Andersen at the University of Colorado, Boulder, soon showed that mammalian cells make similar proteins. Examination of the distribution of the decapping enzymes and other proteins by these researchers and by Reinhardt Luhrmann and colleagues at the Max Planck Institute of Biophysical Chemistry in Gottingen, Germany, revealed that the proteins are concentrated in discrete foci—the P- or Dcp bodies—along with other enzymes involved in mRNA breakdown. This suggested that the particles could be a site of mRNA decapping and breakdown, a supposition confirmed by further experiments. For example, inhibiting the enzyme that degrades decapped mRNAs leads to accumulation of mRNA in P-bodies, which increase in size as a result. The demonstration that P-bodies are the cell's mRNA destruction sites has since led to a growing appreciation of their diverse roles in the cell. They may, for example, help cells protect themselves against certain stresses. Infection by viruses or exposure to insults such as heat causes cells to turn down their protein synthesis by sequestering their mRNAs in granules. Recent work by Anderson, Nancy Kedersha, also at Brigham and Women's, and their colleagues has shown that these stress granules and P-bodies come into contact with one another and carry some of the same mRNAs. Anderson speculates that the interaction may facilitate what he calls an “RNA triage,” with some being maintained in the stress granules while others are shuttled to P-bodies for destruction. A greater understanding of P-body function may also resolve a lingering mystery about RNA interference: Where does the mRNA degradation it elicits take place? About 6 months ago, George Sen and Helen Blau at Stanford University School of Medicine and Parker, working with Gregory Hannon at Cold Spring Harbor Laboratory on New York's Long Island, and colleagues found that the proteins Argonaut 1 and -2, which are key components of the RNAi machinery (known as RISC), concentrate in P-bodies, implicating the particles as the site of degradation. The work is also shedding light on a related phenomenon in which so-called microRNAs (miRNAs), which can be produced naturally by cells, repress the translation of mRNAs into proteins. Although this involves the RISC machinery, it apparently does not result in mRNA degradation. The Parker-Hannon team, as well as that of Witold Filipowicz at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland, found that mRNAs subject to miRNA repression accumulate in P-bodies in a manner dependent on miRNA function. This suggests that RISC proteins direct the mRNAs to the P-bodies, possibly for storage. Such an idea is consistent with other findings suggesting that the particles do not just degrade mRNAs but also temporarily sequester them away from the translation machinery. Parker and his colleagues reported online in Scienceon 1 September that mRNAs can move out of P-bodies and move to the polysomes, where protein synthesis occurs. Parker says he noticed early on that P-bodies resemble the granules that store the maternal mRNAs that function in very early embryo development. “Even in 2003, we speculated that they [P-bodies] are not just dead ends,” he says. The storage of mRNAs in P-bodies could help regulate embryonic development. In the 19 August issue of Molecular Cell, Min Han and his colleagues at the University of Colorado, Boulder, report that a worm developmental control gene encodes a protein that localizes to P-bodies and interacts with the same Argonaut molecules involved in regulation by miRNAs. The structures may even play a direct role in regulating protein synthesis. Working with yeast, Parker and Jeff Coller, also at Arizona, have shown that cells lacking two P-body proteins (Dhh1p and Pat1) can no longer turn off protein translation in conditions in which it would normally be repressed. P-body concentrations declined dramatically in those cells, the researchers reported in the 23 September issue of Cell. Conversely, translation was repressed in cells engineered to have an overabundance of the two proteins—to the point where the cells could no longer grow. These cells had huge P-bodies. Parker proposes that there is a balance in the cell between two competing events: translation at the polysomes and P-body formation. The question for the cell, he says, is “can I assemble an initiation complex [for protein synthesis] before the mRNA is dragged off to P-bodies?” Possible connections between P-bodies and disease are beginning to emerge. One came in 2002 from a team including Marvin Fritzler of the University of Calgary in Canada and Edward Chan of the University of Florida, Gainesville, who chanced upon the particles while studying a patient suffering from an autoimmune form of nerve degeneration. Using antibodies prepared from the patient's blood serum, the researchers identified a protein they called GW182 and showed that it localizes to speckles in the cell cytoplasm. The speckles turned out not to be any of the cell's known particulate structures, Fritzler says, so the researchers dubbed them GW bodies. But the work on P-bodies, which was emerging at the time, caught the attention of Fritzler and Chan, and they joined forces with Seraphin to show that the two cellular bodies were in fact identical. In addition, Seraphin and his colleagues have found that human P-bodies contain a protein called RCK that may help drive cancer development. Researchers have found that its concentration, along with the number of P-bodies, is elevated in various cancers, including breast cancer. A disease link for P-bodies is “a possibility we can't ignore,” Chan says, “but further work is necessary to pin it down.” 12. CANCER BIOLOGY A New Cancer Player Takes the Stage 1. Jennifer Couzin MicroRNAs are being implicated in various human cancers, and scientists are trying to sort out just how culpable they are For Frank Slack, the story began when his worms exploded through their vulvas. It was 1997, and the developmental biologist, now at Yale, had been tinkering with microRNAs (miRNAs), tiny RNA molecules that regulate gene expression. Slack is a worm man, and in his wriggly subjects he had deleted the gene for just one of the 120 known worm