# News this Week

Science  01 May 2009:
Vol. 324, Issue 5927, pp. 572
1. Infectious Diseases

# As Swine Flu Circles Globe, Scientists Grapple With Basic Questions

1. Jon Cohen and
2. Martin Enserink

On 27 April, 6 days after the U.S. Centers for Disease Control and Prevention (CDC) first reported an unusual swine flu outbreak in humans, international agencies were still struggling to determine how serious a threat the virus posed. “Every new strain of the flu virus is unique,” CDC acting Director Richard Besser said at a press conference, “and until the outbreak has progressed, you don't know what it is going to do.”

Shortly after CDC rang the alarm bell on 21 April in a Morbidity and Mortality Weekly Report dispatch about two cases of swine flu in southern California, scientists and health officials around the world went on alert, concerned that this never-before-seen virus could lead to a killer pandemic. They quickly determined the genetic sequence of the virus, linked the U.S. cases to an apparently much larger outbreak in Mexico, and began fashioning international and local responses.

“On the bright side, this event was widely expected,” says Julio Frenk, the former secretary of health in Mexico who now heads Harvard School of Public Health in Boston. In the wake of outbreaks of avian influenza, “there have been good efforts to prepare.”

But others say the world hasn't done nearly enough over the past 10 years to prepare for a pandemic. They worry that most countries will find themselves without access to vaccines or antiviral drugs, which could become especially dangerous if the virus causes severe disease in many people—which is still uncertain—or evolves to do so. Some also question why the disease wasn't recognized as an international emergency several weeks earlier, which might have offered a chance to stop it at the source instead of battling it around the planet.

Much confusion surrounds the origins of the virus, why it seems to cause severe disease in Mexico and not elsewhere, and the overall threat it poses to the world. “Right now, there's more unknown than there is known,” says microbiologist Francis Plummer, who heads the National Microbiology Laboratory in Winnipeg, part of the Public Health Agency of Canada (PHAC) and a key player in unraveling the Mexican link.

By 28 April, Mexico had connected this swine flu to 152 deaths (most of which have yet to be confirmed). But in the United States and Canada, “it doesn't seem to be anything different than seasonal flu,” says Plummer. Solving that riddle will require tests on the suspected cases in Mexico, which totaled nearly 2000, to see whether they indeed are swine flu. But CDC and PHAC—the only two labs that initially had all the reagents necessary to test for the virus—had confirmed a mere two dozen cases as the new H1N1 at the time. Each had scientists in Mexico helping officials build the capacity to do the tests themselves.

As to the virus's spread, newspaper headlines seem to speak volumes. But what's needed to predict spread, says epidemiologist and disease modeler Ira Longini of the University of Washington, Seattle, is an estimate of the virus's basic reproductive number, or R0, a variable that denotes the number of new infections caused by each infected person. Longini and others are trying to get their hands on as much data as they can from the first outbreak clusters to make that estimate.

The outbreak's discovery underscores the axiom that luck comes to those who are prepared. Although Mexico began to experience an unusually high number of hospitalizations with respiratory problems in late March, no special investigation took place, in part because the cases overlapped with the end of flu season. The disease also spared young children and the elderly, the two groups most vulnerable to severe cases of flu, which some researchers say should have triggered suspicions that an altogether new pathogen was responsible. The answer came when two respiratory cases, both of which looked like run-of-the-mill flu, came to the lab at the Naval Health Research Center (NHRC) in San Diego, California, which is conducting sophisticated tests for influenza as part of other studies.

Most people who have the flu never see a doctor, and the virus is rarely analyzed. But the Navy is developing better influenza diagnostics along with CDC's Border Infectious Disease Surveillance project and the Department of Defense's Global Emerging Infections Surveillance and Response System. The standard rapid test for influenza determines whether the virus is strain A or B. The tests under development analyze specific subtypes based on two proteins on the viral surface, hemagglutinin (H) and neuraminidase (N). When the naval lab could not subtype two patient samples, they rushed the samples to CDC, which had determined by 17 April that both were from a novel H1N1 swine flu virus.

Despite the crush of activity since CDC first identified this H1N1, we are still “making decisions with incomplete information,” Besser said. Part of the problem is that swine flu infections of humans have rarely been documented. Virologist Christopher Olsen of the University of Wisconsin, Madison, School of Veterinary Medicine co-authored a study in 2007 that found only 50 cases in the biomedical literature dating back to 1958. During the past 12 years, several new influenza genotypes surfaced in swine, making for “a very confusing picture,” says Olsen.

Researchers would like to know whether a virus must mutate to move from pigs to humans and whether, as is the case with bird flu in humans, a specific mutation makes it more virulent. “There is a feeling that once you know the sequence, you know everything about a virus, and you really don't,” says virologist Robert Webster of St. Jude Children's Research Hospital in Memphis, Tennessee.

CDC and PHAC have found that the current H1N1 combines pieces of influenza from North American swine and avian viruses, with human and swine sequences from Europe and Asia. “It's really a grand old mix-up,” says Webster.

Webster and Olsen also emphasize that just because the first cases surfaced in Mexico, the outbreak did not necessarily originate there. The pig that transmitted the virus may have been imported into the country, or the first transmission to a human may have occurred elsewhere.

Early on, CDC began to brew a “seed” strain for a possible vaccine against swine H1N1, and by 27 April the World Health Organization in Geneva, Switzerland, was already talking to vaccine manufacturers. One key problem is that the world's influenza vaccine production capacity—which still relies on growing the vaccine virus in chicken eggs—is limited to some 400 million vaccine doses a year and is impossible to expand quickly. Manufacturing swine flu vaccine would thus come at the expense of seasonal vaccine production, says retired pharma executive and flu vaccine expert David Fedson, and might lead to higher mortality and morbidity from the three seasonal strains.

For now, WHO says manufacturers should continue preparing vaccine for the 2009–10 flu season. But that could change if swine flu proves particularly severe. “We're in a casino now, and we're placing our bets,” says Fedson.

As to drugs, many countries began stockpiling oseltamivir after avian influenza put the pandemic threat on the political agenda in 2003. Individual governments, mostly in Western countries, have at least 220 million treatment courses in stock, says Martina Rupp, a spokesperson for Roche, the main producer of Tamiflu. Roche could ramp up its production capacity to some 400 million treatment courses annually fairly rapidly, she says; in addition, there are at least 10 generic manufacturers, four of them working under license from Roche, that produce oseltamivir. But the drug's complex manufacturing process makes it too pricey for many poor nations, says Fedson.

Both CDC and WHO have made clear that the careful plans developed over the past 5 years to squelch pandemics at their source don't play a role at all now because the virus is already too widely dispersed. In papers published in 2005 in Science and Nature, scientists concluded that it might be possible to stop a budding pandemic locally by aggressive, targeted use of antivirals and measures such as shutting down transport and schools. WHO had stashed away some 5 million treatment courses of oseltamivir that could be used to that end.

The scenario might have worked for swine flu, says Longini—if it had been tried much earlier. “There were 800 or 900 [suspected] cases before it hit the global radar screen; that's way beyond a containable outbreak,” Longini says.

Why it took so long to garner attention has many scientists puzzled. John Brownstein, the director of HealthMap, one of several systems set up recently to provide the world with realtime information about suspicious disease activity by having software scour news sources around the globe, says the first reports about a respiratory illness appeared in a Mexican newspaper on 1 April. “But there were 300 outbreaks at the same time, so what made this one different?” Brownstein asks. “We have to go back and see if there was a signature that we should have picked up here.”

2. Science and Society

# Hundreds Gather for Rally to Defend Animal Research

1. Greg Miller

LOS ANGELES, CALIFORNIA—Last week marked what some hope will be a turning point in the clash of wills between proponents of biomedical research and animal-rights extremists, who've ratcheted up their attacks on researchers in the United States in recent years. On 20 April, a Los Angeles County grand jury arraigned two animal-rights activists on 10 felony charges each, including stalking and threatening two researchers at the University of California, Los Angeles (UCLA). The following day, the Federal Bureau of Investigation added an animal-rights activist—Daniel Andreas San Diego—to its Most Wanted Terrorists list for his alleged role in bombing two San Francisco–area off ice buildings in 2003. This is the first time a domestic terrorist has been added to the list that includes the likes of Osama bin Laden. And on 22 April, hundreds of people turned out for a pro-research rally on the UCLA campus.

It's too early to tell whether these events will help diminish the recent spate of attacks on researchers at UCLA (Science, 21 December 2007, p. 1856) and elsewhere (Science, 8 August 2008, p. 755). Since 2006, animal-rights extremists have claimed responsibility for at least 10 acts of arson, attempted arson, and other vandalism at UCLA. Researchers there report being intimidated by death threats and harassed at their homes by people in masks who show up in the middle of the night.

Although no charges have been filed in any of the arson or attempted-arson cases, the indictments announced last week charge Linda Faith Greene, 61, and Kevin Richard Olliff, 22, with stalking and threatening UCLA researchers Lynn Fairbanks and Dario Ringach. That announcement follows the arrest on 22 February of four activists in connection with incidents targeting researchers at the University of California campuses in Santa Cruz and Berkeley. The FBI alleges the four violated the Animal Enterprise Terrorism Act, a 2006 law that carries penalties of up to 5 years in prison for using force, violence, or threats to interfere with research or other activities involving animals. “The message has now been sent pretty clearly that law enforcement is invested in this, that they're expending resources to stop the violence,” says Frankie Trull, president of the Foundation for Biomedical Research in Washington, D.C.

A visible police presence may have helped discourage any bad behavior last Wednesday when proponents and opponents of animal research gathered at UCLA. In the morning, several dozen animal-rights advocates set up shop on a street corner bordering UCLA's medical campus, carrying posters with images of bloody animals and slogans decrying animal experimentation as torture and fraud. Several protesters said they oppose animal experimentation, period. Others saw shades of gray but harbored doubts about whether lab animals are treated as humanely as possible, whether the benefits to human medicine are as great as scientists say, and whether researchers are doing too many redundant experiments or trying hard enough to find alternatives. The recent firebombings and other violence have distracted attention from such questions and made it harder for nonviolent activists to get their message out, said 3rd-year UCLA law student Jill Ryther, a member of the campus Animal Law Society. Those tactics “are giving animal-rights activists a bad name,” she said.

