# News this Week

Science  14 Oct 2005:
Vol. 310, Issue 5746, pp. 208
1. PALEOANTHROPOLOGY

# New 'Hobbits' Bolster Species, But Origins Still a Mystery

1. Elizabeth Culotta

Last year's announcement of an astonishingly tiny species of extinct human from the Indonesian island of Flores sent anthropologists reeling. News of the first, nearly complete skeleton ignited a debate about what evolutionary path might have led to humans who stood about 1 meter tall. A few researchers argued that the skeleton, dated to only 18,000 years ago, was simply a diseased modern human (Science, 12 November 2004, p. 1116).

This week, the original Australian-Indonesian discovery team unveiled new specimens of Homo floresiensis. Their paper in Nature describes bones of seven additional adults at least as small as the original, as well as a child's arm and leg bones so tiny that they snuggle neatly on a bank note (see second photograph). The new finds also include the right arm of the original skeleton and a lower jaw estimated at 15,000 years old. The age bolsters the case that the “hobbits” inhabited the Liang Bua cave for thousands of years.

“This destroys the argument that the first skeleton was an aberrant individual,” says paleoanthropologist Russell Ciochon of the University of Iowa in Iowa City. “They have [found] a unique population of small-bodied hominids.”

But a few researchers disagree. A Technical Comment in this week's issue of Science (p. 236) argues that it is possible that the single skull unearthed suffered from microcephaly, a pathological condition that causes small brains and may affect body shape. Daniel Lieberman of Harvard University says that the new bones make pathology unlikely but points out that no one has yet compared H. floresiensis with a wide range of microcephalics, so “everyone still has a right to ask that [microcephaly] question.”

The discovery team, led by Michael Morwood of the University of New England in Armidale, Australia, found the latest bones in Liang Bua cave during the 2004 field season. The H. floresiensis specimens range from 12,000 to at least 74,000 years old, Morwood says. Stone tools, charred pebbles, and extinct animals were also found in the hominid-bearing layers. Because of a dispute with a leading Indonesian researcher (Science, 25 March, p. 1848), Indonesian officials postponed planned work at Liang Bua this year, Morwood says.

Researchers familiar with this week's paper say it underscores how strange the little Flores people were. The first skeleton uncovered, thought to be that of a 30-yearold female, has a tiny skull with a modern-looking face and teeth perched atop a short, chunky body. She has relatively long arms and short legs, and a bizarrely rotated upper arm bone not seen in any other ape. “They're so weird,” says Lieberman.

Paleoanthropologist and team member Peter Brown, who described the bones, says the distinctive similarities among the specimens show that they are a new species rather than diseased moderns. For example, the two jaws both lack a chin, considered a hallmark of modern humans, and the long bones are unusually thick for their length.

Brown draws special attention to the right arm bone because it completes the skeleton of the little lady of Flores. He notes that her limb proportions differ from those of all other known members of Homo but match those of “Lucy,” the 3-million-year-old Australopithecus afarensis from Africa, who also stood about 1 meter tall. “There are so many similarities between the Liang Bua bones and australopithecines that I'm leaning toward the possibility that a small-brained, small-bodied hominid got [to Flores] and shrank further,” he says. The hominid who first made landfall might have been as primitive as an australopithecine, he says.

However, many researchers are skeptical about that idea, because there's no evidence that such primitive hominids ever left Africa. In Ciochon's view, a more likely tale of hobbit origins starts with a relatively small H. erectus with a yen for travel. He notes that new H. erectus specimens from Dmanisi, Georgia, dated to about 1.7 million years ago, have statures of about 1.4 meters and brain sizes of 665 cubic centimeters (cc), or about half the size of a modern human brain. It's not far-fetched to imagine such a human settling on Flores and eventually shrinking to H. floresiensis's 106 centimeters of height and 417-cc brain, he and others say.

Meanwhile, a few researchers find the notion of such a small-brained human creating sophisticated tools so outlandish that they remain open to the idea of microcephaly. Anthropologist Robert D. Martin of the Field Museum in Chicago, Illinois, points out that microcephaly often runs in families and that bones can be jumbled in caves, boosting the chances of finding several microcephalic individuals together. “I'm not 100% convinced it's microcephaly, but I am convinced that that brain size doesn't go with those tools,” he says.

As opinions pour in, Fred Spoor of University College London notes that the first Neandertal skull dug up in the 19th century was labeled degenerate, too. “There's a long history of finding new human species and someone shouting, 'Pathology!'” he says. Lieberman calls for additional analyses of microcephalics and for more-detailed scaling studies. “This is fun,” he says. “But we have a ways to go.”

2. PAKISTAN EARTHQUAKE

# A Seismic Murmur of What's Ahead for India

1. Richard A. Kerr,
2. Pallava Bagla

The death toll from last weekend's major earthquake was soaring past 30,000 at press time. But it could have been worse, seismologists say. And it probably will be.

The magnitude-7.6 quake ruptured 40 kilometers of the westernmost end of a 2500-kilometer fault zone that arcs from northern Pakistan across the top of India, through Nepal, to eastern India. This zone is where the Indian subcontinent—more than 40 million years after colliding with Asia—still dives into the mantle at a rate of 2 meters per century, pushing up the Himalayas in the process. Major quakes broke fault segments just to the east of the latest quake in 1885 and again in 1905, when 19,500 people were killed.

Longer segments have ruptured in the past 200 years, setting off several great quakes up to 30 times more powerful than last week's temblor, according to studies by seismologist Roger Bilham and tectonophysicist Peter Molnar of the University of Colorado, Boulder, and geoscientist Vinod Gaur of the Indian Institute of Astrophysics in Bangalore. But earthquakes have ruptured less than half of the Himalayan arc in that time. Meanwhile, the urban population in the Ganges Plain—which stretches along the Himalayan foothills—has increased by a factor of 10 since the 1905 earthquake. A quake that powerful on long-unbroken segments could kill 200,000 people, the trio wrote in 2001 (Science, 24 August 2001, p. 1442). A plausible great quake striking near a megacity such as Delhi, they estimated, could conceivably kill 2 million.

“Thankfully, the Earth has not delivered as immensely devastating a blow as was being forecast,” says Valangiman Ramamurthy, secretary of the Department of Science and Technology in New Delhi. But the quake, he adds, is “a timely cue to get our act together for seismic planning.”

3. PUBLIC HEALTH

# Pandemic Flu Jitters Grip Washington

1. Martin Enserink

The pandemic prophets are finally being listened to—at least in the United States. Last week saw a flurry of political activity on influenza in Washington, D.C. Flu experts relish the high-level attention but want to see actions to back up the words. Meanwhile, new reports from Turkey and Romania raised alarms that the H5N1 avian influenza strain may sweep through European poultry. Tests were pending when Science went to press.

To address the looming shortage of influenza vaccine during a pandemic, President George W. Bush met with flu vaccine makers at the White House on 7 October. The same day, the State Department met with representatives from more than 80 countries to discuss collaboration on bird flu. Secretary of Health and Human Services (HHS) Michael Leavitt, meanwhile, embarked on a 10-day trip to bird-flu-stricken countries in Asia to discuss collaboration on surveillance and testing, accompanied by the World Health Organization's Director-General Lee Jong-wook and pandemic influenza chief Margaret Chan.

What prompted the Administration's sudden activity last week remains a mystery, although experts have cited factors including criticism about its slow response to Hurricane Katrina and recent papers claiming that the 1918 pandemic flu originated in birds (Science, 7 October, p. 28).

Exactly how the Bush Administration plans to handle a pandemic is the topic of its long-awaited preparedness plan, some details of which were revealed in an 8 October story in The New York Times; the paper reported, for instance, that the plan says the country should be able to produce 600 million doses of vaccine within 6 months. It's not clear, however, how the plan differs from a draft that has been posted on the HHS Web site for more than a year. An HHS spokesperson would not say when the final plan might be released. The Senate, meanwhile, voted last week to spend $3.9 billion to shore up defenses on bird flu, including$3 billion for antiviral drugs.

Worries about a pandemic would ratchet up if H5N1 is found to be the cause of two new outbreaks in birds. Ducks in two villages in Romania are said to have died from what scientists there, based on antibody tests, believe may be bird flu; in Turkey, an outbreak that has killed approximately 1700 turkeys was caused by an H5 virus, Turkish officials say, although its neuraminidase (N) type isn't clear.