miRNAs. The developing animals' stem cells failed to morph into specialized cells as they normally do and instead kept dividing. “The worms looked extended, weirdly floppy; they kind of looked uncoordinated,” he says. The vulvas didn't develop properly and ruptured. A worm skeleton is under hydrostatic pressure, and with the rupture, “the animals burst through,” an experience that killed roughly half of them. When Slack probed the underlying genetics, he uncovered something tantalizing that linked these unfortunate animals to human biology. Deletion of this miRNA, called let-7, prompted overexpression of a gene, Ras, that's strongly associated with many cancers. In other words, when let-7 is expressed normally, it seemed, it blunts Ras. Since Slack's find, the let-7-Ras story has unfolded rapidly, one of a growing bundle of strands tying miRNAs to cancer. More than a dozen papers have shown that miRNAs are expressed differently in cancerous tissue. Braided together, the latest miRNA discoveries suggest potentially vast roles for the tiny molecules in malignancy; they have also sparked spirited debate over whether miRNAs are driving cancer or are simply a marker of it. Either way, the nascent field could eventually assist doctors in diagnosis, prognosis, and possibly treatment. Last week, a paper in the New England Journal of Medicine (NEJM) reported that 13 miRNAs form a signature associated with prognosis and disease progression in patients with chronic lymphocytic leukemia (CLL), a cancer of blood. “There is a whole other world out there, which I don't think we know anything about,” says Phillip Sharp of the Massachusetts Institute of Technology (MIT) in Cambridge, who has studied small RNA molecules for years and is examining their influence on tumors. Cancer connections With rare exceptions, it's far from clear which genes the miRNAs are targeting, how many miRNAs are involved in cancer—and how they're involved—and what governs miRNA behavior. Uncertainties aside, however, Sharp and others are not surprised that miRNAs are being implicated. Many of the dozen or so animal miRNAs of known function play a big role in early development. In fruit flies, some miRNAs govern apoptosis, or cell death; in worms, as Slack witnessed to dramatic effect, they control cell differentiation. Both processes, like many others in development, are critical components of tumor formation and spread. “There were these clues,” says Joshua Mendell, a geneticist and molecular biologist at Johns Hopkins University in Baltimore, Maryland, who set up his own lab last year and began exploring the miRNA-cancer connection. Mendell chose to focus on a proto-oncogene called c-Myc; proto-oncogenes (Ras is another) are often highly expressed in cancerous tissue and implicated in initiating malignancy. “Even though Myc has been studied for several decades, [it's] still not fully understood how it causes tumors,” says Mendell. Examining a human cell line in which c-Myc expression could be manipulated, Mendell and his colleagues found that when expressed, c-Myc activates a cluster of six miRNAs. More important, another gene that's both a target of c-Myc and drives cell division damps down its expression when two miRNAs in Mendell's cluster are active. That suggested that this miRNA pair could control the balance of cell death and proliferation driven by c-Myc. While Mendell and his team were sifting through their cell samples, a cell biologist at the University of North Carolina, Chapel Hill, was studying how miRNAs might drive lymphoma. Unaware of Mendell's findings, Scott Hammond hit on seven relevant miRNAs in human cancer cells; the cluster was nearly identical to Mendell's list. “We both kind of came to the same group of miRNAs,” says Hammond. But Hammond recognized a problem. Cancerous cells contain abundant abnormalities, many a result of cancer rather than a cause. Hammond didn't know into which category his miRNAs, which were strikingly overabundant in cancer tissue compared with normal tissue, fell. Teaming up with Greg Hannon at Cold Spring Harbor Laboratory in New York, the pair and colleagues forced overexpression of six of the miRNAs together in 14 mice predisposed to a form of lymphoma. Cancer accelerated dramatically. After 100 days, all the treated mice had cancer, compared with about a quarter of controls. The work is “precedent setting,” says Sharp, one of the first times miRNAs have been shown to spark cancer. If other miRNAs are found to target either proto-oncogenes, which can trigger cancer, or tumor suppressors, which squelch it, that would further incriminate them. Hammond and Hannon's work appeared in Nature this past June, along with the studies from Mendell's lab and from Todd Golub of Harvard Medical School and the Dana-Farber Cancer Institute in Boston and his colleagues. Golub's research used expression of miRNAs to classify different types of tumors. But the Hammond-Hannon work remains the exception; nearly all the research implicating miRNAs in cancer does so indirectly. One of the only other studies showing potential causality comes from Carlo Croce of Ohio State University in Columbus, the first cancer geneticist to publish on miRNAs. In September, Croce reported that in patients with CLL, the loss of two miRNAs boosts expression of a gene promoting cell survival. The gene is believed to help drive the leukemia in its earliest stages. Without the miRNAs that mediate it, leukemia can set in. Elusive quarry In retrospect, says Harvard RNA expert Gary Ruvkun, given the broad roles being assigned to miRNAs in cancer, it's amazing that cancer geneticists so thoroughly missed miRNAs. “I just find it hard to believe that the cancer people were that lame,” says Ruvkun, who is just now starting to back a miRNA-cancer connection. “We share a collective guilt as a community,” agrees René Bernards, a cancer geneticist at the Netherlands Cancer Institute in Amsterdam who is not studying miRNAs. With a laugh, he recalls his graduate school days, when he tossed “anything small, degraded, uninteresting” in the trash. At the time, miRNAs fell squarely in that category. Furthermore, miRNAs are generated by genes that don't produce proteins—long derided as “junk” DNA. Indeed, Croce, now a consummate miRNA fan, admits being dragged into the field unwittingly. Ten years ago, he grew convinced that a CLL tumor-suppressor gene was nestled in a certain stretch of DNA—but he couldn't spot it. Baffled and stubbornly determined, Croce turned to colleagues in the CLL field, who handed over additional leukemia samples to scour. Only when Croce stopped looking for a coding gene 3 years ago did he settle on the two miRNA genes he's been studying ever since. With the outlines of a miRNA-cancer connection taking shape, researchers are now beginning to tackle some of the toughest questions. Perhaps the most vexing involves finding miRNA targets. Like other types of small RNA molecules, miRNAs influence genes with a similar sequence—but the match need not be exact, making the targets maddeningly hard to pin down. No experiment “can hand you a target on a silver plate,” says Nikolaus Rajewsky, a biologist and mathematician at New York University. These days, says Rajewsky, the best target-finding melds two tactics. The more traditional compares putative miRNA targets in mammals with known targets for the same miRNA in other species. The other calls for over- or underexpressing a miRNA, then running microarray studies to spot affected genes. But “the computational approaches are still evolving; the experimental approaches are labor-intensive,” says Victor Ambros, a geneticist at Dartmouth Medical School in Hanover, New Hampshire. “What we're not sure about is how many targets we're missing.” Several labs are conducting massive miRNA knockout studies to delineate the targets and functions of individual miRNAs. At the University of California, San Francisco, RNA biologist Michael McManus is leading a six-person mouse miRNA consortium; it plans to delete each of the 350 known miRNAs in mice, one at a time. But in cancer especially, biologists warn, painting a comprehensive miRNA picture will likely be exceedingly complex. When miRNAs “get overexpressed or underexpressed or deleted, lots of things can happen,” says Tyler Jacks, director of MIT's Center for Cancer Research. “And trying to figure out exactly which of those things is contributing to tumorigenesis or prognosis or what have you” calls for “a lot of detective work.” Nor is it clear what prompts miRNAs to misbehave in the first place. “We'd really like to know,” says Slack, who theorizes that mutations in miRNAs could be at fault, as could defects in transcription factors, proteins that control gene expression. Croce has found two leukemia patients born with the miRNA mutations implicated in CLL. Looking ahead Given all the unknowns, miRNAs are a long way from the clinic. But some drug companies are dabbling in them nonetheless. Jan Weiler, a chemist at Novartis in Basel, Switzerland, has been studying the role of miRNAs in disease for 2 years. (In addition to cancer, the molecules are tentatively linked to neurological disorders and diabetes.) “It's a lot of speculation, a lot of hope,” says Weiler, who envisions perhaps delivering miRNAs to patients lacking them. “If we don't look at it now, we're probably too late,” he says, while acknowledging the risk that “maybe … in 3 years' time, the whole thing is dropped.” If therapeutics remain distant, diagnostics are closer to reality. Croce co-authored last week's NEJM paper that reported on a 13-miRNA signature in CLL. His group also found that among 94 CLL patients, many of those lacking Croce's original two miRNAs have a milder form of CLL, whereas most with the two functioning miRNAs suffer a more aggressive form. “It looks like CLL is not one disease but two,” he says, and the distinction could be useful in diagnosing and treating the leukemia. Other cancers, too, are being eyed as harboring miRNA culprits. One of the very first miRNAs tied to cancer—let-7 with its exploding worms—was last year found to be lacking in lung cancer tissue taken from patients in Japan. Those with the lowest levels fared the worst—suggesting once again that flawed miRNA expression bodes poorly for one's health. 13. SYNTHETIC BIOLOGY Synthetic Biology Remakes Small Genomes 1. Elizabeth Pennisi Researchers are taking the first steps toward realizing the goal of building chromosomes by wholesale remodeling of organisms' genomes HILTON HEAD, SOUTH CAROLINA—People just can't leave nature alone. They have long stopped mighty rivers with dams, they are now breeding seedless watermelons, and they soon hope to customize microbes. Researchers from civil engineers to molecular biologists are developing ways to mold genomes like a potter does clay. These efforts to remake bacterial and viral DNA go far beyond adding or deleting a gene or two. Scientists are reducing, stretching, and recreating chromosomes as they lay the foundation for the emerging field of synthetic biology. “What we are most excited about are useful things we can make by messing around with the whole genome,” says George Church, a technologist at Harvard University in Cambridge, Massachusetts. Through their genome manipulations, synthetic biologists expect to learn more about how microorganisms function and also harness them to make complex proteins, get rid of toxic wastes, or carry out tasks not yet envisioned. Some of this new field's progress was on display at a genome meeting last month.