# News this Week

Science  11 Dec 2009:
Vol. 326, Issue 5959, pp. 1464
1. Animal Research

# Rejection of Anthrax Study Kicks Up a Dust Storm in Oklahoma

1. Greg Miller

A media maelstrom erupted last week over a primate research project that was rejected by administrators at Oklahoma State University (OSU) despite winning federal funding and approval from the university's animal care and use committee. The move triggered charges that the university had flouted the standard scientific and ethical review process to curry favor with a generous donor who is a vocal animal-rights activist. A university official strenuously denies that charge but says that fears of attacks from animal-rights extremists were a major factor in the decision.

The decision is unusual if not unprecedented, says Mark Lively, a biochemist at the Wake Forest University School of Medicine in Winston-Salem, North Carolina, and president of the Federation of American Societies for Experimental Biology. Lively says he knows of no other example of a university administration overruling its own animal care committee, let alone passing up an opportunity to receive federal research money.

The project aims to develop methods for studying anthrax infection and testing vaccines and treatments in baboons. It is one component of a larger, ongoing research effort led by Shinichiro Kurosawa, an immunologist at Boston University School of Medicine who worked previously at the Oklahoma Medical Research Foundation in Oklahoma City and has continued to collaborate with researchers there and at OSU. The National Institutes of Health agreed to fund the research, and after a lengthy review, OSU's Institutional Animal Care and Use Committee gave it a green light. But in October, Stephen McKeever, OSU's vice president for research, notified Kurosawa that university President Burns Hargis had decided that the project would not be allowed at OSU.

Kurosawa declined to comment, beyond writing in a brief e-mail message: “As guest scientists at OSU, we are obliged to follow their policies and it is unfortunate that we cannot fully complete our research there at this time.” Colleagues say Kurosawa will now have to try to work out an agreement with one of the few labs in the country that have the capacity to handle both primates and infectious anthrax.

The issue gained attention last week when The Oklahoman newspaper picked up the story, and it quickly provoked a commotion in the blogosphere. In response, the university issued a statement saying that “The OSU administration determined that this research was not in the best interest of the university. The testing of lethal pathogens on primates would be a new area for OSU that is outside our current research programs.”

Those sentiments seem at odds with the university's recent investment in a new biosafety level 3 laboratory on the Stillwater campus, where Kurosawa's research would have been conducted. When the lab opened in 2006, officials declared it would help position the university to bring in more federal money for research on biodefense and infectious disease. “OSU and the College of Veterinary Medicine have made a sustained investment in building the resources and infrastructure to do this kind of research, and now suddenly it's off the table,” says Michael Davis, a veterinarian and physiologist at OSU and a member of the animal use committee that approved the anthrax project.

Researchers at OSU and elsewhere were quick to speculate that Hargis's decision was influenced by the university's most prominent donors, billionaire T. Boone Pickens and his wife, Madeleine, an outspoken animal-rights activist. Pickens has donated $458 million to the university in recent years, according to a September article in The New York Times. Madeleine Pickens caused a flap earlier this year when she stipulated that a$5 million donation to OSU could not be used to benefit the veterinary school because of what she described as “barbaric” practices used in the surgical training of students. Faculty members protested that Pickens's allegations were based on faulty information, but the school ultimately changed its policy; it now bans euthanasia of animals used in teaching labs.

McKeever flatly denies that the Pickenses had a role in the decision to block the anthrax project. “We never had any discussions with them about this issue,” McKeever says.

Hargis made the decision based on several factors, McKeever says: “The issue he was mostly concerned about was that he really did not want to attract controversy from the violent elements of various animal-rights groups. He did not want to put OSU in that spotlight and so unnecessarily distract from or interfere with current research.”

The decision has caused anger, confusion, and concern among OSU researchers. “It certainly makes us look like a backwards, hillbilly state university,” says Richard Eberle, a virologist at OSU who had planned to collaborate with Kurosawa. “I suspect OSU is going to be looked at a little more carefully as a potential research partner in the future.” Eberle and others say they've received no clear indication from the administration about what kinds of research it now considers permissible. “The goalposts have definitely shifted,” says Davis. “The problem is we don't even know where they've gone.”

The statement issued by the university last week says: “the administration has simply decided that OSU will not have primates euthanized on its campus.” Although that sounds like a categorical declaration of future policy, McKeever told Science that any future proposals involving primate euthanasia will be judged on a case-by-case basis: “We're in discussions with the faculty about establishing procedures by which we will review such proposals in the future.”

2. Climate Change

# Deforestation Moves to the Fore in Copenhagen

1. Eli Kintisch

As the Copenhagen climate meeting unfolds this week, one key topic will be protecting the world's tropical rainforests. Deforestation is responsible for between 12% and 25% of the world's yearly greenhouse gas emissions. But the 1997 Kyoto agreement, which runs through 2012, didn't address the issue. Participating nations hope to correct that oversight in the next agreement. “It is likely that in Copenhagen the international community will commit to reducing the rate of deforestation by a specific amount, possibly 50% by 2020,” predicts Frances Beinecke of the Natural Resources Defense Council in Washington, D.C.