Meanwhile, a much larger crowd assembled as part of the Pro-Test rally organized by UCLA neuroscientist J. David Jentsch, who woke up the night of 7 March to find his car in flames. With the help of British pro-research activist Tom Holder, Jentsch modeled the rally on protests at the University of Oxford that were widely credited with helping to turn the tide of public opinion against animal-rights activists. Pro-Testers carried homemade signs with slogans such as “Science saves lives” and “Stop bombing us.” The group marched to the science quad for a series of short talks. Fairbanks, the first researcher targeted in the recent string of incidents at UCLA, said she spoke not as a researcher but as the mother of a son who had juvenile diabetes. “Animal research saved my son's life,” she said. “It's not true when they say it doesn't work.”

Others offered refutations to claims made by animal-rights activists—that animal research is unnecessarily cruel, that it's unregulated, and that it reveals nothing that couldn't be learned from tissue culture experiments, computer modeling, and other methods. The public's limited understanding of these issues has been exploited by extremists to justify their actions, said John Young, the director of comparative medicine at Cedars-Sinai Medical Center in Los Angeles and chair of the board of the pro-research group Americans for Medical Progress. He urged scientists to speak up. “The public wants to hear our story,” he said.

Jentsch and Holder said the turnout exceeded their expectations. Jentsch hopes the Pro-Testers sent a strong message to the public as well as those behind the attacks: “I think putting our faces on what we do humanizes the effort and makes it harder to write obscene things in the middle of the night and to brutalize people.”

3. Evolutionary Genetics

# Africans' Deep Genetic Roots Reveal Their Evolutionary Story

1. Ann Gibbons

Africa is the birthplace of modern humans, and so our species has lived longest—200,000 years—on that continent. As a result, Africans have had more time to accumulate changes in their DNA than humans elsewhere. But until now, researchers have barely scratched the surface of the rich diversity in Africans' nuclear DNA. Most genetic studies of Africans and African-Americans are based on data from just a few gene lineages, or on genomewide scans of a handful of the diverse African groups. “Africans have been the most completely neglected and underrepresented genetically of any continental group, because the most diverse groups are often remote,” says evolutionary geneticist Sarah Tishkoff of the University of Pennsylvania. “Hunter-gatherers don't usually get to clinics.”

Now, in the largest study ever of African genetic diversity, an international team of researchers led by Tishkoff has analyzed nuclear DNA collected over a decade from 113 populations of Africans from across the continent. In a report published online in Science (www.sciencemag.org/cgi/content/abstract/1172257) this week, the team has found that Africans are descended from 14 ancestral populations, which often correlate with language and cultural groups. They found that all hunter-gatherers and pygmies in Africa today shared ancestors 35,000 years ago and that East Africa was the source of the great migration that populated the rest of the world. They also found that African-American individuals, on average, have mixed ancestry from all over western Africa, which will make it difficult to trace roots to specific ethnic groups.

“Wow! This data gives us raw material for understanding human evolution that we have never had before,” says geneticist Jeffrey Long of the University of Michigan (UM) Medical School in Ann Arbor. Adds geneticist Noah Rosenberg, also of UM, “It's a treasure trove of information.”

Tishkoff and a team of European and African collaborators, in particular postdoc Floyd Reed, now at the Max Planck Institute for Evolutionary Biology in Plön, Germany, began collecting blood from far-flung tribes in Africa more than a decade ago. They drove off-road to visit peoples as diverse as the pygmies of Cameroon and hunter-gatherers in Tanzania. They set up centrifuges wherever they could find generators, survived a car crash, and spent years negotiating permits to collect blood ethically. “It was no small feat to get these samples,” says Tishkoff.

They ended up with blood from 3194 Africans from 113 populations. Working with additional collaborators, they genotyped the samples for a panel of 1327 well-known markers used to map genetic diseases in diverse populations. They then used various statistical methods to sort the DNA into closely related clusters and to trace patterns of inheritance. They also compared markers in Africans with those from 98 African-Americans, 21 Yemenites, and 952 individuals from around the world.

In many cases, the team found that ethnic, cultural, and linguistic differences reflected real genetic differences, which is “reassuring,” says paleoanthropologist Stanley Ambrose of the University of Illinois, Urbana-Champaign. For example, the hunter-gatherers spread throughout Africa, including the Sandawe and Hadza of Tanzania and the Khoisan speakers of southern Africa, shared common ancestors. All three of these groups speak click languages, which incorporate strong “click” consonants, some similar to the click used to urge a horse to speed up. The click-speakers and other hunter-gatherers from throughout Africa are all descendants of one protohunter-gatherer group that split apart more than 35,000 years ago, says Tishkoff. She also traces the origins of pygmies to that group, which suggests that pygmies may originally have been click-speakers.

The team found that San bushmen of southern Africa were among a handful of groups with the most diverse nuclear DNA, confirming mitochondrial and Y chromosome studies that suggested the ancestors of the San led a major migration throughout Africa, spreading out from their ancient homeland. The data also confirm earlier research indicating that the source population for the out-of-Africa migration of modern humans came from east Africa near the Red Sea.

The team focused on another migration as well: the exodus of slaves from Africa, sampling DNA from African-Americans in four U.S. states. These people inherited, on average, 71% of their DNA from ancestors who came from all over western Africa, 8% from other parts of Africa, and 13% from Europeans. This suggests that most African-Americans had ancestors from all over Africa, which will make it difficult to pinpoint their origins to specific ethnic groups, as ancestry-tracing kits now purport to do. The data will be important for “studies that seek to map disease genes in African-Americans,” says Rosenberg.

Overall, the paper is “a monumental synthesis,” says Ambrose, and the data, which will be posted on Tishkoff's Web site, are likely to be used by both biomedical and evolutionary researchers. “To understand the population genetics of any human population, we really need to understand Africa first,” says geneticist Jonathan Pritchard of the University of Chicago in Illinois. “It is sure to be an important paper and an important data set.”

Tishkoff herself says “there are still gaps in our knowledge.” She hopes to “help people designing biomedical research,” specifically to see how differences in DNA affect how people respond to disease and drugs. Treatments for AIDS, malaria, and tuberculosis can be life-threatening for some people, says Tishkoff, and the key to more effective treatments may be in their genes.

4. U.S. Science Policy

# Obama Courts a Smitten Audience at the National Academy

1. Jeffrey Mervis

Only once before has a newly elected president—John F. Kennedy in 1961—traveled the 10 blocks from the White House to the National Academy of Sciences (NAS) to explain his policies on science and innovation to the nation's most prestigious scientific organization. On Monday, President Barack Obama made the trip, and the symbolism was as important as the message: Many of the promises Obama made—to increase research spending, achieve energy independence, improve science education, and remove ideology from science decision-making—were not new, but having the president himself deliver them made all the difference.

“This is a major deal,” said NAS President Ralph Cicerone, still slightly awestruck half an hour after Obama had finished his 38-minute speech (www.nas.edu), shaken hands with front-row dignitaries, and headed back to the White House to greet a collegiate women's basketball team. “He understands how innovation works, and he has a wonderful way of explaining it to the public. The speech was inspiring and credible. We are extremely lucky to have him in the White House.”

The crowd, which began queuing up at 6 a.m., was already on his side long before presidential science adviser John Holdren introduced his boss at 9:12 a.m. But Obama clinched the deal by appealing both to their sense of duty—“I want to challenge you to use your love and knowledge of science to spark [a] sense of wonder and excitement in a new generation”—and their desire for more support—“We will devote more than 3% of our GDP to research and development, … the largest commitment to scientific research and innovation in American history.”

“Wow. Three percent has sort of been the Holy Grail for research funding,” says Charles Vest, president of the National Academy of Engineering. “It depends on so many things, including the denominator, and it's not really an end in itself. But it's a heck of a good place to start.”

Five countries are above that level, according to the Science and Engineering Indicators 2008 report from the National Science Foundation (NSF), with the United States at 2.6% in 2006. The report warns that the ratio is affected by many factors outside the government's control, from the amount of industrial spending to the health of the global economy, and that “meeting any specific ratio [is] an elusive policy goal.” Even within the government, the puzzle has many pieces: U.S. spending on defense, which is mostly applied research, far exceeds levels in any other country, for example. Speaking briefly after the meeting, Holdren said that no date has been set for reaching or exceeding 3%.

In announcing the target, Obama said his benchmark was the Apollo program of the 1960s, as the U.S. responded to the Soviet Union's launching of Sputnik. “That was the high-water mark of America's investment in research and development,” Obama recalled, “… and it is time for us to lead once again.”