Virus samples from Turkey were slated to be analyzed this week at the Veterinary Laboratories Agency (VLA), a U.K. government lab in Weybridge, and an E.U. team traveled to Romania to help confirm the cause of its outbreak. The virus's genome sequence—as well as epidemiological investigations—should give clues to where the virus came from and how it reached Turkey, says VLA virologist Ian Brown.

On 11 October, French foreign affairs minister Philippe Douste-Blazy called for an urgent E.U. meeting on how to protect Europe's vast poultry sector. If there's evidence that migratory birds carried H5N1 to Turkey, European countries may ramp up measures to try to prevent their flocks from becoming infected, Brown says.

4. MEDICINE

# Teenager's Odd Chromosome Points to Possible Tourette Syndrome Gene

1. Steve Olson*
1. Steve Olson is a writer in Bethesda, Maryland.

A bad break that apparently gave a young boy Tourette syndrome may turn out to be a lucky break for researchers studying the neuropsychiatric disorder.

Tipped off by a suspicious chromosomal rearrangement, a team led by geneticist Matthew State at Yale University Medical School reports on page 317 that it has identified a gene that the researchers believe causes Tourette syndrome when mutated. Although the gene is responsible for at most a small fraction of Tourette cases, it's the best lead yet in tracking down the genetic contributors to the syndrome. “This gives us a key clue to the potential biological pathways that are altered in this disorder,” says neurologist Daniel Geschwind, director of the center for autism research at the University of California, Los Angeles (UCLA).

Traditional genetic analyses of people with Tourette and their families have fingered a half-dozen chromosomal regions that appear to be involved in the syndrome, which causes as many as 1 in every 100 people to involuntarily move or make sounds (Science, 3 September 2004, p. 1390). But difficulties in pinning down susceptibility genes in those regions led State to take a different approach. He has been looking in people with the syndrome for chromosomal breaks and rearrangements that might implicate specific genes.

A little over a year ago, a geneticist associated with a consortium organized by the Tourette Syndrome Association (TSA) told State about a boy who had an inversion in chromosome 13: A portion of his chromosome had an orientation opposite that of normal chromosomes. The boy was the only member of his family with Tourette syndrome and the only one with the inversion.

State and his colleagues found three genes close to the breakpoints of the inversion. Two had no plausible connection to Tourette syndrome, but the third immediately drew their attention. Known as Slit and Trk-like family member 1 (SLITRK1), it was related to a group of genes known to be involved in neuronal growth, guidance, and branching.

To test the gene's association with the syndrome, State and his colleagues sequenced SLITRK1 in 174 people with Tourette. They found one person with a missing nucleotide in the gene that resulted in a truncated protein. State's medical school colleague Nenad Sestan then cultured mouse neurons that expressed either the regular SLITRK1 gene or the version with the missing nucleotide. The cells with the normal gene grew significantly longer dendrites—the portions of the cell that reach out to receive nerve impulses—than did neurons with the mutated gene. Although the link to Tourette syndrome remains to be determined, the gene appears to have a “functionally important” role in neuronal growth and differentiation, says Sestan.

Among the 174 people with the syndrome, State, Sestan, and their colleagues also found two unrelated individuals who had a change near the coding region of the gene. The change altered a binding site for a short RNA molecule, or microRNA, that regulates expression of the gene. And both the microRNA and SLITRK1 are expressed in portions of the brain thought to be involved in Tourette syndrome.

State suspects that mutations in or near SLITRK1 can cause Tourette syndrome when they block or reduce the expression of the gene during development. “This finding needs to be replicated,” he says. “But we have multiple lines of evidence pointing to the involvement of this gene.”

Other researchers warn that the findings, although interesting, remain tentative. “Each piece of the evidence is intriguing but not on its own conclusive,” says UCLA geneticist Nelson Freimer. “To what degree can the pieces be combined to make a persuasive case? Opinions will differ on that.”

To try to resolve the matter, TSA has given funding to State, Sestan, and their colleague neurobiologist Angeliki Louvi to produce a mouse in which SLITRK1 has been knocked out and to study how the SLITRK1 protein functions. “If it holds up, it's a giant leap for Tourette research,” says neuropsychiatrist Neal Swerdlow of the University of California, San Diego, School of Medicine.

5. NOBEL PRIZE: CHEMISTRY

# Molecular Mystery Yields a Trio of Novel Matchmakers

1. Robert F. Service

Three chemists shared the Nobel Prize in chemistry last week for their roles in devising novel catalysts that act like molecular dance instructors, rearranging dance partners to make novel pairings. Such rearrangements are now a staple of organic chemists for producing everything from pharmaceuticals and pheromones to agrochemicals and plastics.

Yves Chauvin, 74, of the French Petroleum Institute in Rueil-Malmaison will receive one-third of the $1.3 million prize for working out the details of the “metathesis” reaction, in which a metal catalyst causes carbon-containing molecules to break bonds and change partners. Richard Schrock, 60, of the Massachusetts Institute of Technology in Cambridge and Robert Grubbs, 63, of the California Institute of Technology in Pasadena each will receive another third for developing novel metathesis catalysts that were more efficient, stable, and environmentally friendly. “This was a widely expected prize and well deserved,” says Peter Stang, a chemist at the University of Utah in Salt Lake City. Even Schrock says he'd picked up hints: “I had heard rumors, of course. But it's something you don't ever expect to happen.” Carbon is central to synthetic chemistry because of the unique ability of its atoms to bind to one another with single, double, and triple bonds and to form chains, branches, and rings of different sizes. In the 1950s, chemists at DuPont and other companies hoped to exploit this molecular dexterity to make novel polymers and other materials. They found that adding certain metals bound to carbon to simple organic compounds known as olefins, which have double bonds between a pair of carbon atoms, caused the reactants to change shape. But how that happened remained more alchemy than science. Clues to the mystery continued to trickle in through the 1960s. Chemists around the globe raced to explain the shape shifting. In 1971, Chauvin cracked the case, describing the steps by which certain transition metals bound to carbon could slice olefins apart. The electron-hungry metal, Chauvin found, homes in on an olefin's electron-rich double bond and grabs one of its carbons much as a dancer grabs a partner with two hands. When the catalyst encounters another olefin, it drops one “hand” with the first carbon and uses it to pull another pair of carbons into a ring of four. Finally, as the ring breaks, the metal grabs a new carbon by two hands, releasing its original partner to form a new compound. The mechanism Chauvin discovered had a wide range of potential uses, such as turning linear compounds into rings, stitching linear chains together, and breaking rings open. “It's extremely versatile,” says Dale Boger, a synthetic chemist at the Scripps Research Institute in San Diego, California. At the time, however, the known metathesis catalysts were inefficient and fell apart when exposed to air or moisture. “Olefin metathesis was a very interesting curiosity until Grubbs and Schrock walked in,” says Amir Hoveyda, a chemist at Boston University. In 1971, Schrock joined DuPont and began exploring tantalum-carbon compounds, whose chemistry was virtually unknown. “I thought that was a good place to look for new chemistry,” says Schrock, who moved to MIT in 1975. He hit upon a metathesis catalyst that he later improved by switching the metal to tungsten and molybdenum. Unfortunately, Schrock's catalysts were unstable in air or around moisture, because the metals at their core readily reacted with oxygen or water. Grubbs and colleagues solved the problem by substituting ruthenium, a less electron-hungry transition metal. The resulting catalysts typically don't work quite as fast as the molybdenum-based compounds, but they are stable in air, water, and a wide variety of other compounds, which has made them widely useful. 6. NOBEL PRIZE: ECONOMICS # Two Honored for the Theory and Practice of Game Theory 1. Constance Holden Two players representing different ends of the spectrum in game theory will share this year's$1.3 million Nobel Prize in economics: Thomas Schelling of the University of Maryland, College Park, and Robert Aumann of Hebrew University in Jerusalem.

Schelling, 84, is best known for analyses directly related to practical questions, such as arms control; Aumann, 75, a mathematician, is credited with more theoretical contributions. Economist Jeffrey Ely of Northwestern University in Evanston, Illinois, says work by Schelling, long admired for his accessible prose, could be characterized as “a user's guide for strategic interaction,” whereas Aumann writes “a manual for specialists.”