Stopping deforestation is among the cheapest ways to reduce emissions, at an estimated cost of less than $10 per ton of carbon dioxide. Last month, Brazil announced that it would voluntarily reduce its carbon emissions, most of which come from deforestation, by 36% to 39% by 2020 (Science, 27 November, p. 1175). But government officials are counting on an international system that compensates landowners, ranchers, and farmers for not cutting down trees. A number of thorny issues must be resolved before that can happen. Last month in Barcelona, Spain, national representatives left dozens of key phrases in brackets in the draft text, indicating language still in dispute. “They didn't even decide whether they would aim for official treaty language or further official ‘guidance’ coming out of Copenhagen,” says Kate Cecys of the Pew Center on Global Climate Change in Arlington, Virginia. Negotiators call the issue Reducing Emissions from Deforestation and Forest Degradation (REDD). But just what shade of REDD will count is a matter of hot debate. Should developing countries get credit for reforestation, or is it enough to simply prevent the destruction of standing forests? Developed countries, which would presumably fund any such system, are leery of anteing up before they receive what they view as credible assurances from participating nations. Deciding what types of activities will be eligible for REDD funds “may be too much to sort out in the time we have,” said Tracy Johns of the Woods Hole Research Center in Massachusetts. Since 1997, scientists have improved their measurements of emissions from deforestation. That knowledge, along with a better understanding of what drives forest emissions and how to combine ground and satellite data, has helped to win over skeptical politicians. In 2003, the Intergovernmental Panel on Climate Change spelled out a step-by-step process to estimate land use, emissions, and uncertainties related to deforestation. The United States and other developed nations prefer those guidelines, but countries with large tropical forests haven't said whether they support such an approach to assess their carbon stocks. Another sticking point is whether countries will get credit for individual projects or instead be held accountable for comprehensive national commitments. Compensating landowners or farmers for REDD could cost$18 billion or more per year, and there is no consensus on how to raise the money. Brazil's federal government, for example, has generally preferred direct payments from an international fund. (Norway has pledged $1 billion toward efforts in the Amazon, contingent on Brazil's actions on REDD.) But Brazil recently warmed to the idea of developed countries using carbon-credit offsets under an international system to pay for REDD projects. (The cap-and-trade bill passed last summer by the U.S. House of Representatives allocates 5% of emissions certificates for such credits.) Other players are thinking locally. The state of Mato Grasso, Brazil, this week announced an arrangement in which U.S. companies operating under future emissions caps could purchase early carbon credits that would fund forest protection in the Amazonian state. “We want to take advantage of the momentum on REDD to get some programs in place,” says forest scientist Daniel Nepstad of Woods Hole, who helped arrange the program. 3. Anthropology # Chagnon Critics Overstepped Bounds, Historian Says 1. Charles C. Mann PHILADELPHIA, PENNSYLVANIA—The scene was familiar. Almost exactly 9 years ago this week, a packed session at the American Anthropological Association's (AAA's) annual meeting rancorously debated the inflammatory misconduct charges in journalist Patrick Tierney's book, Darkness in El Dorado: How Scientists and Journalists Devastated the Amazon. That 2000 session went over its allotted time and dissolved into acrimony. On 2 December, the AAA annual meeting held another panel discussion on Darkness. It, too, was packed (though the room was smaller), filled with ethics charges and bitter, sometimes personal debate, and unable to finish on time, as arguments spilled into the hallways. Leaving the room, Robert Carneiro of the American Museum of Natural History in New York City told Science, “I don't know if this is ever going to end.” This year's meeting had a different slant on the ongoing fight over Tierney's book, which focused on anthropologists' treatment of the Yanamamö Indians of southern Venezuela and northern Brazil. Nine years ago, much of the meeting echoed Tierney's book in attacking Yanamamö researcher Napoleon A. Chagnon, now a professor emeritus at the University of California, Santa Barbara. This time around, most of the criticism was leveled at Chagnon's accusers and the AAA itself. In the 2 December session, historian Alice Domurat Dreger of Northwestern University's Feinberg School of Medicine in Chicago, Illinois, reported on her research into AAA's role in the affair, as part of a book on scientific controversies. So problematic were AAA's actions, she charged, “I can't imagine how any scholar feels safe” as a member. The Yanamamö have become something akin to anthropological celebrities: A relatively large and non-Westernized indigenous group that still largely makes a living by hunting, foraging, and slash-and-burn agriculture, they became well-known through Chagnon's work. His book, Yanomamö: The Fierce People (1968), and documentaries launched a cavalcade of research on the Yanamamö, who have since been studied by as many as 50 anthropologists. From the beginning Chagnon's work attracted criticism, especially his view that warfare is a key building block of Yanamamö society. This attracted the ire of both opponents of evolutionary psychology and indigenous-rights activists, who charged that Chagnon's ideas were being used to justify taking Yanamamö land. Eventually, these criticisms helped to get Chagnon banned from research in both Venezuela and Brazil. But Tierney's charges went well beyond the scientific. Although Darkness excoriated many anthropologists, the book focused on Chagnon, and especially a 1968 incident in which Chagnon and the celebrated late geneticist James R. Neel vaccinated Yanamamö and observed their immune responses. Tierney argued that the pair had never obtained informed consent and exacerbated or even caused a fatal measles epidemic. AAA, apprised of the book's charges in September 2000, asked a commission led by former AAA President James Peacock for a confidential report—“inevitably meaning that Chagnon couldn't confront his accusers,” Dreger said in an interview, and heading “down the path of violation of due process.” Peacock, as he said at the AAA meeting last week, decided the charges had enough evidence to merit “an investigation.” However, the AAA ethics code, adopted in 1998, forbids “adjudicat[ing] claims for unethical behavior,” so AAA assembled a task force to conduct an “inquiry.” The task force exonerated Chagnon and Neel of the epidemics charges (Science, 19 January 2001, p. 416) yet concluded that Tierney's allegations “must be taken seriously” and said Chagnon's work “had been damaging to the Yanamamö.” In 2005, the AAA membership voted by a large majority to rescind the task force report, but it remained on the AAA Web site until September. Despite the task force's conclusion, Dreger obtained an e-mail from the task force chair, former AAA President Jane Hill of the University of Arizona in Tucson, describing the book as “just a piece of sleaze.” And task force member Janet Chernela of the University of Maryland, College Park, Dreger said, told her that “nobody took Tierney's book's claims seriously.” The inquiry was conducted, Dreger charged, largely because AAA wanted to safeguard U.S. researchers' future access to the indigenous peoples in Latin America; they didn't want other anthropologists to become tarred with the same brush. In an e-mail to Science, Chagnon said he had been “dumbfounded” to learn from Dreger that task force members had thought little of Tierney's work but “went ahead with their shameful witch hunt of Neel and me.” Invited to respond, Terence Turner of Cornell University, a longtime Chagnon critic, argued that last week's meeting was unfairly set up—he had 15 minutes to respond to what amounted to an hour of critique. Moreover, he observed, Tierney's book did much more than attack Chagnon, and neither the AAA task force nor Dreger had addressed its discussion of other, putatively unethical work. Tierney did not respond to Dreger's inquiries and was not at the meeting. Reached by Science, he echoed Turner's point and defended his work against specific allegations. As Dreger observed, many of the most bitter feuds in social science erupt over questions of “human identity.” Because that question is central to anthropology—and because indigenous peoples are often involved in political struggle—battles are common. Yet AAA has made no institutional changes to better handle the next eruption, says Dreger, such as altering its code of ethics. “They've learned nothing,” she said. 4. Stem Cells # NIH Approves First New Lines; Many More on the Way 1. Constance Holden At long last, federally funded stem cell researchers will soon have the access to human embryonic stem (ES) cell lines that they have been hankering for over the past 8 years. Last week, the National Institutes of Health (NIH) named the first 13 lines approved for federal funding under President Barack Obama's revised policy—11 derived at Harvard University and two at Rockefeller University. NIH Director Francis Collins was expected shortly to approve 27 more; a further 68 are awaiting review. At a 2 December press conference, Collins said NIH expects submissions soon for at least 100 more. Thirty-one research grants, totaling$21 million, have been on hold pending the official availability of the cell lines.

Last March, Obama announced he was deep-sixing the Bush Administration's stem cell policy, which limited federally funded researchers to 21 cell lines. Scientists had worried that, under exacting new requirements for informed consent by embryo donors, most of those 21 lines wouldn't make the grade. But NIH has fashioned a two-tiered vetting process that allows some flexibility in considering lines generated before 7 July 2009—the date the NIH guidelines were finalized—as well as lines from other countries where the informed-consent procedures may vary slightly.

But that doesn't mean NIH isn't being extremely fastidious about the process. At a 4 December meeting of NIH's Advisory Committee to the Director, its working group for human ES cell eligibility recommended that Collins approve 27 lines derived at Harvard. Harvard had submitted 28 lines for approval, but one line came from an embryo whose donors signed a consent form during a 7-month period when approval for the form by Harvard's Institutional Review Board had lapsed. Harvard researchers decided it was kosher given that the same consent form was used before, during, and after the lapse. But the working group decided to reject that line. The approval process must be “beyond reproach,” said working group chair Jeffrey Botkin, a pediatrician at the University of Utah School of Medicine in Salt Lake City.

Another issue is whether NIH should, in addition to vetting cells for funding eligibility, define restrictions on their use. Botkin pointed out that the “anonymization process” for donors means that there's no way to check whether they approve all the uses to which scientists put their genetic material. Participants decided that all cell populations from the 27 lines should be used only for purposes spelled out in the consent form: “to study the embryonic development of endoderm with a focus on pancreatic formation.” Collins said NIH would establish a policy for how to handle such issues in the future.

Researchers holding sought-after lines must now figure out how to deal with the time and expense involved in distributing them. Ali Brivanlou of Rockefeller University in New York City said last week that he had already received about 50 requests for his lines, which he uses to study brain development. “We generated hundreds of independent tubes for each line,” so they'll have plenty to give away, he says. George Daley of Harvard Medical School in Boston, who so far has received requests from more than a dozen investigators, says it's not going to be easy to satisfy the demand: “Our plan is to get the cells into the hands of a bank that will distribute over the long haul.”

At the meeting, Collins said that “if it turns out this is a real barrier,” NIH is prepared to consider setting up such a repository. “I would certainly welcome that,” says Brivanlou. “It would take the burden of distribution and quality control to a central location, and there's no better place than NIH for that.”

5. ScienceNOW.org

# From Science's Online Daily News Site

Lose Genes, Gain Weight Obesity is a disease of excess, but a new study suggests that a few obese patients are actually lacking something—a piece of one of their chromosomes. The loss might remove a gene that helps the body manage blood sugar and appetite.

Why Your Older Brother Didn't Share If you watch enough television, you'll witness what psychologists describe as birth order stereotypes. Take Alex P. Keaton of the 1980s U.S. sitcom Family Ties. Firstborn Alex was far more brash and competitive than his younger sisters, reading The Wall Street Journal while in high school, for example. Now scientists report that the stereotype is valid: Eldest children are less cooperative, trusting, and reciprocating than their siblings.

An Introduction to Monkey Grammar? It's not quite Shakespearean wordplay, but a species of African monkey can modify individual warning calls to produce novel meanings, according to new research. And because the wild monkeys tack the same sound onto the end of their calls, the authors speculate that they could resemble suffixes. But it's debatable whether the sounds serve a grammatical purpose like that in human language.

The Quasar That Built a Galaxy Which came first, the quasar or the galaxy? Astronomers have long believed that young galaxies feed the black holes at their centers until those black holes become quasars, which are incredibly massive and powerful sources of energy. But scientists have now found a quasar that's apparently churning out new stars in the absence of a host galaxy. The discovery suggests that quasars created at least some galaxies, not the other way around.