* “You sensed a lot of excitement and stirring,” says Ari Patrinos, chief of genome research at the U.S. Department of Energy. “It reminds me of the very early days of the Human Genome Project.” At this point, however, the field is more talk than reality, says J. Craig Venter, president of the J. Craig Venter Institute in Rockville, Maryland. “There's not a lot of data yet.” It's difficult to separate the hype about synthetic biology from the hard results, agrees Patrinos. “This is the frontier” of biology, he notes. Some of the hard results discussed at the meeting came from geneticist Frederick Blattner of the University of Wisconsin, Madison, who has gradually been shrinking the genome of Escherichia coli. The altered bacterium hardly notices, and it may offer advantages for genetic engineering, he reported. Blattner began trimming the microbe's genome after sequencing various E. coli strains. He found that although the strains had 3.7 million bases in common, each also had about another million bases—cordoned off in specific “islands” of DNA—unique to each strain. His group has been deleting these genetic islands and other bits of DNA one by one, checking that the bacteria survive despite each loss. They perform these excisions using the natural process of homologous recombination. For example, they introduce into bacteria a stretch of DNA containing the sequences on either side of an island. A small number of the microbes will then swap out their similar stretch of DNA for the synthetic island-free version. The process is “scarless,” as no extra DNA is left behind. So far, the group has made 43 such deletions, whittling the core E. coli genome to less than 4 million bases and 3500 genes. That's far fewer than the 4444 genes now known to exist in the E. coli sequence. The researchers plan to trim even more, cutting another 30 islands. “By then, we think we will have removed most of the nonessential material,” Blattner said. With its lean bacterial chromosome, the streamlined E. coli strain created by Blattner's group is 10 times better at absorbing new genes than one of the strains commonly used in genetic engineering. Now, “he can take this reduced genome and begin to add in [genes for] important industrial or pharmaceutical pathways,” says Hamilton Smith, a molecular biologist at the Venter Institute. Moreover, notes Blattner, his new strain should be more resistant to certain undesirable genetic changes because it lacks the DNA islands, which tend to hop around the genome creating mutations. Pump up the genome In contrast to those who would shrink microbial chromosomes, Drew Endy of the Massachusetts Institute of Technology (MIT) in Cambridge has been expanding one. A civil engineer, Endy is one of the most visible—and controversial—spokespersons for the synthetic biology field. He runs a yearly contest in synthetic biology that has grown beyond MIT to include international teams (Science, 9 January 2004, p. 158). One of the most innovative entries thus far has been a bacterial camera, in which researchers endowed bacteria with genes for light-sensing proteins and other components for generating an image on culture media. On his lab's synthetic biology Web site, Endy has set up a virtual bulletin board of research ideas, results, and protocols in the field; it draws 15,000 visitors a day. Some of his peers privately complain that Endy is a larger-than-life self-promoter—he's got his own synthetic biology company, gives scores of talks worldwide each year, and has helped create an upcoming comic strip with a main character called Device Dude who is a synthetic biologist. Others argue that he's driving the field forward. “He's injecting a lot of rigor in a field that is still somewhat soft,” says Patrinos. At the meeting, Endy described his lab's unusual work on T7, a virus that infects bacteria. He had been bothered by genes in T7's genome that were embedded or partially embedded in other genes and therefore shared some of the same DNA, as they complicated his ability to predict how infection and the resulting incorporation of viral DNA into the host genome are affected by different host environments. His model treated all the genes as separate entities and didn't take into consideration what happens if genes overlap. So he and his colleagues pulled apart T7's overlapping genes by inserting an extra copy of the overlap next to the original such that both genes, now separated, still had their full complement of bases. Worried that they might kill the virus as they pumped up its chromosome, he and his colleagues only added 600 bases to its 40,000-base genome in this initial round of experiments, hoping that removing the overlaps didn't disrupt the genes' regulation or impair their function. The engineered virus was still able to invade bacteria and replicate, according to Endy. “We've demonstrated it's possible to redesign a genome” beyond adding individual genes, he says. Now, he and his colleagues are adding more bases to the T7 genome, testing the limits of this expansion technique. Making genomes bigger or smaller is just a tiny step in realizing the true potential of synthetic biology. The field needs to move forward on many fronts, says Venter. Synthesizing new chromosomes from scratch, for example, remains a challenge. In one effort in that direction, Smith and his colleagues have for the past few years been knocking out individual genes in Mycoplasma genitalium, which has the smallest known genome of a free-living organism (Science, 14 February 2003, p. 1006). So far, they've identified about 100 genes, out of nearly 500, that M. genitalium can live without. Their eventual goal is to identify the microbe's essential sequences and then see if they can synthesize and assemble just those sequences and use them to create a living organism by inserting the human-made chromosome into a cell. Among the many details to be worked out, says Smith, is how to piece together relatively huge sections of DNA. Ideas include using live cells to put together chunks of DNA into a whole mycoplasma chromosome or putting an efficient DNA repair system—such as seen in bacteria resistant to radiation damage—into a test tube to accomplish this task. Then his team must determine how to stick this DNA into a cell and remove the native DNA, without affecting the cell's ability to function. Ethical and environmental concerns must also be dealt with before synthetic biology fully matures as a field. MIT, the Venter Institute, and the Center for Strategic and International Studies in Washington, D.C., have teamed up to examine issues such as how to keep any new life forms created under control. This effort is funded by a570,000, 15-month grant from the Alfred P. Sloan Foundation. Some researchers are already exploring strategies to incorporate safeguards. For example, Church and Endy are developing ways to keep synthetic genes from escaping and possibly wreaking havoc. One solution: Alter synthetic genetic codes such that they are incompatible with natural ones because there is a mismatch in the gene's coding for amino acids.