Schelling first came to prominence by using game theory to analyze the nuclear arms race in the 1950s. He “basically invented the scholarly study of arms control,” according to the prize committee, offering such counterintuitive ideas as “uncertain retaliation is more credible and more efficient than certain retaliation.”

“Tom's work is so rich and so varied that you could just about take any public policy and find some contribution he made to it,” says fellow Maryland economist Jeffrey Lewis. Lewis says much of Schelling's work has focused on “how the preferences that individual people might have in interacting with others might produce surprising results”—for example, on how weak preferences for living in a mixed neighborhood can result in racial segregation.

Aumann was cited as “the first to conduct a full-fledged formal analysis of so-called infinitely repeated games”; that is, looking at outcomes not from a single interaction but over the long term. “The repeated-games approach clarifies the raison d'être of many institutions, ranging from merchant guilds and organized crime to wage negotiations and international trade agreements,” said the committee.

Ely says he thinks Aumann's “most significant contribution” is in the area of “common knowledge”: the fact that interactions from arms races to stock speculation are influenced not just by knowledge but by knowledge about the knowledge of the other players. Aumann also melds his religion with his economics, as in a 1985 paper entitled “Game-Theoretic Analysis of a Bankruptcy Problem From the Talmud.”

7. NOBEL PRIZE: PEACE

1. John Bohannon

The 2005 Nobel Peace Prize has been awarded to the United Nations International Atomic Energy Agency (IAEA) and its Director General Mohamed ElBaradei for work “of incalculable importance.” Nobel laureate and physicist Burton Richter, an IAEA adviser, praised agency scientists for working “on their own time, with their own resources.” For ElBaradei, a lawyer, the award sends “a very strong message: Keep doing what you are doing.”

8. EPIDEMIOLOGY

# Minnesota Polio Case Stumps Experts

1. Leslie Roberts

Public health experts are mystified about how an unusual strain of poliovirus infected an infant in rural Minnesota—smack in the middle of a country that has been free of wild poliovirus since 1979. Genetic and epidemiological investigations are now under way to try to determine the source of the virus, detected just last week, and whether it poses a public health threat.

The genetic evidence available so far paints a confusing picture, indicating that the strain infecting the child is derived from the so-called Sabin virus used to make oral polio vaccine (OPV). Although the live, attenuated virus in the vaccine is known to revert and cause disease in rare instances, this 7-month-old infant has not been vaccinated. Indeed, while still commonly used in developing countries, OPV has not been used in the United States since 2000.

Experts at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, speculate that this case represents a new and worrisome route of exposure that began in another country more than 2 years ago. “This is one of those scenarios you would never dream up because no one would believe it,” says Mark Pallansch, who leads the CDC group that genetically analyzes poliovirus strains.

The mystery came to light last week when the Minnesota Department of Health was doing a virus check on a stool sample from an infant hospitalized for conditions related to a congenital immune disorder. The child has no symptoms of paralysis, so researchers were shocked when poliovirus turned up. “My initial response was that this can't be possible,” says state epidemiologist Harry Hull, who used to run global polio-eradication efforts out of Geneva.

But it was, CDC confirmed last Thursday. The CDC group, led by Pallansch and Olen Kew, also confirmed that the child's virus is closely related to the OPV strain. By tallying up the number of genetic mutations in the virus—a measure of how much it has diverged from the original virus used to manufacture the vaccine—the CDC team deduced that the virus is older than the child. It seems to have originated in a person immunized with OPV about 2 years ago. The distinctive pattern of mutations also suggests, says Pallansch, that the person was either immune compromised or quickly spread the virus to an immune-compromised person who has been shedding the virus ever since.

While geneticists try to nail down the source and its connection to the infected child, epidemiologists in Minnesota are trying to determine whether the poliovirus has spread within the hospital—they are especially worried about other immune-compromised individuals—or in the child's community. Although the overall risk is low because of high U.S. immunization rates, the child is part of a religious community that avoids vaccination. That's why state epidemiologists are going door to door, in hope of collecting blood and stool samples and persuading community members to be immunized.

9. EVOLUTION

# Better Habits Sometimes Heritable

1. Elizabeth Pennisi

When the price of gas skyrocketed in the U.S. last month, many commuters switched to public transportation. Others just couldn't bear to give up their cars. Those new bus and train riders who adjusted their mode of transport exhibited what evolutionary biologists call phenotypic plasticity.

Although no one would suggest that the children of either type of commuter would inherit a preference for cars or subways, researchers studying birds called great tits have evidence suggesting that phenotypic plasticity runs in families and, when it confers a survival advantage, that this trait will be selected for over time.

By reviewing 32 years of data, Daniel Nussey, a graduate student at the University of Edinburgh, U.K., and his colleagues have found that some great tits and their young have shifted the timing of when they lay their eggs, giving them an edge over other great tits in dealing with global warming. The results, reported on page 304, show that “plasticity plays a critical role in the ability of animals to cope with changing environments,” says evolutionary ecologist Ben Sheldon of Oxford University in the U.K.

Over the past decade, evolutionary biologists working with plants and animals in the lab have established that plasticity depends in part on one's genes. Now, Nussey, working with ecologist Marcel Visser of the Netherlands Institute of Ecology in Heteren, has demonstrated this genetic link in natural populations; they have also shown that this plasticity is truly advantageous and thus should become more common with natural selection.

Nussey and his colleagues analyzed data on great tits living in a national park in the Netherlands to see how the birds were dealing with the gradual warming the area was experiencing. Throughout the 1970s, females timed reproduction so that chicks hatched at a time when their food, caterpillars, was most plentiful. But during the 1980s, warming trends prompted ever-earlier springs and ever-earlier emergence of caterpillars—they now appear 2 weeks sooner than they did in 1985. Most of the birds did not adapt and maintained their original schedule, and the numbers of surviving offspring have begun to decline.

But there were some exceptions. Even in the 1980s, some individuals altered their behavior in accordance with the climate, laying eggs earlier in the warm years and later in the cool years. These climate-attuned females have twice as many surviving offspring. “The ability to adjust their timing allows [reproduction] to coincide with the best conditions,” says Sheldon.

Although there are not yet enough long-term data to say for sure that great tits are evolving greater phenotypic plasticity, says Nussey, this advantage suggests that over time, the more flexible birds may win out, and eventually the population will be better able respond to climate changes.

10. WILDLIFE CONSERVATION

# Kenyan Edict Threatens Famed Park

1. Constance Holden

Kenya's President Mwai Kibaki threw Kenya's wildlife establishment into an uproar late last month when he announced that Amboseli National Park, one of the country's prime game reserves, will be turned over to local control. The move, if not reversed, opens the door for the government to do the same with all the country's wildlife and parks, says David Western, former director of the Kenya Wildlife Service (KWS), which has run the park since 1974. “It makes a mockery of our wildlife policies and the rule of law in Kenya,” he says.

Conservation groups say the 29 September decision to relabel the 400-square-kilometer tract a “national reserve” flouts laws requiring consultation with KWS and approval by the National Assembly. The move has been widely interpreted as an attempt to curry favor with the Maasai people, who believe a proposed new constitution that Kenyans will vote on next month will strip them of control over some of their lands.

Conservation groups have set up a Web site (http://www.saveamboseli.net/) for people to petition the government. Last week, the East African Wildlife Society and seven other groups held a press conference in Nairobi supporting KWS's continued management of the park. Amboseli would be run by the county council of the Kajaido region. Former KWS Director Richard Leakey says county councils don't have the expertise to administer reserves. He adds, “Why should donors like the World Bank provide support … when the government actively promotes the destruction of a major tourist attraction?”