6. Biomedical Research Facilities

# Plans for London 'Cathedral Of Science' Unveiled

1. John Travis

LONDON—Two years ago, as the world's economy was expanding, U.K. Prime Minister Gordon Brown announced plans for a mammoth new biomedical facility to house more than 1200 researchers in the heart of this booming city. Since then, the global financial crisis has derailed many ambitious projects, but the proposed £500 million–plus United Kingdom Centre for Medical Research and Innovation (UKCMRI) apparently remains on track. At a media briefing this week, backers affirmed their financial commitments to the project and unveiled architects' drawings and a “scientific vision” for the facility.

“There's been no dialing back” of ambitions, says Paul Nurse, the British Nobel laureate and head of Rockefeller University who was tasked with developing the facility's science plans. UKCMRI's “design has a simple aim: Keep Britain at the forefront of biomedical research in the world.”

The proposed 'cathedral of science,' as UKCMRI's lead architect calls it, arose from a fight over the National Institute of Medical Research (NIMR) in Mill Hill. That aging but celebrated research center on the outskirts of London has been slated for closure for years after its owner, the Medical Research Council (MRC), decided to move these labs downtown near hospitals and universities to promote translation of basic research into the clinic (Science, 4 February 2005, p. 652). Various relocation plans were fought over and abandoned until 2007, when MRC joined with several others—University College London (UCL) and the biomedical charities Wellcome Trust and Cancer Research UK (CRUK)—to propose UKCMRI (Science, 14 December 2007, p. 1704). “No one group can fund something this big,” says developmental biologist Jim Smith, director of NIMR.

UKCMRI, which won't be ready until the end of 2014 at the earliest, will be built on land purchased for £85 million that sits behind the British Library and next to major train terminals, including one with high-speed rail access to the rest of Europe. Those transport links, as well as cutting-edge facilities, will enable UKCRMI to create an international hub of research, says Nurse. He envisions UKCRMI becoming a “feeder” for the rest of the United Kingdom by training early-career scientists but not keeping them. “This will be different. We will celebrate departures,” says Nurse.

In addition to NIMR scientists, who tend to specialize in stem cells, infectious diseases, and immunity, UKCMRI will incorporate scientists from CRUK's London Research Institute (LRI), which has strengths in cellular and molecular biology and genetics. “It's a marriage made in heaven,” says LRI Director Richard Treisman.

UCL, which plans to have about 150 of its own scientists at the new institute, will provide clinical access to its affiliated hospitals and to the university's chemists, physicists, engineers, and other nonbiological scientists. As planned now, UCL will fund 5% to 10% of UKCMRI's cost, Wellcome Trust 20%, CRUK 25% to 30%, and MRC 45% to 50%.

Like many new science facilities, the designs for UKCMRI incorporate windows that allow the public a view into some laboratory space. To promote interaction across the whole facility, UKCRMI will not be broken up into traditional scientific departments but will have “neighborhoods,” according to architect Larry Malcic of HOK London.

UKCRMI will not have its own patient facilities, although its primary goal remains ultimately translating biological insight into medical advances. UKCMRI officials confirmed that the facility will house an infectious disease facility allowing work on pathogens such as flu viruses but not on the most dangerous microbes such as Ebola. One-third of the proposed building will extend below the surface, including the animal facilities that will enable work only on small animals, including mice and likely ferrets, for flu studies.

The plans for UKCRMI haven't won over everyone. Jonathan Stoye, a virologist at NIMR, remains almost as concerned about the effort as he was in 2007, questioning whether the United Kingdom will get less science for its pound than it does now at NIMR. He notes that he and colleagues had to repeatedly argue for the inclusion of animal facilities at UKCRMI and says, “I have very little faith in the current plan being the final plan.”

Stoye sees other problems. Even though the sale of the NIMR and LRI sites should bring in huge sums, more money will be needed. So far, the Department of Treasury hasn't made a commitment to fill that gap. Nor has the local city council given approval for the project. With a national election due next year and expectations of budget cuts, UKCMRI proponents may have their work cut out for them: “They still have to make the business case to government, and it could be thrown out,” notes Stoye.

Indeed, despite the drawing and blueprints presented this week, much remains uncertain. There's no clear explanation of how NIMR and LRI scientists will be selected for transfer to the new site. No one is guaranteed a spot; MRC chief Leszek Borysiewicz would say only that a “large fraction” of NIMR scientists would make the move. “It's a tricky issue,” admits Treisman. “We've started to discuss how to discuss [the hiring process].”

No director of UKCRMI has been named yet. And there's no clear governance plan in place, although Nurse stresses that UKCRMI will be an independent institute and not run by MRC, UCL, or the charities. Smith ruefully acknowledges that “the name ‘NIMR’ will be no more”—at least not on U.K. soil. Smith recently had a star named after the institute to honor its legacy.

7. Gene Therapy

# β-Thalassemia Treatment Succeeds, With a Caveat

1. Jocelyn Kaiser

Gene therapy researchers are approaching a key milestone: They appear to have controlled an inherited blood disorder called β-thalassemia that's more common than any disease treated so far with gene therapy. A young man who received new genes to repair blood cells no longer needs regular transfusions and, 2 years later, seems healthy. Describing this success last week to a U.S. review panel in Bethesda, Maryland, a researcher added a caveat: The inserted gene may have turned on growth signals, raising the potential for cancer.

So far this does not appear to be causing any harm, the study leader, Philippe Leboulch of the University of Paris and Harvard Medical School in Boston, told a meeting of the U.S. Recombinant DNA Advisory Committee (RAC). Leboulch's team in Paris received approval from a French regulatory review panel last month to treat more patients for β-thalassemia. Still, the unexpected observation of a “clone,” or large group of identical cells with the same gene insertion, suggests that the disabled HIV virus used to carry the new gene into the patient's cells may not live up to its billing as much safer than older types of vectors.

β-thalassemia involves a flaw in the gene coding for β-globin, one of the protein chains that make up the hemoglobin used by red blood cells to transport oxygen. The disease strikes mainly people of Mediterranean and Asian descent. The patient in this trial was typical: Since childhood, he has needed monthly blood transfusions and daily treatments to lower blood iron levels. He was not eligible for a bone marrow transplant, the only cure for the disease, according to Leboulch.

In June 2007, when the patient was 19 years old, Leboulch's team removed some of his bone marrow cells and treated them with a modified HIV virus, or lentivirus, carrying a good copy of the β-globin gene. They infused the repaired cells into the patient; after several months, some of the cells began making β-globin. The patient's hemoglobin levels are now high enough that for the past 16 months he has not needed blood transfusions and feels well, says Leboulch.

A year after the treatment, however, Leboulch and his collaborators noticed something worrisome: A growing portion of the patient's modified blood cells contained an insertion in a gene called HMGA2 that turned the gene on. This suggests that a single cell with this insertion gave rise to cells that had a growth advantage. The pattern is reminiscent of a gene therapy trial for an immune disease in which a different vector inserted near an oncogene, triggering leukemia.

That doesn't appear to be likely in the β-thalassemia case. Growth of HMGA2-marked cells has leveled off at about 10% of the patient's blood cells. The insertion so far “has had no untoward effect,” noted RAC member David Williams of Harvard and Children's Hospital Boston. He says the trial is “undoubtedly a success” and suggests that both thalassemia and a similar disorder, sickle cell disease, could be treated with gene therapy. Others, including RAC chair Howard Federoff of Georgetown University in Washington, D.C., say more evaluation is needed.

For gene therapists, the big question is whether U.S. regulators will approve the first U.S. trial for β-thalassemia. Michel Sadelain of Memorial Sloan-Kettering Cancer Center in New York City, who hopes to launch the trial by next spring, acknowledges that lentiviral vectors may not eliminate all risks: “Safer does not mean absolutely safe.”