A final issue confronting synthetic biology is cost. The bigger the DNA piece synthesized, the less accurate the sequence and the more expensive it is to get it right. But new technologies are rapidly coming on line, note researchers. “The cost of accurate DNA synthesis and sequencing is plummeting, and as it does, we will see a quantum shift in what people dream of and do,” says Church.

• *Genomes, Medicine, and the Environment 2005, 16–19 October, Hilton Head, South Carolina.

14. EDUCATION

Forging a Cosmic Connection Between Students and Science

By deploying cosmic-ray detectors at high schools, physicists hope to inspire students and score real scientific discoveries to boot

Twelfth-grader Treasure Sheppard has aspired to become an aerospace engineer since she was 7 years old. But nothing fired the bright and bubbly 17-year-old's passion for science and technology quite like a weeklong visit to the California Institute of Technology (Caltech) in Pasadena, where she and a classmate assembled a detector to snare cosmic rays—subatomic particles zooming in from space. “I was expecting a few lectures” from Caltech physicists, says Sheppard, who attends nearby South Pasadena High School. “But when we got there, they handed us a piece of paper and said, 'These are the instructions.' They had confidence that we could complete the task.”

That detector is now part of the California High School Cosmic Ray Observatory (CHICOS), an array of detectors stretching across the roofs of 70 high schools and middle schools in metropolitan Los Angeles. Unlike typical high-school science projects, CHICOS aims to do cutting-edge research by probing the nature of cosmic rays. That prospect thrills Sheppard, who last year tended the two detectors on her school's roof. “CHICOS gave me an opportunity to participate in research,” she says, “which some college students can only dream of.”

CHICOS is one of several arrays that have sprouted up across North America and Europe. Using salvaged parts, a little newfangled electronic gadgetry, and student labor, particle physicists are outfitting schools from rural Nebraska to downtown Amsterdam with simple, inexpensive cosmic ray detectors. At least six sizable arrays are up and running, and as many more are in the planning. Physicists aim to stimulate teachers and students by bringing real science into the classroom. At the same time, they hope to grab scientific glory on the cheap by discovering phenomena that more-expensive research arrays might miss.

Cosmic rays enable educators to bring science to the students instead of busing the students to visit some distant lab, says Gregory Snow, a physicist at the University of Nebraska, Lincoln, and leader of the Cosmic Ray Observatory Project (CROP), an array with detectors at 26 schools across the state. “Cosmic rays are going through every high school in the world all the time,” he says. “That allows you to get people involved in research right where they live and go to school.” The National Science Foundation has funded several of the arrays, and the primary goal of the projects is education, says Randal Ruchti, a program officer in experimental particle physics at the foundation. Still, he says, it's possible that “a student could participate in a revolutionary discovery.”

To fulfill both their educational and scientific missions, however, the projects must balance the students' need to tinker with the detectors against researchers' need to keep machinery running full-time. And there's no science that can tell physicists how to strike the proper balance.

Finding a niche

Every second, hundreds of cosmic rays pepper every square meter of Earth. If a ray has enough energy when it crashes into the atmosphere, it produces a cascade of particles known as an “extensive air shower.” For decades, physicists have studied air showers with detectors arrayed on the ground, using the size and the timing of the signals from the individual detectors to estimate the energy and direction of the cosmic ray.

Since the 1990s, physicists have known that a very few cosmic rays crash into the atmosphere packing as much energy as a large hailstone. No one knows how an individual subatomic particle obtains such tremendous energy or precisely how often one strikes. Professional cosmic ray arrays—most notably the Pierre Auger Observatory, an array of 1600 detectors stretching over 3000 square kilometers currently under construction in Argentina—focus on those questions.

But some physicists hope to build arrays on the cheap by placing detectors on the roofs and grounds of schools—and more than one claims to have had the idea first. The detectors typically consist of sheets of plastic “scintillator,” which emit light when penetrated by charged particles. Often, as is the case with CROP and CHICOS, the scintillators are left over from decommissioned professional arrays. For a few thousand dollars, researchers outfit a school with its own miniarray of a few detectors, a Global Positioning System station to tell precisely where each detector is and when it registers a hit, and a computer to collect data and ship it to the researchers via the Internet.

The arrays differ in essential details. For example, the schools in CHICOS are as little as a kilometer apart, so several may register hits from a single large shower. Schools in CROP are separated by hundreds of kilometers, so even a big shower will likely strike only one. Some arrays are more polished and professional than others. For example, physicists build the detectors for the Alberta Large Area Time Coincidence Array (ALTA), which is run by the University of Alberta in Edmonton and has detectors at 15 schools. In contrast, high-school students cobble together the detectors for the Washington Large Area Time Coincidence Array (WALTA), which is run by the University of Washington, Seattle, and has detectors at 11 schools. “Ours is more of a roll-your-own approach,” says Jeffrey Wilkes, a particle physicist at the university.

High-school arrays cannot compete toe-totoe with Auger, says Mark Pearce, a particle physicist at the Royal Institute of Technology in Stockholm, Sweden, and leader of the Stockholm Educational Air Shower Array, an array of detectors at the institute and four secondary schools around the city. But “there are theories that the professional arrays are not designed to test, and certain interesting, welldefined questions that these school arrays might be able to answer,” he says. For example, with schools spread over even larger areas, the arrays might test whether cosmic rays arrive in widespread bursts instead of completely at random. That could happen if an iron nucleus from space collided with a photon from the sun and splintered into pieces.