One way to do that, he said, is to double the budgets for NSF, the Office of Science at the Department of Energy (DOE), and the National Institute of Standards and Technology as part of a boost in spending for the physical sciences. Another initiative would double spending on cancer research at the National Institutes of Health. He also made official his Administration's support for DOE's new Advanced Research Projects Agency-Energy, which was created in 2007 and received $400 million in the recent stimulus package. Although he praised the president's overall message, Lennard Fisk, a former head of the academies' Space Studies Board and of NASA's science program, said it is ironic that Obama is invoking memories of the space race at the same time NASA, which needs billions of dollars more to carry out all the scientific missions on its books, isn't one of the agencies whose budgets the Administration has pledged to double. “What type of space program does he envision?” asked Fisk, an astrophysicist at the University of Michigan, Ann Arbor. “It was fine in its day, but we don't need another Apollo program.” The sole new effort unveiled by the president was a joint education initiative at NSF and DOE to stimulate interest in energy research. NSF Director Arden Bement said that the two agencies would be spending “hundreds of millions of dollars a year” on efforts to entice students to pursue careers in clean energy and to educate the public about the challenges of moving from fossil fuels to renewable sources of energy. The money will go for classroom and laboratory activities at levels ranging from elementary school through graduate training, as well as for informal education. Bement said the initiative, dubbed RE-ENERGYSE in a White House press release, will tap into the 2-year stimulus funding for NSF and DOE along with regular agency budgets in this and subsequent years. He said other agencies may also participate. The biggest applause line of Obama's speech had nothing to do with money. But it is the reason why so many academy members have welcomed his election. Referring to the actions of his predecessor, Obama promised that “under this Administration, the days of science taking a back seat to ideology are over.” Toward that end, he also announced the rest of the members of the President's Council of Advisors on Science and Technology (www.ostp.gov). The 20-member council, co-chaired by Holdren, Harold Varmus, and Eric Lander, wasted no time getting down to business, convening in private only minutes after Obama hit the road. 5. Climate Change # Study Challenges Cosmic Ray–Climate Link 1. Richard A. Kerr If rising levels of greenhouse gases aren't pushing up global temperatures, as contrarians argue, what else could be? The leading alternative has been a fickle sun, and the sun's most likely—or most heavily promoted—agent of change has been cosmic rays. Now scientists have published the first comprehensive modeling of how the sun might indirectly thin cloud cover and thus warm the planet. It suggests that cosmic rays are not up to the task by two orders of magnitude. “It's a really good f irst study,” says modeler Dominick Spracklen of the University of Leeds, U.K., but “the first attempt is always going to be uncertain. There's going to be debate.” Until now, the debate over cosmic rays and climate has dwelt more on wavy lines on graphs than on state-of-the-art global modeling. In 1997, physicists Henrik Svensmark and Eigil Friis-Christensen of the Technical University of Denmark in Copenhagen reported that the extent of Earth's cloud cover seemed to vary in step with galactic cosmic rays—high-energy charged particles from outer space—striking Earth's atmosphere. The more cosmic rays, the more cloud cover screened out the warming rays of the sun and counteracted greenhouse warming. Such correlation does not prove causation, everyone agreed. Some experts disputed the existence of a correlation in the first place, and the consensus reports of the Intergovernmental Panel on Climate Change saw no substantial role for the sun in 20th century climate change. But debate rolled on, in part because researchers had been discussing a plausible physical mechanism since the 1950s. The sun's magnetic field fends off cosmic rays, they noted; lowered solar activity weakens that shield, increasing the flux of cosmic rays streaking into Earth's atmosphere. The cosmic rays ionize more gas molecules, which go on to form 1-nanometer-diameter particles that then grow to become the starter particles for cloud droplets, socalled cloud condensation nuclei (CCN). And the more cloud droplets, the denser and more pervasive the sun-shielding clouds. Although this chain of causation no doubt exists, no one could say whether it is strong enough to make any difference in global climate. So modelers Jeffrey Pierce and Peter Adams of Carnegie Mellon University in Pittsburgh, Pennsylvania, simulated the chain in a global atmospheric computer model of the sort used to model climate. Their model also incorporated the relevant microscale physical processes, from gas ionization to CCN formation. They ran simulations with cosmic-ray fluxes typical of maxima and minima in the 11-year solar cycle, which also happened to approximate the 20% range of cosmic-ray variation across the 20th century. As Pierce and Adams report in a paper in press in Geophysical Research Letters, their model showed that changes in cosmic rays are two orders of magnitude too feeble to cause the changes in clouds. “I'm feeling fairly confident that other models will also show the change in CCN is very weak,” Pierce adds. “It's possible the models are missing something important; it just doesn't seem likely.” The reason cosmic-ray variations don't make themselves felt up the chain, at least in the model, seems to be the daunting matter of millionfold growth. Once a tiny amount of, say, sulfuric acid vapor condenses onto a cosmic–ray–induced ion to form a 1-nanometer particle, a million times more vapor must condense on it within its lifetime of less than a week before it grows large enough to trigger cloud drop formation. All the while, other growing particles are competing for the scarce vapor and gobbling up smaller particles that they collide with. Make only a few ion-nucleated particles, and they are not enough to matter; make a lot, and there's too little vapor to go around, so few particles grow large enough. Other modelers have just started to run global simulations of atmospheric particle formation, provoking a range of reactions. “We see a very similar thing” in our model, says Jan Kazil of the University of Colorado, Boulder. “Cosmic-ray variations have only a small effect on the clouds in our model.” But Fangqun Yu of the University at Albany in New York says he disagrees with the Carnegie Mellon researchers “because of problems in their simulations.” Among other problems, Yu suspects that in simulating only two rates of new particle formation via ionization— very high and much lower—Pierce and Adams may have missed a “sweet spot” production rate in between, at which just enough but not too many particles are produced. Testing the Goldilocks hypothesis will take more modeling and observations. 6. ScienceNOW.org # From Science's Online Daily News Site China Falls Short on Olympic Cleanup. The Chinese government went to great lengths to reduce air pollution in Beijing in advance of the Olympic Games. But a new analysis in Geophysical Research Letters suggests that the country achieved only mediocre results. The problem? Officials didn't take the weather into account. http://tinyurl.com/chjzyo Artificial Blood Vessels Prove Effective. Scientists report in The Lancet that artificial blood vessels made using a person's own skin cells work well in patients receiving kidney dialysis. The new blood vessels mark the first vascular grafts to be derived entirely from a patient's own tissues, which lowers the odds of a harmful immune reaction. Down the road, engineered grafts may also prove useful in treating patients with circulatory problems in their legs and coronary arteries. http://tinyurl.com/d333v6 Presto, Instant Sunglasses! Researchers report in the Journal of the American Chemical Society that they have developed a material that almost instantaneously changes from clear to dark blue when exposed to ultraviolet light, and it just as quickly reverts to clear when the light is turned off. The new material, one of a class called photochromics, could be useful in optical data storage as well as in superfancy sunglasses. http://tinyurl.com/dj2x45 “Shall We Dance?” Pond scum may seem like a mass of ungraceful goop, but look closer: That gunk could be in the midst of an elegant minuet. According to new research in Physical Review Letters, tiny colonies of the common algae Volvox can whirl each other around for hours like ballroom dancers, driven by the rhythm of tiny, tail-like structures called flagella. The findings could shed light on how interaction between primitive organisms evolved. http://tinyurl.com/djrme4 Read the full postings, comments, and more on sciencenow.sciencemag.org. 7. Paleontology # ‘Protein’ in 80-Million-Year-Old Fossil Bolsters Controversial T. rex Claim 1. Robert F. Service A controversial finding that protein fragments can be recovered from dinosaur fossils has been replicated for the first time. Two years ago, Mary Schweitzer, a paleontologist at North Carolina State University in Raleigh, and colleagues stunned the paleontology community when they reported discovering intact protein fragments in a fossil from a Tyrannosaurus rex that died 68 million years ago. The claim has remained contentious, because proteins in tissue normally degrade quickly after an animal dies. On page 626, however, Schweitzer and colleagues report finding an even larger number of protein fragments from an 80-million-year-old fossil from a duck-billed dinosaur, or hadrosaur, known as Brachylophosaurus canadensis. “This will either be nothing or the biggest revolution in paleontology ever,” says Tom Kaye, a paleontologist at the Burke Museum in Seattle, Washington, and a critic of the original T. rex study. If the finding holds up, agrees Matthew Collins, an archaeologist and protein mass spectrometry expert at the University of York in the United Kingdom, “that would transform the way we do paleontology,” turning it into a discipline like genetics and molecular biology, built on molecular data. Similar hopes followed the original T. rex study. That paper (Science, 13 April 2007, p. 280) reported recovering collagen from a T. rex fossil unearthed in Montana and from a fossilized mastodon as much as 600,000 years old. Collagen, the principal protein in connective tissue, is rarely found in fossils more than a few hundred thousand years old. The paper reported that antibodies to collagen bound to the recovered material that had been chemically stripped of its minerals to leave behind what appeared to be soft tissue. When this material was run through a mass spectrometer, which identifies the sequence of amino acids in protein fragments, the sequences resembled those in collagen from birds, supporting fossil evidence that birds are descended from dinosaurs. Outsiders, however, raised several concerns. At the top of the list was the mass spectrometry data. The technique chops proteins into small snippets and then weighs them. By comparing the masses with those of known protein fragments, researchers can work out the amino acid sequences in the original protein fragments. But for some fragments in the samples, the mass signature was barely visible above the noise, lowering the statistical confidence in their proper identification. Kaye also suggested in July 2008 in PloS ONE that the proteins could have come from bacterial contamination (Science, 1 August 2008, p. 623). In a pair of technical comments in Science, Schweitzer and John Asara, a mass spectrometrist at Harvard Medical School (HMS) in Boston who was part of Schweitzer's team, defended the mass spec results and laid out a further case for why they thought the fossil proteins weren't from bacterial contaminants. They also posted all of their mass spec data in a public database, after critics complained that they couldn't evaluate the data without access to the complete data set. “It has been a stressful time,” says Schweitzer of the back and forth. But Schweitzer has welcomed the skepticism. Last November, she invited about a dozen of her staunchest critics to a meeting in Raleigh to go over the latest data. “Everyone discussed the ideas,” says Collins. “But at the end of the meeting, there were still the skeptics” calling for more control studies, independent verification, and better mass spec results, Collins says. The new paper “did a pretty good job in addressing the issues raised previously,” says William Stetler-Stevenson, a biochemist who specializes in studying proteins such as collagen, laminin, and elastin that are found in the extracellular matrix and bone, and who is not affiliated with Schweitzer's collaboration. For starters, Schweitzer's team went to great lengths to avoid contamination, says Martin McIntosh, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, Washington, and critic of the original T. rex paper. During excavation, the researchers used sterilized instruments to expose the bone and immediately placed their samples in sealed jars. Schweitzer then took some of the samples back to her lab and used chemicals to dissolve away the minerals, leaving behind what looks like a network of soft, transparent vessels, cells, and extracellular matrix. Other bone samples were sent to Raghu Kalluri, a biochemist at HMS, who carried out his own demineralization procedure and analysis. Both groups then independently performed biochemical and antibody-binding studies that showed evidence of collagen as well as laminin and elastin, two proteins found in blood vessels. Schweitzer also sent some of her demineralized extracts to Asara, who further processed them and tested them on a mass spectrometer more sensitive than the one used for the T. rex study. Asara's group identified eight collagen fragments. Asara sent some of the processed material to William Lane, another mass spec expert at Harvard University, who confirmed the presence of three of the collagen fragments. A later analysis of the purported hadrosaur collagen sequences found them more closely related to the samples from T. rex and to collagen from birds than to collagen from reptiles or other organisms. “This proves the first [T. rex] study was not a one-hit wonder,” Asara says. Perhaps, McIntosh says. “I'm not saying it's true. But I cannot right now make a plausible argument that it's not true.” He adds: “The door is closing on plausible alternatives.” 8. Conflicts of Interest # IOM Panel Backs Public Disclosure Of Drug Company Payments 1. Jocelyn Kaiser The best way to damp down concerns about doctors' and researchers' financial conflicts of interest is to require full disclosure, according to an expert report that adds its voice to a growing chorus. A panel of the National Academies' Institute of Medicine (IOM) says faculty members at medical institutions should be required to report all industry money they receive from outside their institution—no matter how small the amount—to special committees that would keep track of the data and manage conflicts. Such payments would also have to be reported publicly by the companies. The policy recommended by IOM would be far more intrusive than current U.S. rules, which require National Institutes of Health (NIH) grantees to report to their own institutions outside income of more than$10,000 per year. But IOM's mostly voluntary plan has an important selling point, some say: It could head off more-intrusive federal regulations.