8. ScienceInsider

India has created a climate change assessment network that links 220 scientists at 20 institutions. The goal, explained a government minister, is to develop an “independent and credible research capacity.” It is expected to receive $250 million over 5 years. In its second competition, the Department of Energy's Advanced Research Projects Agency-Energy has offered$100 million for the best ideas in the fields of electrofuels, carbon-capture technologies, and high-density battery storage. ARPA-E made 37 awards worth $151 million in its first competition. A researcher at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Frederick, Maryland, contracted rabbit fever, or tularemia, and is responding well to medicine. It's a rarity for bioweapons scientists to become infected with the pathogens they study. Long-simmering tensions between researchers and the business-oriented governing board at the Australian synchrotron in Melbourne erupted in an open battle as scientists went on strike to protest the firing of the lab's director, temporarily reducing the facility's normal 24-hour operation to a 9-to-5 schedule. A British official has confirmed that the government has recently resumed a controversial pilot program to examine the DNA and isotopes of tissue from asylum seekers, albeit with some changes. White House budget officials are sticking with small increases for science in the president's proposed 2011 budget. That could mean only a 2.9% boost for the National Science Foundation, to$7.2 billion, and a 1.6% bump for the Department of Energy's science shop, to $5 billion. For the full postings and more, go to blogs.sciencemag.org/scienceinsider. 9. Genetics # SNP Study Supports Southern Migration Route to Asia 1. Dennis Normile A massive effort to catalog genetic variation among Asians has just weighed in on the peopling of that vast continent. As described on page 1541, a 40-institution consortium has concluded that Asia was initially settled by a single wave of migration along the coast; exactly when is still to be determined. “It's a fabulous data set,” says Vincent Macaulay, a statistical geneticist at the University of Glasgow in the United Kingdom. The evidence for the southern coastal route and against a northern steppe route “seems very strong,” he adds. Anthropologists, ethnographers, and linguists have long struggled to understand the patchwork-quilt diversity of Asia. Indonesia alone claims some 300 ethnic groups; the Philippines has 180 native languages and dialects. Where did they all come from? In recent years, geneticists joined in, using genomic markers to divine migration patterns and relationships among different ethnic groups. These efforts produced two basic theories to explain the initial peopling of the continent. The dominant one pictures two major waves of migration from the Middle East. One wave followed a southern coastal route, around the rim of present-day India, and continued from island to island across Indonesia, Malaysia, and the Philippines to the Pacific; a separate and distinct wave of immigrants traveled east across the Eurasian steppe and turned south through the Asian mainland. A second theory posits just one initial migration—along the coastal route—with populations moving north into East Asia from there. This new analysis by the HUGO Pan-Asian SNP Consortium “strongly concludes the southern route made a more important contribution to East and Southeast Asian populations than the northern route,” says Li Jin, a population geneticist at Fudan University in Shanghai, China, and one of the paper's lead authors. The results are significant for two other reasons. Scientifically, with samples from more than 1900 individuals representing 73 populations, “this is the most comprehensive study of genetic variation to date in East and Southeast Asia,” says Noah Rosenberg, a bioinformaticist at the University of Michigan, Ann Arbor, who was not part of the consortium. Secondly, the consortium comprises 93 researchers at 40 institutions in 11 countries and regions in Asia, marking this a coming-of-age for the continent's genomic sciences. This project “was conceived by Asians in Asia and executed, funded, and completed by an Asian consortium,” adds Edison Liu, executive director of the Genome Institute of Singapore and one of the consortium's key organizers (Science, 3 December 2004, p. 1667). Previous studies, mostly by researchers in Europe and North America, relied on limited numbers of samples from just a handful of Asia's ethnic populations. This local grassroots effort opened the door to larger numbers of more-representative samples. The job wasn't always easy. About half of the 288 Indonesian samples had been collected previously, primarily from the country's major population groups. But tapping into subpopulations typically required numerous visits to village elders to explain the project, its objectives, and the concept of informed consent, says consortium organizer Sangkot Marzuki of the Eijkman Institute for Molecular Biology in Jakarta. One isolated group in central Sulawesi agreed to participate only if all of its 1000 members were given medical checkups. “So we went back with a mobile medical unit,” Marzuki says. Researchers screened each sample for more than 50,000 single-nucleotide polymorphisms (SNPs)—sites on chromosomes where a single base can vary from one individual to another. The number of variations, or haplotypes, indicates how closely related two individuals are genetically. Not surprisingly, the genetic groupings strongly correlate with linguistic and geographic groupings. But the consortium also found that genetic diversity markedly decreased going from south to north. In addition, most of the genetic variations found in East Asian populations were also present in the Southeast populations, indicating that the former likely derived from the latter. The authors conclude that humans migrated along a coastal route from the Mideast to Southeast Asia and from there moved north, gradually adapting to harsher climates. Jin says their findings do not completely rule out a northern route migration. There is evidence of genetic links across the Eurasian steppe. But Jin thinks these links result from genes flowing back and forth along ancient trade routes rather than moving in as part of a large-scale migration. Macaulay says more data from central Asia could “hammer another hefty nail in the coffin of the [two-wave] model.” Yet Rosenberg says the authors “leave some room for other multiple-wave theories,” specifically that several different migrations across the southern route could account for the distinct populations seen in New Guinea, Australia, and the Pacific Islands. The consortium intends to address these questions in a second project that Liu says will be more ambitious geographically—including, the consortium hopes, central Asian and Pacific Island nations—and scientifically, analyzing far more genetic markers to map diversity and to extend the work to genomic medicine. With the experience gained on the consortium's first project, the riddles of Asia's diversity may yet be solved by the unified efforts of Asian scientists. 10. China # Internet Blockade in Xinjiang Puts A Strain on Science 1. Richard Stone ÜRÜMQI, CHINA—Few researchers can go a day without checking e-mail. Imagine being deprived of Internet access—and being unable to send text messages or make international calls—for 5 months and counting. Such an unprecedented disruption is now hobbling the daily routines of thousands of scientists and students here in Xinjiang Uyghur Autonomous Region. The telecom blockade has affected a U.S.-supported HIV-prevention trial and could jeopardize an effort to build a research base in China's vast western frontier. “If this situation continues, it will affect the region's development,” says Chen Yiyu, president of the National Natural Science Foundation of China (NSFC). The Chinese government imposed the communications blackout (domestic phone service is unaffected) on 6 July, 24 hours after a protest by Uyghurs here in Xinjiang's capital devolved into riots in which scores of people, primarily Han Chinese, were killed. Authorities have asserted that Uyghur separatists in Xinjiang and abroad used social networking Web sites like Facebook and Twitter to orchestrate the violence. In the wake of the unrest, machine gun–toting soldiers and militias have kept the peace. Ecologist Yang Weikang of the Xinjiang Institute of Ecology and Geography (XIEG) of the Chinese Academy of Sciences (CAS) says that in the days following the mob violence he wouldn't have risked leaving his home at night. Now, he says, “we no longer feel unsafe to be out on the streets.” But the Internet remains off limits to the public, with the exception of some officials and journalists allowed access at a downtown site. “This has had a big impact on our work,” says XIEG's Liu Wenjiang. One international project disrupted by the blockade is a novel trial testing whether the antiaddiction drug Suboxone can stem HIV infections by treating heroin addiction. Injecting drug use is a leading route of HIV transmission in western China. Last year, a team of Chinese and U.S. scientists led by prevention researcher David Metzger of the University of Pennsylvania launched the 4-year project funded by the U.S. National Institutes of Health in Ürümqi and Heng County in China's Guangxi Zhuang Autonomous Region. With international links to Xinjiang severed, messages and data are being passed to and from Urumqi via Guangxi. “The inability to interact directly with the staff is a serious concern,” says Metzger. Cyberisolation is forcing scholars elsewhere in Xinjiang to find alternative ways to conduct research and communicate with peers. Researchers at Ürümqi Astronomical Observatory at Nanshan are unable to download daily reports from other observatories; it takes 3 to 4 days to receive reports by express mail from Shanghai. The observatory's deputy director, astronomer Sun Zhengwen, dispatches staff and students on regular trips beyond Xinjiang to commune with colleagues and prepare papers for submission to journals. But because Sun is in charge of the observatory's security, he must stay put. “It's frustrating,” he says. Likewise, XIEG scientists are beating a path to Beijing. Meetings in Ürümqi have been postponed, and a CAS-U.S. National Science Foundation workshop last month on the ecology of the Tarim Basin was moved to Xi'an, says Liu. Scholars who cannot easily travel outside Xinjiang—students or academics with fewer resources or those who conduct fieldwork—must find other lifelines, such as colleagues in Beijing who can check their e-mail and relay important messages by phone. To ease the scholars' plight, CAS headquarters has set up a “Green Channel” through which Xinjiang researchers can call and request articles for express mail delivery. The consequences of an indefinite Internet outage could be severe. This year, NSFC is spending$30 million on more than 600 projects in Xinjiang and four other western provinces to beef up the region's frail science base. “The idea is to keep excellent scientists in the local institutes,” says Chen. Funding decisions were largely wrapped up before the riots, but Chen worries about next year's call for proposals. If the situation drags on, he says, Xinjiang's woes could spark an exodus of scientific talent.

Some academics have managed to find a silver lining in the info blackout. He Jing, an English instructor at Xinjiang University, told the state-owned newspaper China Daily that lack of Internet access has cut down on plagiarism among his students, who often copy material verbatim from the Web. “Now they have to do everything on their own,” he said. But the vast majority of researchers are anxious to come in from the cold.