Some researchers hope to carve out a niche by literally looking where Auger cannot. Auger observes only the southern sky, which may differ from the northern sky when viewed in cosmic rays, notes Robert McKeown, a particle physicist at Caltech and leader of CHICOS. “We are the largest array in the Northern Hemisphere,” he says, “and if an unusual event occurs in the Northern Hemisphere, we may be able to see it.”

Others hope to use high-school arrays to develop new detection techniques. Physicist Helio Takai and colleagues at Brookhaven National Laboratory in Upton, New York, plan to use a high-school array on Long Island to test an antenna that detects radio waves reflected by the charged particles in an air shower. They've dubbed their project Mixed Apparatus for Radio Investigation of Atmospheric Cosmic Rays of High Ionization, or MARIACHI. By comparing readings from the array with those of the antenna, Takai and colleagues hope to show that the low-cost radio technique is effective.

Regardless of their specific scientific goals, all the arrays hope to spark students' interest in science. And some students say that the projects have succeeded handsomely. Mark Jeroncic participated in ALTA while he was a student at Edmonton's Holy Trinity High School. Using data collected with his school's detectors, he found a correlation between the rate of cosmic rays and ozone levels in the city. Now in his second year at the University of Alberta, Jeroncic says his experience with ALTA led him to major in physics.

Most physicists recognize that reaping a rich data harvest may conflict with giving students a chance to take the detectors apart and fiddle with them to see how they work. And they disagree about which aspect projects should emphasize. “We think that the real thrill for the students is to be part of a research project, so we've always strived to make this a professional array,” says James Pinfold, a physicist at the University of Alberta and leader of ALTA. To that end, ALTA researchers build and install the hardware. “We give the students the data to play with rather than the detector,” Pinfold says. ALTA physicists give students smaller scintillator detectors to use in classroom experiments.

But students may feel little connection to the main array if they never get to touch it, says Charles Timmermans, a particle physicist at Raboud University in Nijmegen, Netherlands. Timmermans heads the High-School Project on Astrophysics Research With Cosmics (HiSPARC), an array with 35 miniarrays at schools in Nijmegen, Amsterdam, and other cities. “Small detectors are nice, but you have to give students the feeling that the array on the roof is theirs,” he says. “If you don't give them a chance to work and play with it, I think that after the first generation of students, that feeling will fade pretty fast.” Timmermans favors designating a week each year to let students rebuild the detectors.

Ultimately, it may be hard to predict what will inspire any individual student. Loran de Vries, who attended the Amsterdams Lyceum and participated in HiSPARC, says he was most impressed by the inability of physicists to answer basic questions about the origins of high-energy cosmic rays. “I saw with my own eyes that in this subject, most of these things are not known, and I found that fascinating,” says De Vries, currently a second-year student at the University of Amsterdam. Thanks in part to his experience with HiSPARC, De Vries wants to become a high-school physics teacher. Perhaps when the time comes, he'll be able to answer those questions for his own students.

15. Friendly Faces and Unusual Minds

1. Yudhijit Bhattacharjee

Working with a rare set of individuals who have Williams-Beuren syndrome but still show normal intelligence, scientists are trying to tease out what happens in this neurodevelopmental disorder—and shed light on the brain's normal function

To outsiders, a Williams-Beuren Syndrome (WS) convention can seem like a large family reunion. The 200 or so affected individuals who gather for the 3-day biannual event look similar to one another in many ways, although they are not related. Their upturned noses, wide mouths, and small chins give them an elflike appearance—the reason this rare genetic condition, found in 1 out of 7500 people, is also called elfin face syndrome. What's perhaps most striking is the conventioneers' lack of social inhibition. “You walk into the hotel lobby, and they surround you and start talking to you even though you are a perfect stranger,” says Karen Berman, a psychiatrist at the National Institute of Mental Health (NIMH) in Bethesda, Maryland.

This excessive friendliness is just one indication that the brains of people with WS work a bit differently from typical brains. In another odd example, WS individuals are incapable of putting together the simplest of puzzles, owing to their inability to visualize an object as a set of parts. That impairment, known as the visuospatial construction deficit, also makes it difficult for them to judge distances and to negotiate stairs. More broadly, even though most people with WS have little difficulty using language and in some cases have notable musical talent, general intelligence tests usually show them to be mentally retarded.

The uniform and well-defined cognitive features shared by those with WS have convinced some researchers that the disorder offers a window into the genetic basis of the human mind. Since the discovery in the early 1990s that the syndrome is caused by the deletion of a tiny section of one copy of chromosome 7, researchers have attempted to identify the roles that the different genes within that section play in the development and functioning of the brain. The broader goal of these efforts has been to learn how cognitive and behavioral features arise from specific genetic traits and their interplay with the environment.

These efforts are beginning to pay off. Researchers have drawn links between the genes absent in WS, structural and functional abnormalities in certain brain regions, and cognitive deficits that are the hallmarks of the disorder. Some of the gene-brain-behavior links have subsequently been confirmed in mouse models, and scientists have uncovered neurodevelopmental pathways that are disrupted by the deletion of WS genes. Taken together, these findings “have been invaluable in understanding how relatively subtle developmental defects can have a significant impact on neurological function,” says Dennis O'Leary, a neurobiologist at the Salk Institute for Biological Studies in San Diego, California. The work, he adds, opens the door to explaining how genes work through the brain to make us who we are.