Panel members agreed that some action is called for. “Many relationships between researchers and industry are very constructive, but it has to be overseen and kept in bounds,” says panel chair Bernard Lo, a bioethicist at the University of California, San Francisco (UCSF).

IOM decided to undertake the study 2 years ago amid growing concerns that academic researchers who took drug company payments were withholding data from publication or otherwise biasing results. (Funding for the study came from NIH, IOM, and several foundations.) Similar concerns resulted in a ban on all such payments to intramural scientists at NIH, Lo notes. More recently, as part of an ongoing investigation, Senator Chuck Grassley (R–IA) has identified several psychiatrists who allegedly failed to disclose hundreds of thousands of dollars in consulting income.

Disclosure is “a critical but limited first step” toward addressing conflicts of interest, the IOM panel concludes.* It urges research and physician organizations to develop a standard reporting format. And it endorses a proposal similar to one from Grassley to require that drug and device companies report payments to physicians in a public database. Companies should also disclose money given to institutions, scientific societies, patient groups, and basic researchers, the report says, because their work can lead to clinical trials.

Three of the 17 panel members recommended that physicians and researchers themselves also be required to publicly report their financial ties with companies, including stock. But the others disagreed partly because they felt it would be expensive, could intrude on privacy, and would not add much to the company database.

As a rule, the report says, institutions should ensure that if a significant conflict exists, a researcher “may not conduct research with human participants” unless his or her role is essential to the research. The report also recommends that institutions ban faculty members from accepting drug company gifts, serving as a spokesperson for a company, and authoring articles ghost-written by industry.

Many of these steps have been recommended in past reports from the Association of American Medical Colleges (AAMC), which has also endorsed the company payments database. But not all schools have followed AAMC's advice. “We give a pretty clear warning,” Lo says. “If the [institutions] don't get their act together, they're really inviting the legislators to step in. That, he warns, could lead to “very, very blunt” regulations and “a risk that valuable relationships will be curtailed in ways that will hurt patients.”

9. ScienceInsider

# From the Science Policy Blog

The Department of Health and Human Services (HHS) has decided to maintain limits on travel by National Institutes of Health (NIH) staff established during the Bush Administration. Scientists at the Bethesda, Maryland, NIH campus are unhappy about the continued restrictions, which HHS brass say are needed because of tight budgets. “We should be allowed to spend our money the way we think is best,” says Samuel Cushman, a 30-year NIH veteran. The limits come as NIH rushes to spend more than $10 billion in stimulus funding, the majority of which will go to research grants and construction. Astronauts, lawyers, and scientists met last week at the University of Nebraska to begin to hash out an international framework for dealing with asteroids heading toward Earth. One proposal under consideration was a body that would advise the United Nations on threats. British scientists who had been hoping for a £1 billion stimulus were disappointed when there was no increase for research in the U.K. government's new budget announced last week. Researchers have been hoping for one along the lines of the$21 billion boost U.S. scientists have received. The budget did feature a bonanza of climate-related funding increases, however, in keeping with the government's commitment to reduce greenhouse gas emissions, including £525 million for offshore wind projects, £435 million for energy efficiency, and £405 million to encourage low-carbon energy and advanced green manufacturing.

Elsewhere … A new tally of Iraqi deaths during the Iraq war by that nation's government puts the figure at 87,215. That deepens questions about a 2006 Lancet study that estimated the number at roughly 600,000. … The U.S. Smithsonian National Museum of American History is highlighting Lincoln's scientific bona fides as part of an exhibit marking the president's 200th birthday.

For the full postings and more, go to blogs.sciencemag.org/scienceinsider.

10. Origins

# On the Origin of The Immune System

1. John Travis

Did the immune system evolve to keep out harmful organisms, or is it like a bouncer at a nightclub, trained to allow the right microbes in and kick the less desirable ones out? In the fifth essay in Science's series in honor of the Year of Darwin, John Travis explores the evolution of the immune system.

It was a dramatic moment in the most dramatic confrontation so far between science educators and scientists determined to keep evolution in the classroom and advocates of the quasi-religious theory known as intelligent design (ID). In 2005, Lehigh University biochemist Michael Behe sat on a witness stand in Dover, Pennsylvania, as lawyer Eric Rothschild quizzed him about the claim in Behe's pro-ID book, Darwin's Black Box, that “We can look high or we can look low in books or in journals, but the result is the same. The scientific literature has no answers to the question of the origin of the immune system.”

When Behe reiterated that belief, Rothschild was ready. He began piling in front of the witness a large stack of recent journal articles, books, and book chapters, all relating research on the evolutionary origins of immunity, and asking Behe several times what he thought about the various publications. The biochemist admitted that he hadn't read much of the material, but he wouldn't budge from his position.

“So these are not good enough?” Rothschild asked at one point.

“They're wonderful articles. … They simply just don't address the question that I pose,” Behe responded.

The judge, John E. Jones, found Behe's responses revealing. Behe “was presented with 58 peer-reviewed publications, nine books, and several immunology textbook chapters about the evolution of the immune system; however, he simply insisted that this was still not sufficient evidence of evolution,” the judge wrote in his decision. Jones concluded that ID proponents set “a scientifically unreasonable burden of proof for the theory of evolution.” Score one for evolution, which is now taught without competition from ID in Dover schools.

It is fitting that studies of the origins of immunity provided a strong defense for the ideas first set forth by Charles Darwin 150 years ago. Darwin's elaboration of diversification and natural selection as organizing principles of life inspired early immunologists, helping them see that humans and pathogens are locked in their own survival-of-the-fittest battle. His theory also helped researchers realize that some of our immune defenses depend on a system of diversity coupled with selection among proteins.

As this newfound evolutionary mindset shaped immunological thinking near the turn of the 19th century, researchers also began to speculate about how our complex system of defenses arose. After decades of research, modern immunologists now think that single-celled organisms must have started by harnessing toxic peptides and gene-disabling molecules to thwart invading microbes—these weapons are still found in the simplest eukaryotes and more complex animals. And then when multicellular creatures evolved, they were able to devote specialized cells to tasks such as engulfing bacteria and viruses.

### Online Extras

This essay is the fifth in a monthly series. For more on evolutionary topics online, see Science's Origins blog. For more on the immune system, listen to a podcast by author John Travis [MP3]. And visit our Darwin page to catch up on previous months' Origins essays and the rest of our Year of Darwin coverage.

[Image credit: Wikipedia/George Richmod, From Origins, Richard Leakey and Robert Lewin]

Today, an ancient set of defensive mechanisms based upon protein receptors that recognize common features of dangerous pathogens has become hard-wired into the genome of every animal. (Plants have their own, parallel system.) Considered the first line of defense in animals, this “innate” immunity involves cells and molecules that rush to the site of an infection. Comparative studies of earthworms, sea squirts, sponges, and more suggest that this inflammatory response dates back to the origin of multicellularity.

In what has been called the “big bang of immunology,” most vertebrates later evolved a second form of immunity, in which white blood cells exquisitely targeted to a specific pathogen are rallied and then maintained in the body as an immune memory. This “adaptive” arm seemed to have appeared out of nowhere some 450 million years ago and may be the serendipitous outcome of invading DNA introduced by a virus or microbe infecting a fishlike creature.

It may seem ironic that an infectious agent endowed vertebrates with the keys to a new microbial defense, but it illustrates that microbes have shaped the evolution of animals for millennia. Indeed, a few researchers now suggest that immune systems evolved as much to manage and exploit beneficial microbes as to fend off nasty ones. “It's a paradigm shift in immunology,” says Thomas Bosch of Christian Albrechts University Kiel in Germany. Finding proof for such a radical change in thinking will be challenging, but scientists should soon have a more detailed view of immune evolution as they decipher the genomes of more invertebrates and vertebrates and tally up the defensive weapons shared by the various branches of life.

## Darwinian immunology

It was only shortly after On the Origin of Species was published in 1859 that infectious diseases were discovered and became a compelling example of a Darwinian struggle—humans pitted against pathogens—notes science historian Alfred Tauber of Boston University. To understand that contest, immunology emerged in the late 19th century as the science of host defense. Soon, scientists were fighting over the importance of two competing defense mechanisms: the humoral system of antibodies in the blood versus mobile amoebalike cells known as phagocytes. German biologist Paul Ehrlich and others championed the former; Russian Elie Metchnikoff, an embryologist, lobbied for the latter.

Darwin's ideas permeated Metchnikoff's formulation, says Tauber. The Russian maintained that phagocytes evolved first as nutritive cells—eating and delivering food to cells in animals without a gut—and were eventually enlisted to eat deleterious bacteria as well. In 1882, he observed that phagocytes within a starfish enveloped and digested foreign bodies, including bacteria.

As the field of immunology matured, it embraced both Metchnikoff and the humoralists, as researchers realized that the phagocytes complemented the defense offered by blood factors. In 1908, the embryologist even shared a Nobel Prize with Ehrlich.

A half-century later, another major intellectual advance within immunology bore the fingerprints of Darwin. Darwin's theory of evolution held that a large amount of variation exists among individuals in a species and that species can adapt to new circumstances because evolution weeds out the less fit, favoring variants that improve reproduction and survival. Immunologist Frank Macfarlane Burnet drew heavily on this concept in developing his theory about how the body forms its antibodies, the pathogen-binding molecules secreted by lymphocytes called B cells, according to science historian Arthur Silverstein of Johns Hopkins University School of Medicine in Baltimore, Maryland.

While other immunologists focused on how antibodies might evolve to better target a pathogen, undergoing their own kind of natural selection, Burnet proposed that the lymphocyte was the key evolutionary player being selected within the body. Those white blood cells making antibodies that react to the body's own tissues would be deleted, whereas one whose antibodies recognized a pathogen would survive and indeed be stimulated to expand greatly in number.