Authorities are mum on when Xinjiang might be back online. In late summer, rumors predicted service would be restored after the National Day festivities on 1 October. But as the outage approaches a half-year, researchers here have resigned themselves to finding novel ways to reach out to the world and maintain the rhythm of their scientific lives.

11. Solar Fuels

1. Robert F. Service

Conventional solar technologies produce electricity, but most transportation fuel comes from oil. A new class of solar chemical reactors aims to make liquid fuels from air, water, and sunshine.

ALBUQUERQUE, NEW MEXICO—Inventors seem to have a thing for garages. So it's fitting that Rich Diver's workplace looks like an oversized carport, a metal shed some 8 meters high and 8 meters across sitting under the desert sun. Diver, a solar engineer here at Sandia National Laboratories, flicks a switch, raising the shed's oversized door. Just outside sits a heliostat, a large, flat mirror that tracks the sun, and what looks like a huge window frame holding a massive venetian blind. Inside the shed, propped up on its side, rests a 6.5-meter-wide solar concentrator, a parabolic dish covered with 228 mirrors. During operation, sunlight ricochets off the heliostat, passes through the venetian blind, and hits the parabolic dish, which focuses it on a small keg-sized chemical reactor. Temperatures at the focal point can reach more than 1500°C, hot enough to burn through a fire brick used to line kilns. Diver and his colleagues are using the heat and an iron oxide catalyst in the reactor to split either water or carbon dioxide (CO2), producing hydrogen gas or carbon monoxide. These chemicals can then be used as energy-rich feedstocks for making liquid fuels such as gasoline. In short, the Sandia team is reversing the combustion of fossil fuels, reenergizing molecules from thin air (or water) to make fuels that can then be used anytime, anywhere.

Just not quite yet. At the moment, Diver's reactor is in pieces all around the garage. In the dust covering one of the mirrors is scrawled “I ♥ solar” and “Hi Dad,” written by Diver's daughter Tracy during a recent visit. Diver disassembled the reactor after a recent test run that showed that iron oxide catalysts worked efficiently to split water. But the temperatures got so high, and the temperature changes so dramatic, that they fractured many of the flat, 1-cm-square catalyst tiles and cracked the ceramic housing holding them in place.

Back in town at the Albuquerque Marriott, Diver and about 30 of his colleagues from around the world have spent most of the past 2 days huddled in conference rooms searching for solutions to these sorts of problems and comparing notes on different versions of the technology.* They've sorted through white-boards full of technical challenges with their solar reactors, ranging from boosting the speed at which the catalysts work to keeping the windows on the reactors clean so the focused sunlight can stream in.

The good news is that the technology has been shown to work on a small scale, producing tens to hundreds of liters of energy-rich gases per hour. “This is not a pipe dream,” says Alan Weimer, a chemical engineer and solar-fuels expert at the University of Colorado, Boulder. “We have things that actually work.” And a simpler version of the technology is already close to market (see sidebar, p. 1474).

But there's bad news, too. For now, the process is costly and unlikely ever to compete with producing gasoline from fossil fuels without a price on carbon emissions. “We are not at the point where it is feasible on a commercial scale,” Weimer says. Diver agrees: “It puts us in this in-between land.” This awkward stage of development is a crowded territory known as the “valley of death” among venture capitalists, who specialize in turning promising technologies into moneymaking businesses. Diver and his colleagues have assembled here in hopes of finding a way out of this valley. Their immediate goal has been to put together a white paper that lays out the case for solar fuels—more officially known as solar thermochemical fuels, because heat from concentrated sunlight drives the needed chemical reactions.

This search for the way out of the valley of death has become the quintessential problem facing energy researchers of all stripes today. Whether they work in a relatively sparsely populated area such as solar fuels or in cellulosic ethanol, which is widely hailed to be the future of ethanol technology, they must develop a new technology for producing fuel or electricity. And they must do it cheaply enough to compete with fossil fuels, a technology that engineers have been whipping into shape for more than 100 years and that has trillions of dollars of infrastructure installed to make it work.

At a break during the meeting here, Diver is chatting with Robert Palumbo, a mechanical engineer at Valparaiso University in Indiana. “Is what you are doing harder or easier than landing a man on the moon?” Palumbo asks. “Harder,” Diver says without hesitation. “They only had to do it once.” Besides, he adds, “they didn't have to worry about economics.”

## A matter of scale

NASA engineers were also the beneficiaries of a sustained financial push to develop the technology. Not so with solar thermochemical fuels. The field got an initial boost after the Arab Oil Embargo of the early 1970s raised concerns about rising oil prices and Western countries' dependence on Middle Eastern oil. Groups in Europe, the United States, and Japan spent a few years searching for catalysts to convert heat into fuels regardless of the heat source, but interest had largely died out by 1983 as oil prices again plunged. Solar-fuels programs in Switzerland and Germany took off again in the early 1990s, driven by growing concerns over climate change and fears that world oil production was nearing its peak. Beginning in 2003, a brief bolus of funding for producing hydrogen fuel kick-started several efforts in the United States, including the Sandia effort, but that funding has since disappeared.

Despite the ebbs and flows of funding, attendees at the Albuquerque meeting argue that the need for solar-fuels research is only growing. Anxiety about rising atmospheric CO2 levels—now at 385 parts per million, up 43% from preindustrial levels—“is the underlying premise of why we are here,” says James Miller, a materials scientist at Sandia. Miller helps run the lab's Sunshine to Petrol program, which is now supported by internal Sandia funding. Energy security is another concern. With 58% of U.S. oil now coming from imports, Miller notes, “the transportation sector is very vulnerable to disruptions in supply.”

But a potential plus for solar thermochemical fuels is one that renewable-energy providers rarely mention: scalability. Energy use occurs on a scale unlike any other. In 2006, for example, humans used 472 quadrillion BTUs (quads) of energy, 21% of it in the United States. More than ¼ of the U.S. portion went to transportation, and nearly all of that came from oil. As a result, any new technology hoping to dethrone oil drilling will have to supply not only cheap energy but a lot of it. That's where most renewables hit the skids.

Take biofuels. In 2007, Congress mandated that by 2022 the United States will make an estimated 117 billion liters of ethanol. Producing it is expected to require anywhere from tens of millions to hundreds of millions of hectares of land, depending on future efficiency increases in turning biomass into ethanol. Even so, the 2022 ethanol supply is expected to meet only about 13% of U.S. demand for transportation fuel. With biofuels already increasing the pressure on agricultural and conservation reserve lands, it's hard to imagine the figure approaching 100%.

That's where concentrated solar-fuel plants have an important advantage, says Ellen Stechel, who heads Sandia's Fuels and Energy Transitions Department. Because the technology uses the full solar spectrum and concentrates sunlight, it uses far less land than biomass, photovoltaics, and other technologies that also rely on capturing sunlight. That could make it far more straightforward for the technology someday to supply a large fraction of transportation fuels.

At the Albuquerque meeting, Robert Wegeng, a mechanical engineer at the Pacific Northwest National Laboratory in Richland, Washington, walked attendees through an initial calculation that shows the potential of an intermediate, and simpler, version of solar-fuel technology. Wegeng is developing a solar reactor capable of converting natural gas to a mixture of hydrogen and carbon monoxide—known as synthesis gas—that can be used to make liquid fuels.

Wegeng calculates that a solar-fuel plant made up of an array of 10,000 parabolic dishes would take up only a few square kilometers of land. Yet it could capture 1 gigawatt of energy, enough to upgrade natural gas equivalent to 2 million gallons of gasoline per day or 700 million gallons per year. “Twenty such plants would offset U.S. petroleum exports by 10%,” Wegeng says. And there's plenty of desert land to scale the technology up even further.

“This can potentially make as much fuel as we want,” Stechel says. Even better, because the technology can be used as the first step to producing liquid hydrocarbons, it would allow countries to continue to use their built-up gasoline-based infrastructure without having to rely on mining fossil fuels.

Wegeng and others at the Albuquerque meeting were quick to add that they don't think solar fuels should be considered as an alternative to biofuels. “There is no silver bullet when it comes to replacing fossil fuels,” Palumbo says. Instead, solar thermochemical fuels are one of the pieces of “silver buckshot” needed to do the job. Stechel agrees. “It's another good option,” she says. “We need them all.”

## Next hurdle: Efficiency

In reality, solar thermal fuel technologies are several pieces of buckshot, racing toward the same target: the simple ability to split water or CO2. These compounds can be split directly with heat, but they can create an explosive mixture of gases that need to be separated. By using catalysts, researchers can reduce the temperature of their reactors and produce H2, CO, and O2 in separate steps, eliminating the separation problem.