Western says Amboseli was set up as an open wildlife park integrated into a 5000-square-kilometer ecosystem where migrations of zebras, elephants, wildebeests, and other animals would be preserved. It's the most remunerative one in Kenya, reportedly pulling in $3.4 million from tourism last year. “I've been saying all along that the Maasai should get more benefits from living [near] these wild animals, but this probably isn't the way to do it,” says Cynthia Moss, who has been tracking Amboseli's elephants, now numbering 1400, since 1972. Western, who now heads the African Conservation Center in Nairobi, says this sets a disastrous precedent: “Every other national park and reserve … risks being erased on a political whim at a moment's notice.” KWS is not commenting on the situation, and its future role is unknown. The immediate impact of the president's action has been permission for the Maasai to allow their cattle, hitherto mostly banned from the park, to graze on the land. Western reports that last week he counted 15,000 livestock. Moss says the tourists “are already complaining that they didn't spend several hundreds of dollars a day to come to Africa to look at cattle.” 11. NEWS FOCUS # Betting on Cilia 1. Gretchen Vogel With help from a single-celled alga, scientists are learning that cilia play unexpectedly crucial roles in human development and disease Patients with Bardet-Biedl syndrome have an odd combination of symptoms. The first signs appear at birth: They have extra fingers or toes, which are most often surgically removed. When patients are in their teens and early 20s, more ominous symptoms appear. Their kidneys fail, they start to lose their eyesight, and they become obese and develop diabetes. Some also suffer from mental retardation. For decades, the disease, which affects one in 100,000 people, was a stubborn puzzle for doctors who struggled to link the diverse maladies. But as recent discoveries have made clear, the troubles of Bardet-Biedl can all be blamed on faults in the hairlike cellular projections called cilia. This and other surprises about cilia—and their longer cousins called flagella—are now pointing to a fundamental role for these underappreciated organelles, which are best known for propelling single-celled organisms or moving mucus in the airways. Researchers have recognized for decades that individual cilium appear, at least temporarily, on most cells in the body, but most biologists either ignored them or dismissed them as evolutionary remnants of our single-celled days. Until recently, cilia were largely the purview of a small group of cell biologists whose favorite subject was the double-flagella-equipped alga Chlamydomonas, or Chlamy for short. “For a long time, cilia were in the backwater,” says molecular geneticist Susan Dutcher of Washington University School of Medicine in St. Louis, Missouri. That has changed dramatically. It is now clear that primary cilia—the single, immotile cilium on a cell—perform key tasks for a surprising variety of organs. When mutations interrupt their formation or their function, the consequences can be severe. Some cells grow too quickly; others die before their time. Other evidence suggests that some of the most important developmental signals—cues that shape the body axis, backbone, brain, and limbs—are transmitted, at least in part, through cilia. Cilia, it seems, can serve not only as propellers but also as a sort of cellular antenna, picking up signals from the environment and helping pass them on to the cell's nucleus. In the brain, for example, neurotransmitters may signal nerve cells via cilia. This new understanding of the organelle is “really changing the way we view the cell. We are starting to recognize that inputs are not from random places on the [cell] membrane but at a discrete place” through the cilia, says molecular geneticist Nicholas Katsanis of Johns Hopkins University in Baltimore, Maryland. “It's turning a big chunk of molecular biology on its head.” And that has implications far beyond the rare Bardet-Biedl patients. Scientists are now contemplating whether ciliary defects have a broader role in obesity, high blood pressure, diabetes, and perhaps even cancer. “As more and more people realize that their favorite diseases are ciliopathies, this is going to be a bustling field,” Katsanis predicts. ## Making sense Cilia are impressively sophisticated organelles, tiny machines of microtubules driven by the cell's fuel molecule ATP. They extend from the cell surface, anchored by another organelle called the basal body. The best known cilia beat in unison, moving mucus through the airways or moving a paramecium through the water. (The longer flagella are built the same way but move with a waving motion instead of short strokes.) Evolution has frequently used cilia to connect with the surrounding environment. “We hear, see, and smell with cilia,” says cell biologist William Snell of the University of Texas Southwestern Medical School in Dallas. In the nose, scientists recognized decades ago that odorant receptors congregate on the cilia of olfactory epithelial cells. More recent studies have revealed crucial roles in the eye as well. In the retina's rod and cone cells, the so-called outer segment that contains light-sensitive photoreceptors is a specialized form of cilia. In Bardet-Biedl syndrome, defects in the cilia kill the cells, leading to the degeneration that causes blindness. Cilia can apparently sense touch as well, at least in the kidney—and that insight has offered a surprising explanation for polycystic kidney disease (PKD), one of the most common genetic disorders. Normal kidney cells have one cilium per cell, but like other primary cilia, they stay largely still, which led most experts to dismiss them as unimportant. But a strain of mutant mice with cysts in theirs kidneys prompted scientists to take a closer look. The rodents lacked a gene that scientists first called Tg737. Like patients with PKD, the mice also suffered from cysts in the pancreas and fibroids in the liver; for that reason, the scientists who identified the mutant strain in 1994 suggested that the animal might serve as a model for the human disease. In 2000, Gregory Pazour of the University of Massachusetts Medical School in Worcester, Douglas Cole of the University of Idaho in Moscow, and their colleagues, who were studying Chlamydomonas, found that one of the genes required for building the alga's flagella was strikingly similar to Tg737. And when they looked at the kidneys of the mutant mice, they found that the cilia were much shorter than normal. That Chlamydomonas connection quickly shed new light on PKD. A few years before Pazour and Cole's discovery, cell biologist Joel Rosenbaum of Yale University and his colleagues found inside the alga's flagella a transport system ferrying proteins needed to lengthen or shorten the organelles in response to environmental conditions. The team showed that blocking the so-called intraflagellar transport system (IFT) causes the flagella to shrink. The protein product of the alga version of the Tg737 gene, also called polaris, turned out to be part of the so-called IFT particle that carries cargo up and down the cilia. Since then, the connections between cilia and disease have multiplied. Half a dozen human genes that cause PKD when mutated have been found to affect cilia function. It seems the kidney's cilia do not cause movement but instead detect it. In cultured kidney cells, bending each cell's cilium, either with a micropipette or by forcing a flow of liquid over the cells, triggers a strong release of calcium ions, a key sign of cell activation. How this explains PKD remains somewhat murky, but one possibility is that the kidney cilia sense the flow of fluid through the organ and regulate cell proliferation in response. If this cilia signal is missing, cells might divide too often or incorrectly, forming the cysts and enlarged kidneys typical of the disease. ## Developing importance Cilia also seem to help sense molecular signals. A few years ago, Snell and his colleagues showed that the Chlamydomonas IFT system was not only needed for assembly and disassembly of cilium; the alga also uses it to transport molecular messages during the mating process. Preliminary evidence now suggests that cilia might play a similar role in animal brain cells. Scientists have known for decades that most brain cells, including neurons, have a single primary cilium. But until recently, says Snell, neuroscientists took little notice of these potential antennae, even after separate research teams reported in 1999 and 2000 that receptors for somatostatin and serotonin, two key brain signaling molecules, are on the cilia of rodent neurons. Again, it has taken clues from Bardet-Biedl syndrome to awaken interest in the brain's cilia. The obesity and mental retardation that show up in connection with the syndrome are still a puzzle, but scientists suspect that the answer might lie in the cilium's role as a signal detector for nerve cells. The hypothalamus, a brain region that helps control appetite and metabolism, “has beautiful cilia,” says Dutcher. And several teams have noticed that cilia are present on the brain cells involved in responding to leptin, a molecule involved in weight regulation. One reason that the role of cilia in adult animals has been overlooked for so long is that embryos lacking cilia die very early in development. The developmental importance of cilia first came to light in 1999, when several teams showed that twirling cilia in a key embryonic structure called the node determine whether the heart, stomach, and liver develop on the body's left side or the right (Science, 2 July 1999, p. 23). Many scientists were skeptical at first, but mouse mutants with defective cilia and hearts on the wrong side, along with microscopic videos that enabled scientists to glimpse the movement of the nodal cilia, eventually sealed the case. The connection also explained a long-mysterious genetic condition called Kartagener syndrome in which patients have immotile sperm and defective cilia in their airways—and in about half the cases, their hearts are on the right instead of the left. This condition, called situs inversus, provided one of the early clues that cilia have a role in Bardet-Biedl syndrome as well. In one family affected by the disease, several members' hearts, livers, and stomachs are on the wrong side. Two years ago, Katsanis and his colleagues reported that the family carried mutations in a gene encoding a protein that sits at the base of a cell's cilium, providing the first hard evidence that defects in cilia explain the unusual suite of Bardet-Biedl symptoms. Subsequent studies have shown that seven additional genes that, when mutated, cause Bardet-Biedl are involved somehow in cilia's structure or function. Recent work has also tied cilia to some of the most powerful molecules at work in the early embryo. The molecules called Hedgehog, Smoothened, and Wnt have roles in almost every major developmental process, from the earliest cell movements onward—and they seem to depend on cilia to get their messages across. The first clues came from work by developmental biologist Kathryn Anderson of Memorial Sloan-Kettering Cancer Center in New York City and her colleagues. Anderson studies a signaling pathway that works through the Hedgehog family of proteins. This pathway plays a vital role in setting up the early body plan of animal embryos from flies to humans. They found that gene mutations interrupting IFT in the mouse embryo caused defects very similar to those caused by mutations in a gene called Sonic hedgehog. Since then, several research teams have found evidence that other members of the pathway are also dependent on properly functioning primary cilia. For example, Jeremy Reiter and Didier Stainier of the University of California, San Francisco, reported online on 31 August in Nature that Smoothened, a protein that helps transmit the Hedgehog signal, seems to move to the cilia in response to Hedgehog signaling in both mouse and zebrafish embryos. A mutation that prevented the protein from reaching the cilia also shut down the signaling pathway. More and more papers are implicating cilia in Hedgehog signaling, notes Katsanis, although the case is not yet open and shut. If confirmed, the link might help account for the extra fingers and toes of Bardet-Biedl patients: Hedgehog is vital for proper limb formation. Another of the cell's most important signaling pathways—active in both embryos and adults—might also work through the cilia. The so-called Wnt pathway influences the expression of dozens of genes that control cell division and developmental processes as diverse as kidney formation and hair growth. And when the pathway goes awry after development, cells can divide out of control, causing tumors. In May, Gerd Walz of the University Hospital Freiburg in Germany and his colleagues reported that inversin, a gene involved in left-right reversal, also plays a role in Wnt signaling. The team found that mice lacking a functional inversin gene not only had their hearts and livers on the wrong side but also had kidney problems similar to those in mice with faulty Wnt signaling. In a series of experiments in mice, frogs, zebrafish, and cell cultures, the team built the case that the inversin protein enables the cell to switch from one type of Wnt signaling to another. Katsanis estimates that hundreds of proteins will turn out to be dependent on cilia for their proper function. Although finding defective cilia might help explain a wide range of maladies, fixing the cilia may not be simple. “These are amazingly complex little machines,” Dutcher says. Basal bodies alone involve at least 200 proteins according to the latest estimates, and the cilia themselves might use as many as 500. Although correcting subtle defects in such complex and ubiquitous structures won't be easy, Katsanis notes that there are already drugs such as the anticancer drug Taxol that affect microtubules, the main building block of cilia. “It may be that some of these molecules could rescue ciliary function,” he says, and some conditions might be corrected by tissue-specific treatments that could replace the missing ciliary signal. At the moment, cilia biologists have more questions than answers. Dutcher points out that cilia have been spotted on dendritic cells that serve as the immune system's first responders to viruses and bacteria. “I don't think anyone has any idea what they're doing [there] yet,” she says. And Snell notes that stromal cells in the prostate have prominent cilia—although no one has yet linked them to disease. Given how new the field is, Katsanis predicts that the number of “ciliopathies” will only increase. “I will no longer be surprised if anyone comes to me with any cell type, from any tissue, and shows me they are ciliated,” he says. His confidence has already paid off. Katsanis says he recently won “an excellent bottle of Chablis” from a wager with a neuroscientist who didn't believe that a certain class of neurons had cilia. It's a fairly good bet cilia will continue to surprise. 12. STOCKPILE STEWARDSHIP # Is the U.S. Getting Enough Bang From Los Alamos Tests? 1. Eli Kintisch A key facility for hydrodynamic tests faces questions that could impact a U.S. nuclear weapons complex in transition Experts inside and outside the U.S. government agree that researchers at Los Alamos National Laboratory (LANL) are not blowing up stuff often enough. For decades, scientists at the Department of Energy's (DOE's) nuclear weapons facility have filmed imploding simulated nuclear bomb parts to study how weapons perform. After the United States halted nuclear testing in 1992, these so-called hydrodynamic tests, or hydrotests, became a central duty for Los Alamos scientists, providing crucial clues about the readiness of aging weapons. The lab conducts the tests at its Dual Axis Radiographic Hydrodynamic Test Facility (DARHT), a half-hectare-sized machine that uses a pair of linear accelerators to create x-ray beams fired at right angles through the test site. The resulting x-ray movies, trained on explosions up to the equivalent of 68 kilograms of TNT, give scientists a glimpse of the inside of a nuclear weapon. But all is not well at DARHT. Completed in 2003 to replace an older, less capable instrument, the$350 million facility has missed a series of technical deadlines. A report last month by the DOE inspector general (IG) says the problems could delay refurbishment of the W76, a warhead aboard submarines that officials worry might be degrading over time. “Without critical hydrotest data, scientists lose one of their most important tools for evaluating … the performance of key weapons components and the reliability of the stockpile,” says the new IG report.* DOE officials disagree with the IG's assessment, saying the hydrotest program is on track and has provided outstanding data this year.