“It is a Darwinian theory,” notes Tauber. “You have enormous variation and then selection.” This process, what Burnet called clonal selection, lets the body tailor its response to a particular pathogen. Moreover, some of the selected lymphocytes stick around, providing a “memory” that helps the immune system thwart the same invader even faster if it comes again.

## Understanding the big bang

Clonal selection theory didn't answer all the mysteries about antibody formation. Although Burnet's idea assumed a large variation in preexisting antibodies, immunologists in the 1960s and '70s realized that animals could generate distinct antibodies to almost any protein or other molecular feature of a microbe. In fact, the vertebrate immune system could raise antibodies specific even to humanmade molecules not found in nature. Given the prevailing dogma that behind every protein there was a specific gene, immunologists were at a loss to explain this phenomenon, which became known as the generation of diversity, or GOD, problem.

In the late 1970s, in work that would earn him a Nobel Prize, Susumu Tonegawa of the Massachusetts Institute of Technology in Cambridge demonstrated that B cells can produce such a vast array of antibodies thanks to a complicated process called VDJ recombination. A maturing B cell starts with dozens to hundreds of three classes of gene segments—the V's, D's, and J's—and as it develops, the cell excises all but one of each class. The surviving V, D, and J then get stitched together into a DNA sequence that encodes an antibody unique to each mature B cell. (The other key player in the adaptive system, the T cell, also bypasses the one gene–one protein hurdle and similarly recombines gene segments to create distinct cell-surface receptors for pathogens.)

The elucidation of VDJ recombination gradually exposed immunology's big bang, recalls David Schatz of the Yale School of Medicine. By 1990, he and other colleagues then working in David Baltimore's lab at the Whitehead Institute for Biomedical Research in Cambridge had identified two genes essential to VDJ recombination, RAG1 and RAG2 (for recombination-activating genes). Sharks and all the other jawed vertebrates with adaptive immunity have these genes, but all the evidence at the time indicated that hagfish, lampreys, and invertebrates didn't. So, where did RAG1 and RAG2 come from?

Several clues, including that the two genes are located immediately next to each other, prompted Schatz and his colleagues to wonder whether the pair had once been part of a DNA recombination system in fungi or viruses that got incorporated into vertebrates. As immunologists teased out what the proteins encoded by the two did, they realized the molecules are the scissors and knitting needles that cut out all but one V, D, and J and stitch those remaining three gene segments together.

In 1995, Craig Thompson, then at the University of Chicago in Illinois, formally proposed that the DNA now encoding RAG1 and RAG2 was once a mobile genetic element called a transposon. Transposons can cut themselves out of one DNA sequence and stick themselves back in another, so immunologists could envision those skills being co-opted to recombine V, D, and J gene segments. In this “transposon hypothesis,” Thompson suggested that at some point after jawed and jawless vertebrates split into two branches, about 450 million years ago, a transposon invaded the former lineage, perhaps brought in by a virus that infected a germ cell. Boom—the enzymes that would ultimately provide adaptive immunity, by creating diverse antibodies and T cell receptors, were now in place and could mutate into that new role.

Many research teams began trying to verify the transposon hypothesis. In 1998, for example, Schatz's team and one led by Martin Gellert of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, independently showed that the enzymes encoded by RAG1 and RAG2 could, in addition to cutting out DNA sequences, actually insert one stretch of DNA into another. In a commentary in Nature, immunologist Ronald Plasterk of the Netherlands Cancer Institute in Amsterdam expressed the awe of many at this solid evidence of the transposon hypothesis. “We may owe our existence to one transposition event that occurred 450 million years ago,” he wrote.

At the Dover trial, much of the research literature piled in front of Behe detailed the increasing evidence for this transposon hypothesis. Although those papers satisfied the judge and show why the hypothesis is widely accepted, a major surprise since the Dover verdict suggests that this transposon invasion took place even earlier.

In 2006, a team led by Jonathan Rast of the University of Toronto in Canada and Sebastian Fugmann of the National Institute on Aging in Bethesda, Maryland, analyzed the genome of the purple sea urchin and found genes that closely resemble RAG1 and RAG2, the first time they've been uncovered in invertebrates. Their existence in the urchin suggests that the transposon with these enzymes invaded animals far earlier than had been thought but was lost in most lineages except for jawed vertebrates, which adapted them to perform VDJ recombination. That's an easier version of the story for some immunologists to swallow, as it allows more time for mutations to deactivate the jumping ability of a transposon and convert its DNA to a new job. “There was never a big bang of immunology,” suggests Bosch.

Thompson and others aren't so ready to defuse the explosive hypothesis, however. The RAG1-RAG2 transposon may have entered sea urchins and vertebrates independently, they stress. The role of RAG1 and RAG2 in sea urchins remains unknown, and Rast agrees that the timing of the transposon invasion responsible for adaptive immunity won't be nailed down until more invertebrate genomes are deciphered over the next few years. “The basic idea of an immune ‘big bang’ in the vertebrates has led to a variety of oversimplifications and conceptual problems,” says Rast. “Whatever the actual evolutionary pathway that led to the very complex vertebrate adaptive system, it was surely a gradual progression that co-opted many preexisting immune mechanisms.”

## First line of defense

Researchers have also made progress understanding the origins of innate immunity, encouraged by the recent appreciation that these defenses can be as sophisticated and effective as the adaptive arm. After all, about 90% of animal species have no adaptive immunity, yet they thrive, with many living for decades, in a world of microbes.

At the heart of this protection are proteins, called Toll-like receptors (TLRs), on cells of the innate immune system. Over the past decade, it has become clear that TLRs are the long-sought cell-surface receptors that recognize common microbial features such as bacterial wall components or the distinctive DNA sequences of a virus. This role could date back to the earliest multicellular organisms, as humans and some of the most evolutionarily primitive animals share TLRs and the molecules involved in the TLR signaling cascade.

The sea urchin genome revealed more than 200 TLR genes, for example, and in 2006, a group headed by Werner E. G. Müller of the University of Mainz in Germany reported that sponges also encode these microbial sensors. And plant disease-resistance proteins that recognize bacteria, viruses, and fungi include portions that structurally resemble TLRs, hinting that ancestors of these microbial sensors were on patrol long before plants and animals diverged.

As additional genomes reveal their secrets, evolutionary biologists should ultimately sort out which creatures have which immune molecules. Making sense of that data may demand conceptual breakthroughs in understanding the purpose of our immune defenses. Many immunologists accustomed to studying people, mammals, or other vertebrates assume that the adaptive immune system emerged because it allowed these more complex animals to deal with more complex microbial threats. And Thompson, now scientific director at the Abramson Family Cancer Research Institute in Philadelphia, Pennsylvania, thinks the key advantage is that the adaptive response conserves scarce resources by quickly fine-tuning the otherwise all-out assault mounted by the innate immune system. “Specificity gives you the advantage of being able to use the least amount of an immune system,” he says.

Still, some invertebrate biologists aren't convinced that their colleagues have nailed down the selective advantage of the adaptive immune system. “It's very hard to say what is the benefit,” says Bosch. He predicts one important line of future inquiry in the evolutionary study of immunology will be how immune systems have helped organisms adapt to their specific environments or ecological niches.

Bosch also cites the growing realization that animals harbor within their bodies a world of microbes that are crucial to development, nutrition, and more; by some estimates, humans are 90% bacterial cells. Immunologists, says Bosch, need to shift their thinking “from bacteria make you sick to bacteria make you healthy.” Such a shift may ultimately force a reconsideration of the roots of the immune system. Did the innate and adaptive arms truly evolve to keep out harmful organisms? Or instead, are one or both more like bouncers at a nightclub, honed for the more subtle task of allowing the right microbes in and kicking the less desirable ones out? If another evolutionversus-ID trial ever takes place, biologists addressing this provocative question will no doubt have added to the impressive stack of literature on how our immune system arose.

## References

A. Agrawal, Q. M. Eastman, D. G. Schatz, "Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system." Nature 394, 744 (1998).

G. Beck et al., Primordial immunity: foundations for the vertebrate immune system (New York Academy of Sciences, New York, 1994).

T. C. G. Bosch et al., "Uncovering the evolutionary history of innate immunity: The simple metazoan Hydra uses epithelial cells for host defence." Developmental & Comparative Immunology 33, 559 (2009).

A. Bottaro, M. A. Inlay, N. J. Matzke, "Immunology in the spotlight at the Dover 'Intelligent Design' trial." Nature Immunology 7, 433 (2006).

E. L. Cooper, E. Kauschke, A. Cossarizza, "Digging for innate immunity since Darwin and Metchnikoff." BioEssays 24, 319 (2002).

S. D. Fugmann, C. Messier, L. A. Novack, R. A. Cameron, J. P. Rast, "An ancient evolutionary origin of the Rag1/2 gene locus." Proceedings of the National Academy of Sciences 103, 3728 (2006).

K. Hiom, M. Melek, M. Gellert, "DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations." Cell 94, 463 (1998).

G. W. Litman and M. D. Cooper, "Why study the evolution of immunity?" Nature Immunology 8, 547 (2007).

P. Rosenstiel, E. E. R. Philipp, S. Schreiber, T. C. G. Bosch, "Evolution and Function of Innate Immune Receptors--Insights from Marine Invertebrates." Journal of Innate Immunity 1, 291 (2009).

A. M. Silverstein, "Darwinism and immunology: from Metchnikoff to Burnet." Nature Immunology 4, 3 (2003).

A. I. Tauber, "Metchnikoff and the phagocytosis theory." Nature Reviews Molecular Cell Biology 4, 897 (2003).

A. I. Tauber and L. Chernyak, Metchnikoff and the origins of immunology: from metaphor to theory (Oxford University Press: Oxford, 1991).

C. B. Thompson, "New Insights into V(D)J Recombination and Its Role in the Evolution of the Immune System." Immunity 3, 531 (1995).

M. Wiens et al., "Toll-Like Receptors are Part of the Innate Immune Defense System of Sponges (Demospongiae: Porifera)." Molecular Biology and Evolution 24(3), 792 (2007).