Take Diver's setup, at least when it's not scattered in pieces around the garage. Inside the reactor sit 14 cobalt ferrite rings, made from a mixture of cobalt and iron oxide, or rust. Each ring is about 1/3 of a meter in diameter and rotates between two separate reaction chambers. Sunlight from the heliostat and the parabolic mirror is focused through a window in the reactor, heating the interior to as high as 1500°C. At that temperature, the flakes of iron oxide catalyst on the outside of each ring spit out oxygen molecules, which are vented to the outside (see figure, below). As the disks turn, they enter the second, 1100°C chamber, which is spiked with CO2 or water vapor from which the catalyst swipes oxygen atoms. This reaction generates the energetic gases (H2 or CO), which are collected, and restores the catalyst to its original composition, ready for another turn of the wheel.

Other reactors use different catalysts and in some cases different designs. A group led by Aldo Steinfeld, who heads the Solar Technology Laboratory at the Paul Scherrer Institute in Villigen, Switzerland, cycles a catalyst between zinc oxide and metallic zinc. The process has already proved to convert 3.1% of incoming solar thermal energy into chemical energy. Researchers at the German Aerospace Center in Cologne and Almeria, Spain, use their own blend of iron oxide–based catalysts. They said at the meeting that they are seeing efficiency numbers similar to those of Steinfeld's group. Finally, groups at the California Institute of Technology and the University of Minnesota have been experimenting with a promising catalyst based on the metal ceria, and both the Sandia and Paul Scherrer teams are now gearing up to test ceria catalysts in their reactors.

For now, however, none of these catalysts is good enough. Although the iron oxides can give up a large percentage of their oxygen atoms in the first, high-temperature step, they melt at 1800°C, just above the typical temperature in the reactors. And when they cool, they form an inert slag that is far less reactive in subsequent catalytic cycles. The iron oxide portion is also brittle and unstable. So it is typically mixed with large quantities of inert ceramics, which must be heated even though they don't perform any catalytic work. Moreover, because the ferrites are relatively large chunks of solid material, not all of the catalytic material in the center of each flake participates in the reaction.

Zinc oxide, by contrast, dissociates in a 1700°C reactor to form a zinc vapor and oxygen, thus ensuring that nearly all of it reacts. But the zinc vapor can condense on the reactor's window, blocking the incoming sunlight. Ceria is solid like the ferrites and is quick to take up and release oxygen. But because it grabs and releases less oxygen than the ferrites do, a reactor must include more of it. Right now, Stechel says, “there are lots of different tradeoffs.” However, she adds, “we have not even begun to explore the full material spectrum” of possible catalysts out there.

For now, the Swiss group has the best reported efficiency in converting heat from incoming sunlight into fuel, at just over 3%. For the technology to have a shot commercially, however, solar-fuels researchers say they will need to do significantly better. Solar electric generators are already 20% efficient at converting sunlight to electricity. And current commercial electrolyzers can convert electrical energy to hydrogen gas at 65% efficiency. By combining the two devices, engineers can convert sunlight into hydrogen at more than 13% efficiency with conventional technology. “We're trying to do it more directly and more efficiently,” Miller says.

There's reason for optimism, Miller adds: The theoretical maximum efficiency of converting heat to chemical bonds is 75%, limited by the Carnot efficiency of the heat engine. For a successful catalyst, he says, “we only have to get to about half of that,” probably resulting in an overall reactor efficiency of slightly more than 20%. “A factor of less than 10 improvement certainly seems manageable,” Miller concludes.

Others agree and suggest that the goal for the field should be a reactor that converts 20% of incoming heat to fuel by 2020. Better efficiency will have other payoffs as well. Most important, it could enable engineers to use smaller concentrators and heliostats, which account for roughly half the cost of current solar thermal systems.

So how much would fuel from concentrated sunlight likely cost? “We are confident we can get this number down to less than $10 for a gallon of gas,” Miller says. At that price, Steinfeld says, “it's clear solar fuels will have a hard time competing directly with fossil fuels.” But if the world begins to move away from fossil fuels to CO2-neutral fuels, Steinfeld says he's convinced that solar thermochemical reactors could step in to meet the demand. Improving catalyst efficiency and getting the price down won't be the only hurdles solar-fuels researchers have to leap. Catalyst lifetimes in the reactors need to improve. And researchers will need to find a way to run the reactors on stored heat at night so that future commercial plants can run 24/7, typically an industry and financial requirement. But even though that list sounds daunting, solar-fuel researchers insist that most of the items are fairly standard engineering challenges that will be overcome with sustained work on the technology. “There is every reason to believe there are no showstoppers here and it will be viable,” Stechel says. The question now, and the hardest challenge ahead, is whether the field's successes to date and promise for the future will persuade funding agencies to put them on the path to commercial reality. • * Workshop on Solar Thermochemical Cycles, 2–4 November 2009, Albuquerque, New Mexico. 12. Solar Fuels # Biomass Fuel Starts to See the Light 1. Robert F. Service Even with a major push, commercial plants capable of turning CO2 or water into liquid fuels are still likely to be 2 decades away. A simpler version of the technology, however, already appears headed to market. Even with a major push, commercial plants capable of turning CO2 or water into liquid fuels are still likely to be 2 decades away. A simpler version of the technology, however, already appears headed to market. Sundrop Fuels Inc., an energy start-up based in Louisville, Colorado, recently commissioned a 1-megawatt solar array to convert wood waste and other forms of biomass into a gaseous blend of carbon monoxide and hydrogen—known as synthesis gas—that can be converted into gasoline. The plant uses an array of 2700 mirrors to concentrate sunlight on a 20-meter-tall solar tower to produce heat needed to drive the chemical reactor. The company has told Science that in 2012 it intends to open a commercial plant capable of capturing 60 megawatts and use that energy to produce 19 million liters of gasoline annually. “This is a very good development,” says James Miller, a materials scientist at Sandia National Laboratories in Albuquerque, New Mexico, who helps direct the lab's Sunshine to Petrol program. “If this is successful, it will help demonstrate that solar thermal energy will be an important piece of how we produce liquid transportation fuels in the future.” At a recent workshop on solar fuels, participants spent considerable time debating whether the small solar-fuels research community should push for large-scale demonstration plants akin to Sundrop's. Such plants offer a way to take a carbon source, such as biomass or coal, and increase its energy content while converting it into a liquid hydrocarbon. “On the one hand, it's a distraction” from the ultimate goal of converting CO2 to fuel with sunlight, says Ellen Stechel, who heads Sandia's Fuels and Energy Transitions Department. “But on the other hand, it's a steppingstone to where we want to be.” That steppingstone is easier to reach because it employs a simpler chemical reactor. Splitting CO2 and water requires specialized catalysts that must be transferred between two separate stages to carry out different reactions. Converting biomass to syngas, by contrast, requires only quickly heating the biomass in the presence of steam. Biomass gasification in conventional chemical reactors has been explored for decades. But the technology has been held back in part because some of the biomass itself, or other fossil fuels, must be burned for heat to power the reaction. Getting the heat from solar concentrators eliminates that heating cost and avoids generating excess CO2. But how the initial cost of the solar concentrators affects the economics of the process remains to be seen. “Building a demonstration plant gives you the opportunity to work some of those issues out,” Miller says. In related work, researchers around the globe are investigating using heat from concentrated solar energy to convert methane in natural gas into liquid fuels, turn limestone into cement, and reduce metal oxides into metals. These industrial processes currently use massive amounts of energy and emit copious quantities of CO2. Jane Davidson, a mechanical engineer at the University of Minnesota, Minneapolis, says solar thermal systems are ready to take this first big step. “This is realistic,” Davidson says. “This can happen, and it can make a big difference.” 13. AIDS Vaccine Research # HIV Natural Resistance Field Finally Overcomes Resistance 1. Jon Cohen People who fend off HIV despite repeated exposures may have genetic or immunologic factors working for them that can help guide AIDS vaccine research. WINNIPEG, CANADA—In 1989, Stuart Shapiro and his pregnant wife, Awuor, went to the obstetrician to learn whether she carried the gene for sickle cell anemia common in people from Kenya, her home country. The results shocked the young couple: No, she did not have the gene, but the doctor said Awuor was infected with HIV. “With one sentence, our world fell apart,” said Shapiro, who had been with Awuor for 7 years. The doctor suggested that they consider terminating the pregnancy, but Awuor carried to term and gave birth to a daughter. To their great relief, Stuart was not infected, and Awuor did not transmit the virus to their daughter. In part because he wanted inside information about the latest anti-HIV drugs to help Awuor, Stuart, a retrovirologist, went to work for the U.S. Food and Drug Administration. But Awuor's health steadily deteriorated, and in 1996, she died from AIDS. As the years passed, Stuart became increasingly convinced that studies of his blood might help spare others from the fate his wife had suffered. He had, after all, likely been exposed to the virus repeatedly. If some combination of genetic and immunologic factors had protected him, unraveling them might inform researchers struggling to develop an AIDS vaccine and other biomedical preventives. From 15 to 17 November, the first-ever meeting on natural immunity to HIV was held in this small city on the Canadian prairie, and Shapiro was one of 100 scientists from around the world who attended. Now a program officer at the U.S. National Institute of Allergy and Infectious Diseases (NIAID), Shapiro oversees a$50 million annual grant to an academic consortium called the Center for HIV/AIDS Vaccine Immunology (CHAVI). At the meeting, he not only represented NIAID but also spoke for other people who have dodged the HIV bullet and donated their blood for study, and who are frustrated that the field remains so disjointed and underappreciated. “I want them to study the phenomenon extensively,” said Shapiro. “I don't want them to leave any stone unturned.”