The neural connection

Although other physicians may have come across earlier cases of the disorder, British physician J. Williams was the first to identify it in a 1961 paper that described children with a unique set of facial, cognitive, and heart defects. A second research group, led by German cardiologst Alois J. Beuren, independently identified the syndrome the following year, adding excessively social behavior to its list of characteristics.

As a step toward understanding how genes contribute to the cognitive profile in WS, researchers have sought to determine the neural mechanisms that underlie signature traits of the illness. One challenge they have faced is the mental retardation of most people with WS, which makes it difficult to perform many experimental tasks testing cognition. Karen Berman, along with NIMH neurologist Andreas Meyer-Lindenberg, psychologist Carolyn Mervis of the University of Louisville, Kentucky, and others, got around that hurdle by assembling from around the world 13 volunteers with WS who had both the chromosomal deletion and the cognitive deficits characteristic of the syndrome but showed normal overall intelligence.

In one set of experiments, the researchers had the volunteers perform two tasks aimed at elucidating the visuospatial construction deficit. In the first, they asked the individuals whether two pieces of a puzzle presented on a computer screen could fit together to form a square. In the second, volunteers had to determine whether images presented one after the other were located at the same height on the screen. Comparing the functional magnetic resonance images (fMRI) of the WS group with those of healthy controls, the researchers found that the WS individuals showed significantly lower neuronal activity in a part of the brain used by the spatial processing pathway of the visual system. In contrast, the people with WS showed normal brain activity along the neural pathway responsible for identifying objects, which may explain why they seem to have little difficulty in recognizing faces or other visual material.

Using MRI scans to examine structural details of WS-affected brains, the researchers found an abnormally low density of nerve tissue adjacent to areas where activation was weak during the two tasks, suggesting that this region was not contributing its fair share of input to the spatial processing stream. This anatomical flaw—in the fold separating the parietal and occipital lobes (parietooccipital sulcus)—was a likely basis for the visuo- spatial construction problem in WS patients, Berman and her colleagues concluded last year in a report in Neuron. The researchers have now followed up by analyzing the geometry of the fold; they reported in the 24 August Journal of Neuroscience that it was significantly shallower in the WS volunteers than in controls. And in the 1 July Journal of Clinical Investigation, the group reported other studies on the same set of patients that revealed structural and functional abnormalities in the hippocampal region, which offers a possible explanation for long-term memory impairments and other cognitive deficits in WS.

To some WS researchers, the normal intelligence of the volunteers in the NIMH-led studies presents a problem. “What's vexing is that their IQ makes them unrepresentative of the general population of WS patients, and yet that very feature makes them good experimental subjects,” says Allan Reiss, a psychiatrist at the Stanford University School of Medicine.

Meyer-Lindenberg rejects such skepticism. The WS people his team recruited showed the same visual deficits as mentally retarded WS patients, which means they were not able to circumvent their defective neural mechanisms while performing the assigned tasks. “If we'd had a negative finding—that is, if the volunteers had performed as well as the controls, we could have suspected that their intelligence was helping them to somehow compensate for their handicap. But to find eye-popping abnormalities and still ascribe that to the IQ difference between them and the general WS population, we'd have to make up some very convoluted reasoning,” he says.

Despite this disagreement, Reiss and his colleagues have come up with some of the same results. In one experiment, Reiss's team compared brain scans of 43 WS individuals with characteristically low IQs to those of 40 healthy subjects and found low densities of nerve tissue in certain regions along the spatial processing pathway. In another study, the researchers looked at fMRI scans of 11 patients who were asked to determine whether faces presented on a computer screen were gazing at or away from them. (This was a simpler task than the ones used by Berman's group.) Not only were the people with WS slower in their responses than controls, but they also showed significantly less activity in their primary and secondary visual cortices while performing the task, Reiss and his colleagues reported in Neurology last year.

A faulty template

Pinpointing the neural underpinnings of cognitive deficits in WS is only one piece of the puzzle. Another is linking genes to those anatomical and functional defects. Even though the chromosomal deletion in WS encompasses just 28 known genes—a very small number given that thousands of genes are involved in brain development—isolating their specific contributions to the cognitive aspects of the disorder is a complex problem. “These genes could be interacting among themselves and with other genes in a ridiculous number of ways,” says Julia Korenberg, a molecular geneticist at the Cedars Sinai Health System in Los Angeles, California.

Researchers have attempted to narrow the list by studying a few people who have shorter deletions on chromosome 7 than is seen in individuals with WS and yet show some of the same cognitive characteristics. For example, in a study published online by Science this week (www.sciencemag.org/cgi/content/abstract/1116142), a British-American team led by May Tassabehji, a medical geneticist at the University of Manchester, U.K., adds to the evidence that a gene called GTF2IRD1 plays a role in the visuospatial deficit. The researchers identified a 4.5-year-old girl with a chromosome 7 deletion that included this gene but excluded many of the other candidates. The report centers on how the gene's loss may explain the girl's WS-like facial features, but the researchers note that she also has serious problems with spatial navigation

In some of the earliest work using this partial-deletion strategy, reported in 1996, Mervis and geneticist Colleen Morris of the University of Nevada, Las Vegas, identified a gene called LIM kinase 1 as a strong candidate to explain the visuospatial construction deficit. (The group also used the technique to identify a gene that codes for elastin as a contributor to the vascular and heart defects in WS.) But the LIM kinase 1 story is confusing: Researchers have identified individuals missing one copy of the gene who show none of the WS cognitive defects.