DARHT's ups and downs could have a ripple effect on the nation's nuclear weapons program. This year, Congress is expected to roughly triple DOE's funding to explore new bomb designs, which would need to be validated by hydrotesting. The new IG report also raises questions about the ability of the University of California (UC) to manage LANL on the eve of DOE's decision to either extend the university's contract or hand over management to a team led by Lockheed Martin and the University of Texas. “This could not come at a worse time,” says Hugh Gusterson, a Massachusetts Institute of Technology anthropologist and expert on the labs, about the competition for the $2.2-billion-a-year lab. DARHT isn't the only major element of stockpile science managed by UC that's in hot water: Congress is currently debating shutting down the long-troubled National Ignition Facility, a$3.5 billion megalaser at Lawrence Livermore National Laboratory in California (Science, 2 September, p. 1479).

## Blasts away

The IG's report raises several questions about whether DARHT is meeting its obligation to validate the nation's nuclear stockpile. One bone of contention is the work schedule. DOE says the second of the two linear accelerators that make up DARHT won't be ready until 2008, 5 years late. Of seven shots originally planned for the fiscal year that just ended, the lab conducted only three.

DOE officials say an 8-month shutdown of the lab last year, ordered by former director George “Pete” Nanos after computer disks with classified data were reported missing (Science, 23 July 2004, p. 462), forced them to alter their original plans. But they insist the facility remains on schedule. However, even the plan for six firings next year suggests that the lab could have trouble reaching the level of 11 per year called for by 2009. Last year, the lab conducted seven of 10 scheduled hydrotests, but only by relying on an older facility called PHERMEX, which provides much less data than DARHT does. PHERMEX was closed last year after officials decided it was redundant with a similar facility at Livermore.

Another major hurdle for the lab is containing debris from DARHT's open-air shots. The lab had hoped to have hard containers in place by 1999, DOE auditors say. But researchers are still developing a rigid, mobile container that doesn't disrupt x-rays. Meanwhile, foam-filled tents catch debris. Los Alamos officials acknowledged to the IG that the foam system extends the time needed to clean up after each test and prepare for the next one. But David Crandall, an official with DOE's National Nuclear Security Administration (NNSA), which oversees Los Alamos, says preparing the experiments, not the cleanup, is the limiting factor.