Just as Edward Jenner used milkmaids who did not develop smallpox to design a vaccine that ultimately eradicated that disease, researchers here had high hopes that their findings will help in designing an effective AIDS vaccine. But so far, few tangible advances have come from studying people like Shapiro, despite years of efforts.

Dozens of studies have been examining men and women who sell sex but remain uninfected, and similarly, clients of sex workers, “discordant couples” like Shapiro and his wife, hemophiliacs who received tainted lots of blood, babies like Shapiro's daughter, injecting drug users, health care workers who accidentally poked themselves with contaminated needles, and men who have sex with many male partners. But all too often the leads point in contradictory directions, in part because investigators use different assays to probe their samples, and there is little coordination among them. Many labs also use wildly varying criteria to decide who qualifies as HIV-resistant, making it difficult to sort out which study subjects were truly exposed and uninfected, were exposed and have an occult infection, or were never exposed in the first place. “If we are getting anything out of this meeting, it will be to come to some agreement about the people we're studying and the degree of risk they have faced,” said Frank Plummer, the meeting's organizer and head of Canada's National Microbiology Laboratory, which is based here and has an \$8.3 million grant from the Bill and Melinda Gates Foundation to study natural immunity. “And it's quite possible there are different mechanisms at work in different groups.”

For more than 20 years, Plummer has followed a group of sex workers in a Nairobi slum that includes more than 100 women who by all odds should have become infected but are not. With a nudge from the Gates Foundation, Plummer and his team invited colleagues who have similar cohorts to Winnipeg to see whether they could all collaborate. “Before, this was seen as a freakish phenomenon,” said Mario Clerici, an immunologist at the University of Milan in Italy who helped pioneer the field with Gene Shearer of the U.S. National Cancer Institute (NCI). “Gene and I were totally in left field: Nobody believed natural immunity to HIV existed. Now opinion leaders are jumping into it.”

Studies of the Nairobi sex workers continue to provide clues about protection. Keith Fowke, a microbiologist at the University of Manitoba here who works with Plummer, explained that they have focused on the 5% of more than 3000 women in their cohort who on sensitive PCR blood tests remain uninfected by HIV after at least 3 years of selling sex. Some of the women deemed resistant have later become infected, leading Fowke to stress that the protection against HIV is not absolute. Yet he is certain that these resistant women have genetic and immune responses that helped them thwart the virus. Fowke, Plummer, and their co-workers at the University of Nairobi have homed in on the resistant sex workers' unusual CD4 white blood cells, which coordinate the immune response against HIV and are also its main target. Unlike people at low risk of HIV infections, CD4 cells from these women copy themselves vigorously—or “activate”—when exposed to pieces of the virus in test tube studies, indicating that they have confronted the enemy before and can quickly rev up the immune system to block infection. But these HIV-specific first responders make up a tiny fraction of the CD4 cell population. And the general CD4 cell population in the resistant women had unusually low levels of activation markers. This indicates that most of their CD4 cells are in a “resting,” or quiescent, state, save for those that are actively responding to HIV—and that may be key to their resistance.

Various cellular factors make it difficult for HIV to infect resting CD4 cells in the blood, forcing the virus to rely mostly on the activated ones to establish an infection. So smaller populations of activated CD4s mean fewer targets for HIV. In something of a paradox, activation is good when it's directed against HIV but bad when CD4s are turned on high for other reasons.

In support of their immune-quiescence hypothesis, Plummer, Fowke, and colleagues found that the resistant women had higher levels of regulatory T cells that directly tamp down activation. When Fowke's lab compared gene expression in CD4 cells in resistant women and uninfected controls, the resistant group had far fewer genes turned on high, also suggesting a quiescent state.

Fowke suspects that the reduced number of targets in immunologically quiescent people makes it harder for HIV to succeed because even if a few cells do become infected, the immune system has a better chance of snuffing out the fire before it spreads. It made a compelling story, but as often happens in this field, Clerici followed with a study in discordant heterosexuals in Milan that suggested activation helped people avoid HIV, putting a damper on the quiescence theory. “I have data that are absolutely the opposite,” apologized Clerici, who noted differences in the way they analyzed samples. “I don't know what to say.”

Other disparate findings presented here suggest that myriad factors contribute to HIV resistance. Activation is part of the refined adaptive immune system that remembers specific pathogens and mounts attacks when they reappear. Gianfranco Pancino of the Pasteur Institute in Paris linked protection in exposed injecting drug users in Vietnam to the more primitive innate immune system, showing that they had unusually high levels of natural killer cells—which are much less selective than adaptive immune actors like HIV-specific CD4s—to clear infections. Kristina Broliden and Klara Hasselrot of the Karolinska University Hospital in Stockholm found that uninfected men who had oral sex with long-term infected male partners developed powerful “neutralizing” HIV antibodies in saliva that might prevent infection by that route. Several genetic studies identified a handful of specific genes associated with protection that may turn on underappreciated immune responses.

Immunologist Michael Lederman of Case Western Reserve University in Cleveland, Ohio, found the often-conflicting leads sobering. “This is one of the most interesting and important problems that's facing HIV research today,” he said. “But I'm actually quite pessimistic that we're going to be able to sort this out.”

Lederman said he was not confident that the populations being studied were “clean enough” to fish out correlates of protection. “When we're talking about folks who are exposed through sexual exposure, quantifying the risk is kind of difficult,” he said, because there is no way to determine what HIV dose—if any—they have actually thwarted. So Lederman has turned to studying the carefully characterized groups of uninfected hemophiliacs who received contaminated lots of blood-clotting factors in the early 1980s. As a group led by NCI's James Goedert showed in 1994, just 5% of hemophiliacs in the United States and Europe who received moderate to high doses of contaminated clotting factor did not become infected. That makes this group of uninfected hemophiliacs the most unequivocally resistant people to study.

Lederman and co-workers compared stored blood samples of 36 HIV-uninfected hemophiliacs from this group with samples from healthy controls. They looked for differences in susceptibility to infection, neutralizing antibodies, and chemokines but found nothing notable. The team did discover, however, that their cells were less likely to be activated to copy themselves, supporting the Plummer group's findings. But Lederman remained circumspect: “Correlation does not confirm causality.”

Investigators working with CHAVI recently began intensive genetic and immunologic studies of blood samples from additional hemophiliacs who meet the same criteria. Shapiro says they hope to have 600 samples within the year, and they have already started to do genome-wide association studies and full-genome sequencing of some individuals. CHAVI is also ramping up resistance studies in men who have sex with men, discordant couples, and mother-infant pairs.

By meeting's end, the researchers agreed to form a consortium to hammer out how they will share samples, standardize assays, and agree on definitions of HIV resistance. Although sorting wheat from chaff will remain challenging, one thing will not, says Shapiro: finding HIV-resistant people to volunteer for the studies. “We all wonder why we didn't get infected,” said Shapiro. “It's almost like being a Holocaust survivor. And if studying us can help bring an end to the epidemic, it can help us make some sense of our lives and the suffering we've seen and felt.”

14. Human Evolution

# What's for Dinner? Researchers Seek Our Ancestors' Answers

1. Ann Gibbons

To help prevent diseases like diabetes and heart disease today, evolutionary biologists are seeking to understand the tastes of our diverse ancestors.