Studies in recent years have implicated other genes within the cluster of 21 for the visual deficit, two prominent ones being GTF2IRD1 and Gtf2i, both identified by Korenberg in collaboration with the Salk Institute's Ursula Bellugi and others. Findings from other partial-deletion cases have thrown two more genes to the mix: frizzled 9 and cycln2.

Mouse models are helping sort out the roles of the different candidates. In work reported in Neuron 3 years ago, for example, Zhengping Jia of the University of Toronto in Canada and his colleagues knocked out the LIM kinase 1 gene in mice and demonstrated that the animals had poor synaptic function and memory. Neurons in these mice had inadequate dendritic spines, the protruding tendrils on the surface of a nerve cell that help form excitatory synapses.

And in experiments described in the June issue of Development, clinical neurologist Samuel Pleasure of the University of California, San Francisco, and his colleagues found that mice lacking one or both copies of the frizzled 9 gene ended up with fewer-than-normal neurons in their hippo-campus, due to a surge in programmed cell death in that region. The gene defect significantly hampered the animals' spatial learning abilities.

Brain autopsies of WS patients are also shedding light on the disorder's visual problem. Surveying the molecular landscape of one such brain, Harvard neurologist Albert Galaburda and his colleagues found an abnormally low expression of Gtf2i in the peripheral visual cortex and superior parietal regions. In earlier WS autopsies, the same group had discovered that the neurons in the dorsal parietal cortex—a part of the spatial processing system—were larger and stubbier than normal, suggesting that they had not been patterned correctly during the brain's development. “It's possible that Gtf2i lies in the pathway of certain dorsal patterning genes, and its low expression is selectively detrimental to neuronal development in the dorsal parietal cortex,” speculates Galaburda, whose group presented the work at the Society for Neuroscience meeting last year.

So which of these half-dozen genes actually underlies the syndrome's visuospatial construction deficit? “I don't think anybody would want to get into a contest about whose gene is more important,” says Pleasure. “The likely scenario is that multiple genes are responsible. This may be a more well-defined syndrome than other genetic disorders, but it's still quite complicated.”

Afraid of none

A video clip running on Berman's desktop computer provides a vivid illustration of the excessively social nature of people with WS. The video shows an 18-month-old girl with the disorder interacting with a normal 5-year-old boy who's sitting on the floor. She walks up to within a few inches of him and peers into his face with great intensity. When the boy starts to get uncomfortable after a few seconds and turns his head, she shifts position to continue staring at him from up close. Even after he stands up and begins bouncing a basketball on the floor, she doesn't relent.

Despite such social fearlessness, WS patients typically display high levels of nonsocial anxiety, such as fear of heights. Berman and her colleagues have sought to tease apart the neural basis of this paradoxical behavior by asking their normal-IQ WS volunteers to perform two tasks. In the first, the researchers presented them with an image of a face showing anger or fear and, a few seconds later, two other faces simultaneously. They were then asked to pick which of the latter faces bore the same emotion as the first. The second task required a similar kind of matching—only, instead of faces, the images presented on the computer were of fear-provoking scenes such as a boat sinking or a house burning. As a control task, the volunteers had to match one of two geometrical shapes to a shape shown earlier.

Comparing fMRI scans taken during these tasks, the researchers found significant differences between the WS group and a control group in the activation of the amygdala, a brain region known to regulate people's fear response. For the task involving threatening faces, the amygdala in the WS individuals was much less active. In contrast, while performing the second task, using scenes rather than faces, these volunteers showed higher amygdala activation than did the controls. The researchers also found that during either task, the orbito-frontal cortex (OFC) was less active among the people with WS than in controls, while the medial prefrontal cortex (MPFC) was more active. Berman says the findings, reported in the August issue of Nature Neuroscience, fit nicely into a model of social cognition in which amygdala function—and therefore fear response—is regulated by both the OFC and MPFC. She notes that her group has documented a structural abnormality in the OFCs of WS individuals, which may explain their low fear response to faces.

A complete account of the cognitive problems in WS must include the role of the environment in mediating the syndrome's effects, researchers stress. That role could be especially important for social cognition, says Ralph Adolph, a cognitive neuroscientist at the California Institute of Technology in Pasadena. “Since the genes influence social behavior very early on in WS individuals, their unusual social behavior in turn is likely to construct an abnormal social environment—that is, other people will socially interact with a WS child differently than with a child without the syndrome,” he says. “I think we can certainly draw a link between genes and cognition, as long as we realize that the link is very complex and always brings in the environment in its mediation.”

Evidence that more than genes governs the cognitive abilities of those with WS comes from findings that “individuals with the same classic WS deletion vary considerably in their visuospatial construction ability, although almost all show a significant deficit,” says Louisville's Mervis. “On average, individuals who have a parent who is good at drawing are themselves better at drawing than are other individuals with the same deletion; this is likely due to a transaction between genes from outside the deleted region and the environment. Children in these families may well have more opportunities to draw, in addition to having better adult models of how to draw.”

Nobody expects that there's a simple, straight line connecting genes to the mind, says Reiss, who along with his colleagues is planning a longitudinal study of children with WS. Such work, he hopes, will shed light on both the genetic and environmental pieces of the puzzle. “We have the possibility of unraveling how genes and environmental moderators shape cognition and behavior,” he says. “Now that is really exciting stuff.”