Planning and management challenges also loom large at DARHT. A 2003 report criticized the program for $58 million in cost overruns that other programs had to absorb. And the new report complains that administrators have “often dispersed responsibility for completing the work among several organizations, … lessening control and accountability for completing specific tasks.” NNSA officials say they've implemented management changes that address these problems. Shelving PHERMEX was another sign of poor planning, says Los Alamos experimentalist John Horne. It “should never have been closed,” he says, arguing that the data, although not as rich as those from DARHT, would still have been very useful. “If you don't collect [hydrodynamics] data, you can't make changes if necessary.” NNSA adviser Jeremiah Sullivan of the University of Illinois, Urbana-Champaign, said the problems with the program are not serious. But he agrees that “deadlines should be met” to maintain credibility. Hydrotesting isn't the only element in the lab's effort to certify weapons. A prime distraction, says Raymond Jeanloz, a UC Berkeley physicist and member of an LANL oversight committee, is the Robust Reliable Warhead (RRW) program, a nascent effort by the weapons labs to redesign components of currently deployed weapons—or whole new bombs—instead of simply copying existing ones. Created by Congress last year, the RRW program is seen by lab managers as a way to mend what in May they declared was an “increasingly unstable” stockpile stewardship program. Critics worry that designing new weapons would give foreign powers an excuse to build their own new weapons or lead to calls for nuclear testing to ensure the new designs actually work. The failure to perform routine tasks such as hydrotests is “going to add arrows to the quiver of proponents of the RRW,” says John Pike, director of GlobalSecurity.org in Alexandria, Virginia. NNSA officials say the IG report fails to account for routine adjustments to the DARHT program. Some of the shots originally planned for this year have turned out to be unnecessary, they say, and the two shots the lab fired provided “critical” hydrotest data for the W76 refurbishment. Los Alamos has cut the turnaround time between shots while using the foam, Crandall says, and a lab spokesperson says RRW work has not diverted resources from other missions, which are on schedule. Spending panel staff from the House and Senate who oversee the lab say they are confident the program is heading in the right direction. But as U.S. policymakers debate the need for new weapons, they will also be wondering how well the nation is preserving existing ones. 13. BUILDING SAFETY # Directing the Herd: Crowds and the Science of Evacuation 1. John Bohannon No skyscrapers are designed to be able to disgorge all their occupants in a dire emergency like the attack on the World Trade Center towers. Can they be made safer? VIENNA, AUSTRIA—In the hour and 42 minutes that elapsed between the first airplane strike on the World Trade Center (WTC) on 11 September 2001 and the collapse of both towers, more than 2000 people failed to escape. Roughly 500 occupants are believed to have died immediately upon impact, and more than 1500 trapped in upper floors died in the aftermath. The toll might have been far worse, according to studies presented here at the International Conference on Pedestrian and Evacuation Dynamics on 28 to 30 September. Had the same attack come when the towers were at their full capacity of 20,000 people each, says Jason Averill, a fire safety engineer at the National Institute of Standards and Technology (NIST) in Gaithersburg, Maryland, the staircases would have quickly gridlocked, resulting in some 14,000 deaths. No tall building is designed to be fully evacuated. Instead, regulations typically require that a few floors be emptied, assuming nothing worse than a localized fire. “This has to change,” says Shyam Sunder, deputy director of NIST's Building and Fire Research Laboratory, “because in the lifetime of a building, there will be situations where you've got to get everyone out.” But getting everyone out of harm's way will require a deeper understanding of the collective behavior of crowds, says Jake Pauls, a veteran building safety consultant now based in Silver Spring, Maryland. Researchers are “just scratching the surface,” says Averill, although they have made leaps and bounds over the past few years. Studies presented at the meeting offered a glimpse of how evacuations could be conducted more safely. ## Modeling mobs Until recently, there was little science in emergency planning, says Ed Galea, a fire safety engineer at the University of Greenwich, U.K. That is changing as scientists try to capture the behavior of crowds using computer simulations. A diverse effort is under way to refine these models with real-world data. For example, a team led by Jean Berrou, a computer scientist at the Maia Institute in Monaco, has been secretly filming pedestrians in 10 different cities around the world, analyzing nearly 1000 hours of video to measure different cultural patterns of walking. For example, he says, “pedestrians in London are faster than those in New York.” The goal is to find rules that individual pedestrians unconsciously follow to navigate crowded spaces. “What's amazing is that people don't collide with each other more often on a typical city sidewalk,” says Jon Kerridge, a computer scientist at Napier University in Edinburgh, U.K. On a scale of microseconds, people negotiate priority with cues transmitted through body language. “If we can understand how that works,” he says, we might learn why certain geometries of corridors and portals work better than others. The next step is to understand how an emergency changes everything. Researchers use a parameter called drive to define the level of motivation people have to go from A to B. “This is where things get very difficult to model,” says Kerridge, “because we're talking about innate, personal factors.” Strange things happen when fear is added to the mix. Take the paradox that the more urgently people want to leave a crowded room with a narrow exit, the longer it takes to get out. That occurs in part because of a breakdown in normal communications. Daniel Parisi and Claudio Dorso, computer scientists at the University of Buenos Aires, Argentina, have found that the optimum exit speed is a fast walk of about 1.38 meters per second. Such studies reveal that “the fundamental unit of a crowd is not the individual but the cluster,” says Kerridge. This is because “the first thing we do in an emergency situation is look to each other for support and information.” But that response slows movement dramatically. On a larger scale, people form groups similar to animal herds in which individuals let the crowd do the navigating, often passing right by exits within clear view. Learning to predict and control these behaviors may save lives—and not just in big buildings. The main killer when people mass is not trampling, as is commonly thought, but “crowd crush.” When two large groups merge or file into a dead end, the density makes it impossible to fall down, says Pauls. But the accumulated pushing creates forces that can bend steel barriers. “The situation is horrible,” he says: “Suddenly everything goes quiet as peoples' lungs are compressed. No one realizes what's happening as people die silently.” Dangers like these make designing architecture and procedures for evacuation like a tightrope walk, says Pauls: “You have to get people out fast, but safely.” ## Revisiting 9/11 Armed with these insights, two separate groups have been trying to model the WTC evacuation to see what lessons can be learned. In 2002, the U.S. Congress ordered NIST to investigate the WTC safety and emergency response, and the U.K. government commissioned a team led by Galea, which has paved the way for a larger study called HEED. “This was one of the largest full-scale evacuations of people in modern times,” says Galea. To build a minute-by-minute chronology of the event, the NIST team has conducted more than 1000 interviews with survivors by telephone, and Galea's team is set to do up to 2000 face-to-face interviews next year. One of the most surprising discoveries, says Galea, is the long lag time between the first attack and the start of evacuation. Galea's team found that although 77% of survivors began the egress within 5 minutes of the impact, it took another hour for the next 19% to get going, and 4% stayed in their offices for over an hour. “In some cases people were more worried about saving their computers,” he says. Both teams have incorporated these data into a model called EXODUS, designed by Galea. When the NIST team used the model to play out the WTC disaster with full occupancy, it estimated roughly 14,000 deaths, most among those stuck on the stairs. This didn't surprise Pauls. “Those stairs were not designed to handle a full evacuation,” he says. “In fact, no tall building is prepared for it.” Sunder says NIST is pushing to include full evacuation for many tall buildings in the next review of U.S. building codes in 2008. “There is a lot of resistance” to requiring full evacuation capability even after the WTC attacks because people “believe that was a one-time-only event,” he says. But he notes that a building's typical lifetime is a century; designers should be preparing for other “extreme events” like multifloor fires, earthquakes, and hurricanes. Until the existing tall buildings are replaced with a new generation, experts say, improvements will have to come through better emergency procedures and retrofitting. For one, elevators should be made usable during emergencies, says Sunder. WTC tower number 2 emptied far more efficiently than tower 1 because its elevators were available before it was hit by the second plane, the studies found. New elevator systems that include independent power supplies and computers that prevent them from opening on a burning floor will be available within a few years, says Averill. Galea suggests another possible innovation: adding sky bridges to create new escape routes linked to other buildings. His simulation of a WTC evacuation with the towers linked by a bridge was far more efficient. Evacuation experts say they are continuing to look at all kinds of evacuation backups, even far-out ones. For example, a pole system that can be attached to the outside of buildings is being tested. By strapping into a vest attached to the pole, people could slide down safely using electromagnetic brakes. Another option: People could jump into fabric tubes and bounce their way down to the bottom—although this would likely cause friction burns. Even parachutes have been proposed as a last chance resource. “But really, the best thing we can do to make these buildings safer,” says Pauls, “is to focus on the basics.” That means better stairs, elevators, and fire drills. 14. SUSAN HOCKFIELD AND ROBERT BROWN PROFILES # New Leaders for MIT and BU Herald Fresh Era in Boston 1. Andrew Lawler A scientist and an engineer are charting new courses for their institutions, drawing on their insider status and progressive social views about modern universities BOSTON—This city and environs are flush with 5000 life scientists,$1.5 billion in National Institutes of Health funding, and dozens of pharmaceutical giants and small biotechnology firms. At the core of what attracts the people, funding, and business to this region is its wealth of universities. Two former bench scientists are now at the helms of two of the largest and most prestigious schools, and they are revving up their universities' research engines to break down the walls between biology and other disciplines. They also are quietly advocating a social agenda designed to make their campuses more hospitable to women scientists and engineers—and more competitive in netting the best brains in a tough market.