11. Newsmaker Interview

# Defying Skeptics, Richard Scheller Thinks Genentech Will Thrive

1. Greg Miller

Finally allowed to speak publicly, Richard Scheller, Genentech's new executive vice president for research and early development, spoke with Science last week about what the merger with Roche will (and mostly won't) mean for research at Genentech.

At the end of March, Swiss drugmaker Roche achieved its long-sought acquisition of Genentech, the pioneering biotechnology company in South San Francisco, California. Long before the deal was official, biotech analysts, former Genentech employees, and others bemoaned what they saw as the end of an era. Surely the buttoned-down pharmaceutical behemoth would crush the famously innovative culture at Genentech, where scientists have relished their freedom to pursue pet projects in basic science and the laid-back work environment, which among other niceties features Friday night “hohos,” or keg parties. People inside and outside Genentech credit its culture for its success as the first biotech company (it was founded in 1976) and one of the most profitable.

Richard Scheller, Genentech's new executive vice president for research and early development, says his number-one job is to prove the naysayers wrong. He will run Genentech as an independent research center, Roche announced on 14 April. Formerly a neuroscientist at Stanford University in Palo Alto, California, Scheller joined Genentech in 2001 and served as its executive vice president for research and chief scientific officer prior to the merger. Finally allowed to speak publicly, he spoke with Science last week about what the merger will (and mostly won't) mean for research at Genentech. His comments have been edited for brevity.

Q:Can you explain how Genentech will operate independently?

R.S.:I will report directly to the CEO of Roche and will operate independently here in South San Francisco a group of folks who do the research and clinical trials through phase II. We have complete decision-making authority over which projects we work on, how long we work on them, when to propose to move them forward, et cetera. The idea is, we'll be able to maintain the independence we had when Genentech was a publicly traded company.

Q:Are you saying nothing will change?

R.S.:No. If anything, now that phase I and II clinical development will also report to me, I think the research group will be even closer to the earlier stages of clinical development, which is absolutely critical. The first stages of clinical development are really more like basic science, attempting to obtain proof of concept for your hypothesis in man. [In] phase III, you're attempting to replicate the data on a larger number of patients. That's more of a logistical task. That part is best left to the global Roche development group. Our goal will be to hand them molecules that are ready for this final stage of clinical development.

Q:Many people saw Arthur Levinson as personifying the science-first culture of Genentech. What will be the impact of his departure as Genentech CEO?

R.S.:Art will remain on our scientific advisory board. He will come to research-review meetings. He will be chair of the board of Genentech. Art will still have a strong presence here, but he will not have the role [in daily operations] he had as CEO.

Q:How do you plan to maintain the famous Genentech culture?

R.S.:By making sure that scientists continue to have time to work on their own projects that aren't translational, that aren't governed in any specific way, and that scientists have time to think and imagine and invent, not just do routine things.

Q:Is that all there is to it?

R.S.:Coming up with a compensation system that's motivating to employees will be extremely important. And the ability to publish. The ability for scientists to develop their own international reputation, where they're not prevented from publishing or they only publish in the patent literature, for example, is something that will continue. We will continue to have a postdoc program. We have 120 postdocs at Genentech. The goal is for people to come and do interesting science and publish papers. There's no requirement that any of the work be translational. That keeps young and exciting people coming in to Genentech.

Q:Will the merger affect your ability to attract and retain top talent?

R.S.:I hope not. Time will tell. Since the bid for the merger was announced, Morgan Sheng joined us from MIT [Massachusetts Institute of Technology]. Morgan knew the bid would likely be successful and still decided to leave his position as a professor at MIT and a Howard Hughes investigator to move across the country to run neuroscience for Genentech. I think that's a pretty good sign.

Q:Why the push in neuroscience when so many disorders have proven frustratingly difficult to treat?

R.S.:It's a little bit ironic. When I came to Genentech, all work in neuroscience [here] was … being dismantled. I didn't believe at the time there was enough insight into the cellular and molecular basis of neurological disorders … to make an impact there. Two things have happened: Now we have a world-class small-molecule drug-discovery group. And we've learned enough about neuroscience—from finishing the genome to all that we've learned about ion channels and signal transduction and development—to think more rationally about diseases. It's not going to be easy, but in our opinion, it's time to get really, really serious about neuroscience.

12. Astronomy

# Herschel Will Open a New Vista On Infant Stars and Galaxies …

1. Daniel Clery

With the biggest mirror yet flown in space, Europe's new observatory will peer through a new wavelength window at the cool regions of the universe.

Over the years, astronomers have scoured most of the electromagnetic spectrum, from long-wavelength radio waves to very high-energy gamma rays, for information about the universe and its denizens. Later this month, Europe's Herschel Space Observatory will start to fill one of the remaining gaps: a region of the far infrared and submillimeter radiation with wavelengths between 200 and 850 micrometers. Researchers are keen to peer through this unseen window because they hope to see stars and galaxies in their formative years, periods during which they are obscured by gas and dust at other wavelengths. “Herschel gives us a picture of the cold universe, the dusty universe. Galaxy and star formation generate most energy here,” says astrophysicist Michael Rowan-Robinson of Imperial College London.

For the first part of its journey into space, Herschel will have company. The European Space Agency (ESA) will launch the €1 billion observatory together with Planck—a mission to map the cosmic microwave background radiation in unprecedented detail (see below)—on board a European Ariane 5 rocket. Although their scientific missions are very different, the two probes were managed as a single project by the same industrial team and have similar final destinations, around the Lagrangian point L2.

Lagrangian points are gravitational wells in the sun-Earth system. L2 lies on the night side of Earth, 1.5 million kilometers farther from the sun—a place far from interfering signals from Earth, where spacecraft can hover without using too much fuel (see figure, p. 585). Planck will settle into an orbit around L2 roughly 2 months after launch; Herschel will arrive more than a month later and take up a wider orbit. “It's an ingenious place to put such missions,” says Rowan-Robinson.

Astronomers studying infrared and submillimeter wavelengths have a tough time: Earth's atmosphere blocks such photons, and warm objects emit infrared radiation that swamps astronomical signals. Scientists have had some success putting telescopes in very high, dry places, but the real breakthrough came with the Infrared Astronomical Satellite, launched in 1983. ESA's Infrared Space Observatory followed in 1995, and then NASA's Spitzer Space Telescope in 2003 and Japan's AKARI in 2006.

“These were extremely powerful and successful missions, but they were limited by the need to have very cold instruments and telescopes,” says Matt Griffin of the University of Wales, Cardiff, a principal investigator of one of Herschel's detectors. To damp down infrared signals from the spacecraft, those probes used liquid helium to cool their detectors and mirrors. But it takes a lot of helium to cool a large mirror, and it is heavy stuff to loft into space. Hence, none of the earlier missions had mirrors larger than 1 meter, a limitation that restricted their ability to resolve distant objects.

“Herschel is a different kind of mission,” says Rowan-Robinson. Its wavelength range of 60 to 670 micrometers covers much of the gap between earlier infrared missions (up to about 200 micrometers) and ground-based submillimeter telescopes (850 micrometers and above). Not only is Herschel venturing into unexplored terrain, but it also carries the biggest mirror yet to fly in space, 3.5 meters across. To make such a size work, “we had to take the mirror out of the cryostat,” says Göran Pilbratt, ESA's project scientist for Herschel. Once that was done, “we were constrained by the size of the rocket,” he says. The huge reflector boosts angular resolution and sensitivity, allowing Herschel to see fainter objects, but leaving it at the slightly warmer ambient temperature of space adds noise. “Most of the power falling on the detectors comes from the telescope, not the sky,” says Pilbratt, and this signal has to be removed in later processing.

Herschel had a long gestation. The idea for such a mission arose in a workshop on submillimeter astronomy in 1982. When ESA announced a call for proposals for its Horizon 2000 science program later that year, some participants in the workshop put together a proposal. By 1986, the mission, then known as the Far Infrared Space Telescope (FIRST), was selected as one of Horizon 2000's four cornerstone projects, but it was the last of the four. ESA's science directorate, with a limited budget, had to work through three other large and complex missions before Herschel got its chance. “We had an opportunity to develop our instruments and get better detectors. They improved by an order of magnitude over the years,” says Thijs de Graauw, one of FIRST's originators and now director of the Atacama Large Millimeter/submillimeter Array (ALMA) in Chile.

One challenge was to develop detectors for Herschel's range of wavelengths. Astronomers working in the infrared have benefited from the military, which likes to spot warm things on the ground from space and has developed sensitive infrared detectors. At Herschel's slightly longer wavelengths, “there's been nothing done by anyone other than astronomers,” says Pilbratt. It's also an awkward middle ground between optics and radio electronics: Two of Herschel's detectors take an optics approach, whereas the third relies on radio techniques. The radio detector, known as HIFI, is a “remarkable achievement,” says Pilbratt. “Ten years ago, there was nothing like what you see in HIFI today.”

The mirror also had problems along the way. The plans originally called for it to be made of lightweight carbon fiber, but it proved difficult to build one large enough out of that material. A NASA team produced a prototype but had to pull out of developing it because of funding constraints. The managers decided to switch to silicon carbide, which ESA researchers had been experimenting with as a backup.

With its huge telescope, Herschel will be able to peer through gas and dust to construct a history of star formation from the early years of the universe to today. Griffin says the distant galaxies seen by the likes of the Hubble Space Telescope are already grown up. Hubble “doesn't see the ones in formation, behind the dust and gas,” he says. “We don't know how many of them there are,” adds De Graauw. Such star-forming galaxies emit radiation mostly in the cool infrared, and Herschel's wavelength range lets it spy on regions cooler than earlier satellites could. Herschel will be able to count the number of these distant galaxies in six different wavelength bands, charting their evolution. “We'll be able to say what's going on in these galaxies … [and] say how a galaxy like our own evolved into what it is today,” says Pilbratt.

Closer to home, Herschel will study in detail the life cycle of stars—how old first-generation stars explode, seeding the interstellar medium with heavy elements that then form part of the next generation of stars. “It's an ecosystem in balance,” says Griffin. “We can get a handle on all parts of the cycle. The chemistry and physics is not well understood.” De Graauw hopes researchers will find the trigger for star formation. “What starts the early ones—those without heavy atoms—is still a riddle,” he says.