BERLIN—As evolutionary scientists from around the world loaded their plates with fish, potatoes, and pork at a lunch buffet at the Berlin Medical Historical Museum, talk naturally turned to what's best for humans to eat. Compared with us, our ancestors ate “meat. More protein, less refined carbohydrates, and no milk,” pronounced exercise physiologist Loren Cordain of Colorado State University, Fort Collins, who advocates a similar regimen to prevent disease. (He passed up the pasta.) At a nearby table, though, his colleagues ate … pudding.

Sixteen researchers from multiple disciplines chewed on the question of whether there is an ideal diet for humans as part of a recent workshop on evolution and modern diseases.* Those focusing on diet hoped to test the common belief that diseases such as obesity, diabetes, and high blood pressure arise because our bodies are poorly adapted to the modern diet, rich in fat, sugar, and salt. “Is there a single Paleolithic diet that is going to be a magic bullet for everyone?” asked biological anthropologist William Leonard of Northwestern University in Evanston, Illinois, who led the diet workshop. “Or do we have to tailor diets specifically to regional populations?”

After comparing emerging evidence from ancient humans and diverse modern cultures, the researchers concluded that many factors—including genes, sex, ancestry, and fetal and childhood conditions—influence how we digest foods and store fat. Physiological stress in mothers can leave lingering imprints on descendants for generations. So although it's true that humans evolved to eat a diet relatively high in protein and low in carbohydrates and fat, there's no single Paleolithic prescription for better health. “It is the internal environment inside yourself that is key—how genes are expressed and how you started off in life,” says paleoanthropologist Peter Ungar of the University of Arkansas, Fayetteville.

## The first suppers

From the beginning, our ancestors had varied tastes. “Early humans had many choices as they bellied up to the biospheric buffet,” says Ungar. The 3- to 4-million-year-old australopithecines were omnivores who ate a wider range of foods than chimpanzees or other apes, according to microscopic wear patterns on fossil teeth and chemical isotopes in tooth enamel. Soon after the origin of our genus Homo about 2 million years ago, our lineage began to eat more meat, butchering it with stone tools (Science, 15 June 2007, p. 1558).

By the time modern humans swept into Europe about 40,000 years ago, these hunter-gatherers were adept at hunting large game and had also expanded their palates to dine regularly on small animals and freshwater fish, says Michael Richards of the University of British Columbia, Vancouver in Canada.

By studying the ratios of carbon and nitrogen isotopes from collagen in bones, Richards traced the main sources of dietary protein of 27 early Europeans and Neandertals; fish eaters, for example, have more nitrogen-15 in their bones than meat eaters. Richards found that the oldest known modern human in Europe—the 35,000-year-old jawbone from Peștera cu Oase cave in Romania—got much of his protein from fish. By 30,000 years ago, other modern humans got as much as 20% of their protein from fish. Meanwhile, the isotopes show that Neandertals in Europe stuck to meat from bigger animals, even when they lived at the same time in the same region as modern humans. This is the first direct evidence that Neandertals had a narrower diet, Richards reported in August in the Proceedings of the National Academy of Sciences.

The next big dietary shift came about 10,000 years ago, when humans began to domesticate plants and, later, animals. The move to agriculture introduced staples of the Western diet: cereal grains, sugars, and milk after weaning. For most of human evolution, our ancestors seldom ate these foods, says Cordain, who advocates avoiding refined grains and dairy products.

The agricultural revolution favored people lucky enough to have gene variants that helped them digest milk, alcohol, and starch. Those mutations therefore spread among farmers. But other populations remained more carnivorous, such as the Saami of frigid northern Norway, whose ancestors herded reindeer. Among Saami ancestors, genes to digest meat and fat efficiently were apparently favored. One gene variant, for example, makes living Saami less likely to get uric acid kidney stones—common in people who eat high-protein diets—than are people whose ancestors were vegetarian Hindus and lack this gene variant, says geneticist Mark Thomas of University College London (UCL).

But when ethnic groups abandon traditional lifestyles and rapidly adopt Western diets, they often suffer. Researchers have known for more than a decade that the Pima of the southwestern United States have “thrifty phenotypes”: sluggish metabolisms that store fat efficiently and boost survival on low-calorie diets. That's probably because their ancestors in Mexico underwent frequent famine. When they eat the calorie-rich Western diet, the Pima develop high rates of obesity, diabetes, and high cholesterol, although their blood pressure stays relatively low.

Indeed, an epidemic of obesity is now spreading into ethnic groups from Siberia to Peru, as quickly as grocery stores open their doors. But although fast food is becoming the universal diet, not all people respond alike to this nutritional transition. For example, unlike the Pima, the Evenki reindeer herders and other indigenous peoples of Siberia have very high metabolisms, an adaptation to the cold that allows them to convert fat into energy efficiently. When the Soviet Union collapsed in the 1990s, many Siberians abandoned traditional lifestyles and diets. They too became obese and developed heart disease but in a different way from the Pima: The Evenki retained low levels of cholesterol and diabetes but developed high blood pressure, as University of Oregon, Eugene, anthropologist J. Josh Snodgrass reported recently in the American Journal of Physical Anthropology. In terms of disease risk, “the Pima are the mirror image of the Siberians,” says Leonard.

These disparate responses reflect a trend: In general, people who evolved in warm lowland environments where food may be scarce may have slow metabolisms for their body size, probably as adaptations to famine or heat stress; examples include the Pima and the Tsimane' of lowland Bolivia. Groups that adapted to frigid or high-altitude climates, such as the Evenki or the Quechua of Peru, have high metabolisms, probably to convert fat into energy efficiently. Despite their differences, all of these groups risk disease when they switch to the Western diet. “They are telescoping into one generation trends that rolled out over a century or more in Western countries,” says pediatric nutritionist Jonathan Wells of the UCL Institute of Child Health.

## From mother to child

Although we are what our ancestors ate, we are also what they didn't eat. In India, for example, more than 66% of the population in some regions experienced famine during British colonialism a century ago. Women who survived tended to have low-birth-weight babies, whose bodies were small and efficient at storing fat, says Wells. It's as though these babies took cues during fetal and early development about their mothers' lifelong nutritional experience and adjusted their growth and body and organ size accordingly. Human stature often tracks the nutritional status of mothers, and it can take generations for descendants to recover. In India, average height in males dropped at a rate of almost 2 centimeters per century in the decades following colonialism, Wells reported online in October in the American Journal of Human Biology.

When these small babies gain weight in childhood, though, it stresses their smaller organs, such as the pancreas and heart, making them more susceptible to obesity, diabetes, and heart disease. This is the case in south India today, says Wells. There, many people have thrifty phenotypes with less muscle and more fat per body size. Yet they are shifting rapidly to a high-fat, high-sugar diet. As a result, Wells predicts, “India risks becoming the diabetes capital of the world.” Others agree: “I think there's no question that people in south India are at higher risk,” says biological anthropologist Chris Kuzawa of Northwestern University, who says this is true of many other populations that have been poor in the past.

One way to prevent obesity and disease is to improve the diet of pregnant mothers and young children. But feeding pregnant women extra calories alone is not enough, warns Kuzawa, who says that a fetus takes in subtle cues about the quality of the mother's nutrition, as well as her developmental history and that of her recent ancestors. He is part of a team exploring intergenerational effects in 3000 women in the Philippines.

Cordain proposed that everyone mimic a Paleolithic diet, adding protein and reducing refined carbohydrates and dairy, in a more extreme version of the low-carb Atkins-style diets. “It's hard to get too fat on a diet without carbohydrates,” he says. He also cited a small study of 14 diabetic men in Sweden whose blood sugar improved on a diet free of carbohydrates and dairy products (Science, 13 July 2007, p. 175).

But other researchers argued that the problem is, simply, consuming too many calories. “What is clear is having low weight is positive,” says immunologist Andreas Pfeiffer of the Charité Berlin and the German Institute of Human Nutrition in Berlin. All agreed that controlled studies are needed to see whether all calories are alike or whether the same number of calories from protein, fat, or sugar have different effects.

Others noted that even if one paleodiet proves particularly healthy, it would be hard for people in different cultures to comply with it. “Food is identity,” says Ungar. “You can't tell an Eastern European Jew to eat pork” or an Italian to skip pasta. The bottom line, says Leonard, is that although some diets are better than others, “there isn't a perfect diet that is the same for everyone. The nature of our success is to find and make a meal in virtually any environment. But our different responses are structured by the basic biology we bring to the table.”

• * Evolution and Diseases of Modern Environments, at Charité University Medicine Berlin, Humboldt University, 12–14 October.