Both Susan Hockfield—a Yale neuroscientist who last December became president of the Massachusetts Institute of Technology—and former MIT engineer Robert Brown, who last month crossed the Charles River to take the reins at Boston University (BU)—are technically savvy academic insiders with reputations for collegiality. Their backgrounds and personalities stand in sharp contrast to those of Brown's predecessor John Silber and the current president of the academic colossus down the road, Harvard's Lawrence Summers. Both Silber and Summers are social scientists notorious for their bluntness, political connections, and autocratic styles.

As they settle into their jobs, both new presidents face formidable challenges. Brown's task is to restore BU's battered reputation, build its small endowment, and vault it into the top tier of U.S. research universities. Hockfield's assignment is just as tough: Keep MIT in that top rank amid stiff competition for the best brains and become a national spokesperson for the science and technology community. Science recently spoke with both novice presidents about what they hope to accomplish.

## Susan Hockfield: Finding her voice

Hockfield scored two firsts in succeeding Charles Vest, a mechanical engineer whose 14-year tenure featured a seat on the President's Council of Advisors on Science and Technology (PCAST) along with a host of other national organizations. She is the first woman and the first biologist to run MIT, a momentous change at an institution long dominated by male engineers.

Her appointment reflects MIT's deliberate effort to retool itself in two key areas: equal opportunity and biological research. An internal report released in 1999 found that women at MIT—even senior professors—faced career impediments. MIT responded quickly, bringing more women into senior administrative positions, providing better daycare and more flexible family options, and closely monitoring faculty appointments. At the same time, MIT moved to integrate some of its fiercely independent fiefdoms to take advantage of the biological revolution. This fall, a new building housing cross-disciplinary neuroscience studies will open its doors, and a new computational and systems biology initiative now pulls together some 80 biologists, computer scientists, and engineers from 10 separate academic units.

Although Hockfield is helping MIT move in new directions, she says she has had little direct experience either with professional discrimination or interdisciplinary work. She spent 20 years at Yale studying brain development in mammals, in particular deadly brain tumors called gliomas. Previously, she had worked under James Watson at Cold Spring Harbor Laboratory in New York.

Given MIT's reputation as an engineering center, Hockfield acknowledges that the appointment of a life scientist as president raised eyebrows. But she sees it as an example of MIT's eagerness to adapt to the rapidly changing research environment. Beginning in the 1930s, she notes, the institute chief brought in top-ranked physicists despite skepticism from engineers. That influx “provided an understanding of the nuts and bolts of the physical universe,” she says, making the institution “a vehicle” for better engineering. The blossoming of engineering science in the 1950s revolutionized the field. A half-century later, she says, molecular genetics is providing a “similar convergence of life sciences with engineering.”

Discrimination is not part of her professional experience, says 54-year-old Hockfield, although she has been subject to “the subtle or not-so-subtle slights that women suffer.” Still, she's not afraid to speak out on the subject. In February, she coauthored an editorial in The Boston Globe that roundly criticized Summers's widely publicized remarks that genetic differences might explain why men outrank women in science (Science, 28 January, p. 492). “The question we must ask as a society is not 'Can women excel in math, science, and engineering?'—Marie Curie exploded that myth a century ago—but 'How can we encourage more women with exceptional abilities to pursue careers in these fields?'” she asserted. “Colleges and universities must develop a culture, as well as specific policies, that enable women with children to strike a sustainable balance between workplace and home.”

One of Hockfield's first initiatives is to tackle the problem of energy. Based on feedback from students, faculty, and alumni, she recently organized a council to lay out what energy research is being conducted at MIT and “to design programs and figure out what we need. I expect a report in early spring.” She says that the post-9/11 visa restrictions on foreign students have been significantly eased, but she is worried about assuring an adequate supply of U.S. scientists and engineers. “Eighty-five percent of our undergraduate degrees are in science and engineering,” she says. “Nationwide, it is 17%. At the undergraduate level in Singapore, it is 68%. … I am very concerned about the position of America in the global economy.”

Hockfield is more cautious about her role as a spokesperson for science on the national stage, where the MIT president has traditionally loomed large. (In addition to his current spot on PCAST, Vest is past chair of the 62-member Association of American Universities in Washington, D.C.) Although she joined the upper echelon of U.S. academia when she became Yale's provost in 2003, national politics has been outside her field of vision. “This is a new area to me,” she says.

Hockfield meets at least monthly with federal lawmakers and Administration officials in Washington. She's also been quietly talking with other presidents of major research universities about how to deal with a range of hot-button issues, from intelligent design to global warming to stem-cell research, in a coordinated fashion. But she weighs her words carefully when asked whether Republicans are waging a “war” on science. “I have no idea; I'm not in a position to judge that,” she says, adding: “I'm very concerned when interesting and dynamic science … gets subverted by political agendas.”

Hockfield says one of her primary concerns is that government support for science is not keeping up with the expanding opportunities. She also acknowledges widespread concerns about the potential for private funding to alter or quash research results. Hockfield says that “my sense is that we are not overly swayed by the interests of any funder—but one has to be always vigilant.” While praising the “entrepreneurial spirit” of MIT faculty, she recently warned her deans to adhere closely to the institution's ethical policies.

## Robert Brown: Aiming for the top

When Bob Brown looks out the wall of glass behind his desk, his view of the spires, domes, and high rises of Harvard and MIT across the Charles River remind him what he faces in putting BU on the list of major research universities. The institution he now leads has spent the past 3 years lurching from crisis to controversy. “BU is a very fine university that just tends to get itself into the paper,” he says diplomatically. It is, he insists, “much better than its public image.”

During his 30 years as BU's president ending in 2002, Silber turned a lackluster commuter school into the country's fourth largest private university. His extensive political connections helped attract the resources needed to build national reputations in high-energy physics, photonics, and medicine. But Silber also frequently angered faculty members by his involvement in what was taught in the classroom and by his public comments against feminists and homosexuals. He also faced criticism for leaving the school with a modest endowment of $620 million in 2003, 73rd in the nation. MIT, by contrast, had a$5.1 billion endowment, and Harvard's $25.9 billion rules the academic roost. Silber's departure was as controversial as his tenure. He stepped aside to become chancellor in 1996, only to resume the presidency when his handpicked successor abruptly resigned in 2002. A long search for a successor produced former NASA chief Daniel Goldin, who immediately began discussing plans for radical changes in senior management. Alarmed trustees rescinded their offer 1 day before Goldin was to start work, paying him a$1.8 million settlement. Alluding to the recent difficult years, Brown says, “My sense is that many people believe we lost” track of the university's principles. “A lot of faculty have put their head down, done great research and teaching, but are very quiet about where they work.”

Although Brown praises Silber for many accomplishments, he says he hopes to graft what he learned at MIT onto his new institution. At MIT, he says, “there was a feeling that being critical was not being disloyal.” He also intends to make his administration more transparent. “I am more open about data, about processes, trying to get people around the table to talk and work together to create a consensus,” he says. “But I'm not looking for a vote to drive the university forward, because that won't lead to a great university either.”

One immediate test of leadership will be the construction of an advanced laboratory to study dangerous biological agents in the heart of the university's medical center in the middle of the city. Although BU sees the planned facility as key to expanding its research portfolio, community activists fear it might release toxins or draw a terrorist attack.

Brown insists that BU is doing “a superb job of being responsive to concerns” and disputes any damage to its reputation as a community-based organization. “BU is taking on an initiative to build a great research infrastructure and a great group working on infectious disease in all kinds of contexts, not just bioterrorism,” he says. And he argues that its location is an asset. “How much synergy can you get by putting it in the middle of a health science complex? What we're banking on is that you get a lot.”

Given BU's myriad difficulties, Brown's decision to take the job stunned many faculty members. “Why would he choose to come here?” asked one incredulously. “He's really good!” University sources say he was gunning for the top MIT job after Vest's departure last year, rejecting overtures from the University of California, Berkeley, and Rice University in Houston, Texas. Brown declines comment.

The 53-year-old Brown arrived at MIT as a chemistry professor in 1979, and by 1998 he had become provost. While Vest met with policymakers in Washington, D.C., and wooed donors around the world, Brown stayed in Cambridge and quietly revolutionized the 140-year-old school. As engineering dean, he cannily asserted control over empty faculty slots. “If that hadn't happened, there would not be a biological engineering division today,” he says. That control, Brown adds, allowed MIT to reshape itself to address the increasingly interdisciplinary nature of biology, engineering, and the physical sciences.