Aside from the formation of galaxies and stars, astronomers also hope to use Herschel to study comets, asteroids, and planetary atmospheres in our solar system and how debris disks around stars form into planets. “It's a very good general-purpose observatory,” says Griffin. But Herschel had better not wait too long to make an impact, because another major general-purpose observatory will soon be snapping at its heels. ALMA, an array of 66 giant dishes under construction in Chile, will be producing science in just a few years and will cover wavelengths ranging from about 1 centimeter down to 300 micrometers. Says De Graauw: “There's quite an overlap. Herschel's going to be just in time.”

13. Astronomy

# …While Planck Dusts the Skies For the Fingerprints of Inflation

The newborn universe supposedly expanded faster than the speed of light. The European Space Agency's Planck satellite might prove it.

The big bang: The universe bursts into existence, an infinitely dense and hot soup of subatomic particles and radiation. In a fraction of a nanosecond, it doubles its size again and again, in a faster-than-light growth spurt known as inflation. That bizarre, hypothetical stretching evens out the universe but also sets off ripples in space and time called gravitational waves, which 13.7 billion years later should have left traces in the afterglow of the big bang, the cosmic microwave background (CMB). The 400 researchers working with the European Space Agency's (ESA's) Planck satellite hope to spot those traces—subtle patterns in the polarization of the microwaves called “B modes”—before anyone else does.

“The next Nobel Prize [for CMB studies] will go to the experiment that detects these modes,” predicts Nazzareno Mandolesi, a Planck team member from the Institute of Spatial Astrophysics and Physical Cosmology in Bologna, Italy. “That will prove without a doubt that inflation happened.”

The CMB has been a scientific treasure trove. Its accidental discovery in 1964 bolstered the then-controversial notion of the big bang and netted a Nobel Prize 14 years later. In 1992, NASA's Cosmic Background Explorer (COBE) spacecraft measured the spectrum of the microwaves and from its shape confirmed that the universe emerged in a single instant. COBE also detected tiny variations in the radiation's temperature across the sky. Those advances won a Nobel in 2006.

Sixteen years in the planning, the €700 million Planck satellite will be the third to study the CMB. The second was NASA's Wilkinson Microwave Anisotropy Probe (WMAP), which in 2003 charted in detail the temperature variations COBE had glimpsed. Those variations arose from the sloshing of matter and radiation in the early universe. With the data, researchers nailed down the makeup of the universe: 4% ordinary matter; 23% mysterious dark matter, whose gravity holds the galaxies together; and 73% space-stretching dark energy, which is speeding up the expansion of the universe.

Planck will chart the temperature variations in CMB with 10 times WMAP's sensitivity and three times its angular resolution. The microwaves are also polarized so that the electric fields in waves coming from any particular spot in the sky wiggle in a definite direction—just as ordinary light waves reflected from a pond are polarized so they oscillate horizontally as they zip into your eye. WMAP sketched the polarization of the CMB; Planck will render it in great detail.

Still, Planck may not be the sure-fire winner that COBE and WMAP were, some researchers say. “If it works as it should, then at the minimum, Planck will do very good science,” says David Spergel, a cosmologist at Princeton University and a member of the WMAP team. But there's no guarantee that Planck will spot something completely new, Spergel says: “That's what happens when you're the third satellite.”

Planck will be far more sophisticated than its predecessors. WMAP sampled microwaves at five frequencies; Planck will monitor nine of them over a range 12 times wider. WMAP cooled its detectors by exposing them to the frigidity of space; some of Planck's detectors must be cooled to within a fraction of a degree of absolute zero with a liquid-helium refrigerator. As WMAP did, Planck will circle the sun in synchrony with Earth, hovering at the so-called second Lagrange point, or L2 (see figure, above). There it will spin, scanning its microwave eyes across the sky and amassing in 18 months more than 100 billion measurements.

At the least, Planck should make superior measurements of the part-in-100,000 temperature variations. These variations reflect differences in the density of the primordial universe, irregularities that seeded the formation of the galaxies. With their stronger gravity, the denser regions drew in more matter, both dark and ordinary. Simultaneously, radiation pushed against the gathering ordinary matter, causing the matter to rebound. That jostling is encoded in the temperature variations, which is why WMAP could measure the relative amounts of dark and ordinary matter in the universe.

Planck should be able to nail down another key piece of information: the distribution of the original density variations. These variations can be broken down into longer and shorter wavelike undulations, much as a musical chord can be broken into individual notes. The relative strength of longer and shorter wavelength variations can be described by a single number called a spectral index, a cosmological parameter perhaps more important than any that WMAP measured, says Joseph Silk, a cosmologist at the University of Oxford, U.K., who works on Planck. “Planck is going to [measure] it much, much better than WMAP,” he says. “It's going to be beautiful.”

But the prize quarry for Planck researchers is the B modes. These features are swirls in the CMB polarization mapped across the sky, and spotting them would essentially clinch the case for the mind-bending theory of inflation.

The notion that the universe briefly expanded at faster than light speed might seem absurd, but it solves some thorny problems in cosmology, including a big one posed by the CMB itself. The temperature of background radiation is almost exactly the same—2.725 kelvin—all over the sky. That's perplexing because the distant reaches of the universe in opposite directions are so far apart that not even light has had time to travel between them. So they could not have interacted and should have no reason to have reached so nearly the same temperature. Inflation solves this problem by positing that opposite ends of the universe were cheek-by-jowl until the sudden expansion pulled them very far apart.

Although inflation fits the facts so far, researchers do not yet have direct proof that it occurred. The B modes would provide that. Current theory predicts that inflation should have generated gravitational waves and that those waves should have left lingering swirls in the polarization of the CMB.

Unfortunately, theory doesn't guarantee that the swirls will be strong enough for Planck to detect. Even if they are, Planck will have to sift through the effects created by our galaxy, which can also generate swirling polarization patterns. Planck's sensitivity to higher frequencies should help it identify such “foregrounds.” Planck will also have to beat out ground-based and balloon experiments searching for the B modes. Such small-scale efforts stole some of WMAP's thunder by precisely measuring the temperature variations first (Science, 28 April 2000, p. 595).

In principle, a spacecraft should have an edge over any instrument staring up through Earth's microwave-emitting atmosphere, says Alan Kogut, an astrophysicist at NASA's Goddard Space Flight Center in Greenbelt, Maryland. But Planck was designed primarily to study the CMB temperature variations, Kogut says, not to search for the B modes. Still, Planck has one advantage, says cosmologist John Carlstrom of the University of Chicago in Illinois. Mapping the whole sky, Planck will be able to look for the largest swirls. Ground-based experiments will be more sensitive to smaller ones. “Each has its niche where it offers more than the other,” Carlstrom says.

The future of CMB space missions may depend on Planck's and its rivals' at least glimpsing the B modes. Researchers are already planning more-sensitive spacecraft, but “if we do not find that signal, then I do not know how strong the argument will be to go that next step,” says Jan Tauber, Planck project scientist at ESA in Noordwijk, Netherlands. Among CMB studies, Planck should be either a very good satellite or a great one. If it's not a great one, it might also be the last of them.

14. Biofuels

# Corn-Based Ethanol Flunks Key Test

1. Dan Charles

In setting state rules for low-carbon fuels, California officials have calculated that corn ethanol is worse than gasoline.

A California regulatory agency charged with reducing greenhouse emissions from the state's cars has embraced a controversial approach for determining the true environmental impact of alternative transportation fuels. Its analysis could have broad implications for the future of corn-based ethanol or other fuels grown on U.S. cropland.

Last week, the California Air Resources Board (CARB) adopted a low-carbon fuel standard that requires greater use of fuels that cause lower greenhouse emissions, compared with gasoline (see graph). Corn-based ethanol doesn't meet that test and won't benefit from the new standard, CARB says, because diverting corn into ethanol production increases deforestation and the clearing of grasslands.

The biofuels industry has attacked the board's methodology, as well as similar conclusions in a regulation drafted last year by the U.S. Environmental Protection Agency (EPA) that is under review by the Obama Administration. Matt Hartwig, a spokesperson for the Renewable Fuels Association in Washington, D.C., says the California regulation will “have a tremendously chilling effect on future investment.”

But such a pullback would please Timothy Searchinger, a biofuel critic at Princeton University. Searchinger says that much of the claimed environmental benefit from biofuels depends on “an accounting error. They treat land as free.”

The debate was once confined to the pages of scientific publications. For example, Searchinger has found that corn ethanol produces twice the greenhouse gas emissions of gasoline, for every mile driven, once emissions from land conversion are counted (Science, 29 February 2008, p. 1238). Searchinger used a global model of agriculture to calculate the effects of increasing ethanol production. (About one-quarter of this year's U.S. corn crop will be turned into ethanol.) The model indicates that if U.S. farmers devote more land to growing corn for ethanol, food prices would increase, leading farmers around the world to convert grasslands and forests into crops. That shift, in turn, would release large amounts of greenhouse gases.

But other researchers expect farmers and agribusinesses to respond to higher food prices in less destructive ways. They foresee innovations that increase yields on existing land.

Government efforts to promote alternative fuels are now drawing regulators into the crossfire. California's new low-carbon fuel standard will require a 10% reduction in greenhouse gas emissions from the average liter of transportation fuel by 2020. To calculate that reduction, CARB's staff measured the “carbon intensity” of alternative fuels, including likely emissions from the ripple effects of biofuel production on global agriculture. At the federal level, a 2007 law requires EPA to calculate the “life cycle greenhouse gas emissions” of renewable fuels, to make sure they meet minimum standards.

CARB relied on a model, developed by researchers at Purdue University, that concluded that corn-based ethanol produces slightly greater greenhouse emissions than does gasoline, with about 30% of those emissions occurring as farmers clear land for crops.

EPA has not yet released its studies, but some who have been briefed on them say the agency anticipates an even larger area of the world's forest and grassland being converted into food and ethanol production. Ethanol receives a better overall grade, however, because EPA assumes that current ethanol refineries are more efficient.

The analyses have infuriated biofuel advocates, who last week condemned the board's methodology as unfair, artificial, and lacking any real-world data. More than 100 scientists, many of them involved in biofuel research, have told CARB that the science of estimating emissions from land conversion is “far too limited and uncertain” to use in regulations. In Congress, a dozen farm-state senators want EPA to halt any effort to calculate the greenhouse effects of land-use change caused by biofuels. “It defies common sense that EPA would publish a proposed rulemaking with harmful conclusions for biofuels based on incomplete science and inaccurate assumptions,” said Senator Charles Grassley (R–IA) in March.

CARB, for now, is sticking to its guns. “We feel that our recommended value [for greenhouse emissions from land-use change] is very reasonable,” said CARB staffer Wes Ingram. However, the board promised a full review of the issue in January 2011, 1 year before the regulation takes effect.

Searchinger, for one, thinks that CARB's estimate is too low. He points out that CARB's model predicts that higher prices would lead to less food produced globally, which he says probably means more hunger. Efforts to avoid that fate would increase greenhouse emissions, he says.

Bruce Babcock, an economist at Iowa State University in Ames who is working with EPA, says broader consideration of land-use decisions could spark new controversies. The best way to reduce the clearing of land for crops, says Babcock, would be to impose a tax on meat consumption. “If we all turned into vegetarians, we could get by on one-tenth of the land,” he says.

15. American Association of Physical Anthropologists

# Civilization's Cost: The Decline and Fall of Human Health

1. Ann Gibbons

AMERICAN ASSOCIATION OF PHYSICAL ANTHROPOLOGISTS, 31 MARCH-4 APRIL 2009, CHICAGO, ILLINOIS

When humans were freed from searching for food from dawn to dusk, they finally had time to build cities, create art, and even muse about the gods. Agriculture and cities made human life better, right? Wrong, say archaeologists who presented stunning new evidence that most people's health deteriorated over the past 3000 years. “We document a general decline in health across Europe and the Mediterranean,” says bioarchaeologist Clark Spencer Larsen of Ohio State University in Columbus. He's a coinvestigator of the European Global History of Health Project, an ambitious new effort to study the health of Europeans during the past 10,000 years.

Most bioarchaeology studies tend to tell the tale of illness and death of people from a single site, such as a burial pit for plague victims or an ancient cemetery. Larsen's project is one of the first—and the largest—to try to reveal broad trends by assembling standardized data from large samples. In a series of posters, the team presented the first analysis of data on 11,000 individuals who lived from 3000 years ago until 200 years ago throughout Europe and the Mediterranean. “This is a real tour de force,” says bioarchaeologist George Armelagos of Emory University in Atlanta, after reviewing the posters.

The project has taken 8 years and \$1.2 million to organize so far. The goal was to pool 72 researchers' data on standardized indicators of health from skeletal remains, including stature, dental health, degenerative joint disease, anemia, trauma, and the isotopic signatures of what they ate, says project leader Richard Steckel of Ohio State. They also gathered data on settlement size, latitude, and socioeconomic and subsistence patterns so that they could compare rich and poor, urban and rural, farmers and hunter-gatherers.

They found that the health of many Europeans began to worsen markedly about 3000 years ago, after agriculture became widely adopted in Europe and during the rise of the Greek and Roman civilizations. They document shrinking stature and growing numbers of skeletal lesions from leprosy and tuberculosis, caused by living close to livestock and other humans in settlements where waste accumulated. The numbers of dental hypoplasias and cavities also increased as people switched to a grain-based diet with fewer nutrients and more sugars.

The so-called Dark Ages were indeed grim for many people who suffered from more cavities, tooth loss, rickets, scurvy, and bone infections than had their ancestors living in hunter-gatherer cultures. People became shorter over time, with males shrinking from an average of 173 centimeters in 400 B.C.E., for example, to 166 centimeters in the 17th century—a sure sign that children who were not members of the elite were eating less nutritious food or suffering from disease.

Why would people want to settle in towns or cities if it made them sick? One answer is that settlers suffered less bone trauma than nomadic hunter-gatherers, suggesting to Steckel that they might have felt safer in villages and, later, towns where an emerging elite punished violent behavior—but also controlled access to food.

The social and political inequities in urban centers meant that for nonelites, moving into cities was “almost a death sentence” for centuries, notes Armelagos. In the Middle Ages, people in the countryside were generally taller than people in cities.

After a long, slow decline through the Middle Ages, health began to improve in the mid-19th century. Stature increased, probably because of several factors: The little Ice Age ended and food production rose, and better trade networks, sanitation, and medicine developed, says Steckel. But take heed: Overall health and stature in the United States has been declining slightly since the 1950s, possibly because obese Americans eat a poor-quality diet, not unlike early farmers whose diet was less diverse and nutritious than that of hunter-gatherers. By understanding how disease and malnutrition spread in the past, researchers hope to apply those lessons in the future. “Our goal is to understand the health context for what we have today,” says Larsen.

16. American Association of Physical Anthropologists

# Of Tools and Tubers

1. Ann Gibbons

AMERICAN ASSOCIATION OF PHYSICAL ANTHROPOLOGISTS, 31 MARCH-4 APRIL 2009, CHICAGO, ILLINOIS

If tools make the man, then sharp, durable tools make an even handier man or woman. That knowledge was not lost on our ancestors as early as 2 million years ago, according to a new analysis of stone tools and bones left behind near Lake Victoria in Kenya. At the Paleoanthropology Society gathering, which met concurrently with the larger meeting, researchers reported that at this early date humans purposely selected the highest-quality stone and transported it more than 13 kilometers to an animal butchery site. A collaborating team also reported that these early humans, presumably Homo habilis or early H. erectus, used tools not only to deflesh carcasses but also to slice tuberous roots, possibly a key part of their diet.

These tools, found at the site of Kanjera South in Kenya, are not the oldest known, which date back to 2.6 million years ago in Ethiopia. But they are “the first evidence that [early humans] were not just using tools to eat meat but to process plants, and possibly woodworking,” observes paleoanthropologist Alison Brooks of George Washington University in Washington, D.C. “This shows dietary diversity and the investment of energy to have the best tools to enhance that diversity.”

Paleoanthropologists Thomas Plummer of Queens College in New York City and David Braun of the University of Cape Town in South Africa found that one-third of the stone tools at Kanjera were made of durable stone, such as quartzite and rhyolite, that came from at least 13 kilometers away. The team tested the stone for durability and ease of flaking and found that the imported stone kept a sharp edge far longer than did the site's local limestone. “This suggests [early humans] are being selective and that the quality of the lithics is important. Otherwise, why transport it?” says Plummer.

To find out just what early Homo was doing with the tools, Plummer enlisted archaeologist Cristina Lemorini of the University of Rome, “La Sapienza.” She studied replicas of the Kanjera tools, made with the same kinds of stone, that modern Hadza hunter-gatherers of Tanzania had used to butcher animals, process wild tubers, cut grass, and work wood. Then, using confocal and metallographic microscopes, she compared patterns of wear on the edges of the Kanjera tools with those on the replicas. She reported that the ancient tools had telltale signs of being used to process plant materials, such as cutting grass, and the distinct striations made by sediment as tools were used to clean and section fibrous tubers. She also saw patterns consistent with defleshing carcasses and woodworking, possibly to make wooden tools.

Researchers have proposed before that early humans relied on tuberous root vegetables as an important fallback food (Science, 7 October 2005, p. 46), but they lacked direct evidence and so have failed to convince skeptics. In a separate talk at the meeting, anthropologist Margaret Schoeninger of the University of California, San Diego, offered a new reason why tubers might have been important: as a source of water.

In a study of the Hadza, Schoeninger found that they chewed tuberous roots such as panjuko and makaritakos. But they didn't swallow the fibrous wad, which would yield few calories. Instead, they spit it out, apparently after sucking the liquid out of the tubers, which are 80% water. Schoeninger suggests that tubers were portable canteens as well as a fallback food. “Tubers could have provided much-needed water as our ancestors moved into open, more seasonal environments,” she says. One test of this idea would be to see if other hunter-gatherers also quench their thirst with starchy tubers, says Brooks. For now, it seems that sharp tools helped humans develop two distinct dietary tastes, for meat—and root vegetables.

17. American Association of Physical Anthropologists

# Reproductive Fate Versus Environment

1. Ann Gibbons

AMERICAN ASSOCIATION OF PHYSICAL ANTHROPOLOGISTS, 31 MARCH-4 APRIL 2009, CHICAGO, ILLINOIS

Women's fertility is determined in large part at birth. They are born with their total number of ovarian follicles, for example, which normally influences the age at which menopause begins. But in the 1990s, researchers proposed that if a child's energy is depleted by malnutrition, disease, or other factors, he or she would be less fertile as an adult. By using the natural experiment of migration, researchers demonstrated in a talk how differences during childhood do indeed alter the course of reproduction in adult women.

Biological anthropologist Gillian Bentley of Durham University in the United Kingdom and colleagues compared levels of reproductive hormones in 250 Bangladeshi women, including women who migrated from Sylhet, Bangladesh, to London; women who stayed in Sylhet; and Bangladeshi women born in London. In the first stage of their study, Bentley and Alejandra Núñez-de la Mora of Durham University found that women who migrated from Bangladesh as children had higher levels of the hormone progesterone in their saliva than women who lived in Sylhet, but less than women born in London. This had a direct effect on fecundity: Migrant women in London had an 11% higher rate of ovulation during their lives than did women in Sylhet, the team reported in 2007. “We're beginning to see how the ovaries get feedback from the environment” to determine how many eggs are allowed to mature, says anthropologist Benjamin Campbell of the University of Wisconsin, Milwaukee.

The team has now studied 900 women between the ages of 35 and 60 to see if the onset of menopause varies between migrants and women in Sylhet. Bentley presented preliminary results from their measurement of hormones that regulate the maturation of ovarian follicles and are indirect indices of how many ova they can still produce. Her team found that women who migrated as adults had higher levels of inhibin B and anti-Müllerian hormone in their blood than women in Sylhet did but less than women born in London. This suggests that migrants enter menopause later than did women who stayed in Bangladesh but earlier than did those born in London. “The adult migrants seem to be sensitive to improved conditions,” says Bentley.

The group is trying to find out which environmental factors in Bangladesh lower growing girls' fertility. All the Bangladeshi women in the study came from middle-class, land-owning families, who grew up with adequate calories. However, girls growing up in Bangladesh were probably exposed to more infectious diseases, including parasitic worms, during crucial developmental years. So, they may have had to make tradeoffs among using energy to grow, to maintain their bodies, or to maximize their reproductive potential as adults. Bentley plans to test that idea next year when her team returns to Bangladesh to see if girls there suffer from more diseases than do those in London. “In other words,” says Bentley, “where you spend your childhood influences adult reproductive function.”