It's an area in which Brown expects BU can shine, too. “When you have the top five departments in the world, the tendency to want to interact outside that department is less. BU hasn't had the luxury of those very, very strong departments, so you see an enormous amount of interaction between faculty. The best example is the new engineering and life sciences building, which is not owned by a department. The floors are laid out in terms of research areas. At one of these great top-tier universities, [such synergy] would be very difficult.”

At MIT, Brown also oversaw construction of a flashy computer science and artificial intelligence center designed by Frank Gehry, and he brokered a difficult and time-consuming deal with Harvard to create the Broad Institute to combine genomics with medical research. He's also been a leading advocate for revamping the way women scientists are treated in academia.

Does BU have a similar problem? “I have no data, but it is definitely on the radar screen,” he says. Brown is organizing a group that would do for BU what the 1999 report did for MIT. “There are some [issues] that are easy, such as daycare,” he says, but to standardize hiring procedures across units is more difficult. He says he soon will set up a committee charged by the president and provost to gather data and propose changes.

In the meantime, Brown must compete with other Boston-area universities and industry for top science and engineering faculty. He knows that, without a huge endowment, he's starting at a disadvantage. “I can't see how you easily ever make it up. You are going to need to build a philanthropic tradition that has not been in this institution.” He also knows that those domes and spires across the river can't be ignored. “Will Harvard always cast a shadow?” he asks. “Yes.”

15. SCIENCE EDUCATION

# New Curricula Aim to Make High School Labs Less Boring

1. Yudhijit Bhattacharjee

A cadre of education researchers is remaking science labs to give students a taste of the real thing

This year, Barrington Ross made cell division a life-or-death matter for his seventh-grade class at Shepherd Middle School in Durham, North Carolina. Instead of peering into a microscope or acting out the process, the students worked through a series of computer simulations to select which of three plant extracts is most likely to be active against the unchecked proliferation of cells that is the hallmark of cancer. Then they defended their choice in an online debate. “Having an authentic problem to work on made them think and feel like real scientists,” says Ross, noting that some students added personal dimensions to the exercise by talking about family members suffering from cancer.

Ross doesn't expect all his students to become scientists. But he does want them to understand the scientific method—and what it's like to develop and test a hypothesis. Those goals are rarely achieved in secondary school science labs, says a new report* by the National Academies. The study, requested by the National Science Foundation, found that most labs focus on mechanical procedures such as slide preparation and pH measurement instead of scientific principles. “For many students,” says Vincent Lunetta, an education researcher at Pennsylvania State University, University Park, “lab work is manipulating equipment, not ideas.”

A growing number of education researchers are trying to change that pattern. Some of the new materials take students beyond the traditional tasks of observation and data collection into the realms of theory-building and scientific reasoning. “The goal is to put students through a process that mirrors what scientists do,” says Marcia Linn, an education professor at the University of California (UC), Berkeley.

## Embrace the unknown

The academy is not the first to conclude that most science labs are dull, dry affairs in which students are told ahead of time what they will learn. Many teachers aren't sufficiently trained to conduct open-ended, inquiry-based labs, for one, and few have the time and resources needed to go beyond the cookbook approach. There's also little incentive for schools to transform labs when state assessment tests—the real drivers of curriculum change—emphasize factual knowledge rather than scientific reasoning. “Following instructions out of a textbook is much easier” for teachers, says Joseph Kracjik, a professor of science education at the University of Michigan, Ann Arbor.

The new wave of education materials is meant to be more appealing to students without being more difficult for teachers. In one exercise designed by Norman Lederman, a science and math education researcher at the Illinois Institute of Technology in Chicago, students are asked to study the effect of temperature on the heart rate of the water flea—a translucent crustacean—without being given any specific instructions. “All they know is that the water flea is a cold-blooded organism that has to adapt to cold conditions,” Lederman says. Each group must figure out how many beakers of water to use and what the water temperature should be in each one. “In many labs, students know the research question, the procedure, and even the answer in advance,” he says. “Our goal is to take it all away” and let them figure it out on their own.

Through repeated observations, students discover the minimum temperature difference between water samples that's needed to have a discernible effect on heart rate; they also learn that they might miss important data points if they set the temperatures too far apart. Lederman says the experience helps students realize a fundamental principle: that experimental design can have an impact on the findings of a study.

Another ingredient of scientific inquiry absent from most traditional labs is hypothesis development and testing, says Linn, who along with her colleagues at UC Berkeley has designed a dozen Web-based exercises to address that shortcoming (wise.berkeley.edu). The cancer lab that Ross used was one such project, presented in a set of four 45-minute lessons.

Another exercise, on heat and temperature, begins by asking students to predict the temperature of different objects. Many mistakenly think that metallic objects will be colder than wooden ones because metal feels colder. After discovering that everything is at room temperature, the students are asked to propose their own explanations for why objects feel different to the touch.

Then, after watching a simulation of heat flow from the hand into metal and wood, students revise their explanations and “reconcile their sensory experience with the empirical evidence (observed temperatures) and a visualization of heat flow,” says Linn. The exercise drives home two fundamental principles: Objects in the same surroundings will reach the same temperature in the absence of a heat source, and heat flows faster through certain materials (conductors) than through others (insulators). Diane Drazinski, a science teacher at Mesquite High School in Gilbert, Arizona, says the activity has helped her students nail down the distinction between heat and temperature, an Achilles' heel in high school physics learning.

In the same vein, to illustrate how ground cover affects climate, Daniel Edelson, a researcher at Northwestern University in Evanston, Illinois, asks high school students first to study the reflectivity of different colored envelopes under a lamp and then predict the reflectivity of grass, sand, and ice. Finally, the students analyze global remote-sensing data that show how deserts reflect more heat than forests. “The sequence enables them to go from direct experience of reflectivity to an analysis of its implications in the actual world,” says Christine Nichols, a teacher at Englewood High School in Colorado, who used the activity last year.

## Pressed for time

Even the most artfully designed inquiry-based lab, however, must compete for time in a crowded academic schedule. Theresa Dzoga-Borg, who teaches at Roberto Clemente High School in Chicago, Illinois, discovered that hard fact recently when she tried to teach her ninth-grade environmental science class the relation between potential and kinetic energy. She gave the students marbles of different sizes, ramps of different heights, and milk cartons; the activity involved rolling marbles down the ramps and measuring how far a carton placed at the bottom of the ramp traveled upon impact.

The exercise engaged the students, she admits. But she and her students were foiled by the clock on the wall. “By the time some of the kids figured out that the distance moved by the carton depended on both the weight of the marble and the height of the ramp, we had only 10 minutes left,” says Dzoga-Borg. “They were far from setting up an experiment and recording observations in a systematic way, which would have allowed them to compare their results. We also never got to the point of discussing the conservation of energy in the environment, which was the whole purpose of the exercise.” With so much else to cover in subsequent classes, Dzoga-Borg reluctantly abandoned the effort and went back to the textbook.

To help teachers deliver the goods within the allotted time, Michael Lach, director of science for Chicago Public Schools, recommends ongoing professional development. He started an initiative 3 years ago that provides Chicago science teachers with 60 hours of training every year—much of it focused on inquiry-based labs. Schools also need systems in place to facilitate quality lab instruction, says Stephen Flisk, a former science teacher who is now principal of Walsh Elementary School in Chicago. “Ordering supplies, maintaining equipment, setting up the lab at the beginning of each class, cleaning up after—the materials management alone can be overwhelming,” Flisk says. “Unless the school dedicates staff for those duties, teachers are more likely to demonstrate the activity instead of having every student do it.”

Initiating such sweeping changes, however, won't be easy, reformers acknowledge. “Schools are complicated places with lots of people, traditions, and histories, and it's hard to change them overnight,” says Lach.

But some schools appear to be making progress. Pre- and posttests given to Ross's students showed considerable learning gains from the cell division unit. Encouraged by Ross's experience, two fellow science teachers at the middle school are now taking Web-based tutorials so they can teach similar units to their students this school year.

“Hopefully, this is the start of a paradigm shift in how we teach labs,” Ross says. He plans to squeeze out more time from classroom instruction for inquiry-based labs next year and to recommend them to teachers at other schools in his district.