# News this Week

Science  03 Oct 2008:
Vol. 322, Issue 5898, pp. 26
1. INFECTIOUS DISEASE

# New Malaria Plan Called Ambitious By Some, Unrealistic by Others

1. Leslie Roberts

It was standing room only last week at U.N. headquarters in New York City when a star-studded cast, including philanthropist Bill Gates, U2 rocker Bono, and British Prime Minister Gordon Brown, kicked off the latest in a string of grand plans to conquer malaria, the mosquito-transmitted scourge that kills some 1 million people a year, mostly African children.

The goals of the Global Malaria Action Plan (GMAP) are stunningly ambitious: Reduce malaria deaths to near zero by 2015, then progressively eliminate the disease from countries and regions until it is eradicated from the planet. That will take mosquito- and parasite-foiling technologies that have yet to be invented, along with billions of new dollars a year that the plan's architects hope generous donors will provide. GMAP, assembled over the past year with input from more than 250 experts, is the creation of the Roll Back Malaria (RBM) partnership, a coalition of international agencies, public and private donors, and malaria-affected countries.

Regina Rabinovich, head of infectious diseases at the Bill and Melinda Gates Foundation and one of the key forces behind the plan, calls the goals “ambitious but achievable.” But many malaria experts say it's unlikely that GMAP will meet its targets—even with abundant funding—although they applaud the renewed commitment. Several also caution that donors and agencies should be careful in what they promise, given the humbling outcomes of previous grand plans (see table, above).

Scientists and the World Health Organization (WHO) also exuded confidence in the 1950s when they vowed to eradicate malaria, for instance. After that initiative's spectacular demise in the 1960s, malaria cases surged worldwide, and support for malaria control and research essentially dried up.

After a long hiatus, international health and development agencies reentered the fight against malaria in the late 1990s, setting a series of increasingly ambitious targets. They culminated in Bill and Melinda Gates' unexpected call last year to again attempt to eradicate the disease, a word that hadn't been uttered in the context of malaria for some 40 years (Science, 7 December 2007, p. 1544).

“We set year after year new goals and never meet any of them,” says Christian Lengeler, a malaria researcher at the Swiss Tropical Institute. Lengeler, who has worked extensively in Tanzania, calls GMAP's 2015 target of zero deaths “totally unrealistic.” “Silly,” says another scientist. As for the eventual eradication of malaria, “maybe, but not in my lifetime,” seems to be the general consensus.

This time it is different, insist Rabinovich and Awa Marie Coll-Seck, executive director of RBM. For one, coffers are flush. Thanks to contributions from the Gates Foundation, the Global Fund to Fight AIDS, Tuberculosis and Malaria, the World Bank, the President's Malaria Initiative, and others, international funding for malaria control jumped from $51 million in 2003 to an estimated$1.1 billion in 2008. Last week, the Global Fund announced that it will award $1.62 billion over the next 2 years to help poor countries fight malaria, and the World Bank pledged$1.1 billion to expand its Malaria Booster Program. These and other smaller contributions unveiled last week still fall significantly short of the $5 billion or$6 billion a year GMAP says is needed.

Also in the past few years, malaria interventions, such as long-lasting insecticide-treated bed nets and a new class of drugs known as artemisinin-based combination therapies (ACTs), have proved their mettle (Science, 26 October 2007, p. 556). A half-dozen African countries with committed leadership and a lot of outside support have scaled up these interventions rapidly—Ethiopia, for instance, distributed 20 million bed nets in just 18 months. A few of these countries or areas, those with small populations and high access to prevention and treatment, have seen roughly a 50% decline in malaria cases and deaths since 2000, WHO notes in its 2008 World Malaria Report. Ensuring universal access to these and other tools such as indoor insecticide spraying and preventive treatments in pregnant women can halve deaths by 2010, says GMAP, and then reduce them to near zero 5 years out.

But none of the countries has reached the target of 80% coverage with existing interventions, set just a few years ago, much less the 90% called for by GMAP. Across the continent, just 23% of children slept under a bed net in 2006, and only 3% of patients were treated with ACTs, according to WHO estimates.

The challenges facing big countries like the Democratic Republic of the Congo (DRC) and Nigeria are especially daunting. They account for about 20% to 25% of malaria deaths, although hard data are scarce, and are plagued by civil unrest and weak health systems. “That it can be done in Zambia, with a population of 10 million and a dynamic minister of health, does not say a thing about what to do in DRC,” agrees Rabinovich.

To develop the radical types of new vaccines, drugs, and insecticides needed for the toughest areas—as well as for eradication many decades from now—GMAP calls for pumping $750 million to$900 million a year into research. A working group is already hammering out a detailed research and development plan, which Rabinovich says should be ready in 15 months.

To prime the pump, Gates announced $168 million for research on the next generation of malaria vaccines. The award is going to the Bethesda, Maryland-based PATH Malaria Vaccine Initiative, which will try to build off the experience gained from vaccine candidates already in the pipeline, says MVI Director Christian Loucq. GlaxoSmithKline's RTS,S, which targets the malaria parasite form that infects the liver, for instance, is about to enter phase III trials—the first malaria vaccine candidate to get that far. MVI is investigating additional antigens that target different stages in the parasite's life cycle that could be used in combination, as well as novel adjuvants to boost vaccine power. Although expected to be significantly more efficacious, such second-generation vaccines won't be available until well after 2015 and, like RTS,S, will still be only partially protective. Another intriguing possibility is a transmission- blocking vaccine that would be administered to humans but that would target the parasite after it is taken up by the mosquito in her blood meal. Loucq calls the approach “elegant,” the equivalent of an “immunological bed net,” but cautions that it is early days. Whether the exact targets are met is beside the point, says RBM leader Coll-Seck. “I am a glass-half-full person,” she says. If GMAP leads to a significant reduction in malaria cases and deaths—even if the plan promised much more—who would call that a failure, she asks. 2. ANTHRAX INVESTIGATION # NAS Study May Fail to Settle Anthrax Case 1. Yudhijit Bhattacharjee The Federal Bureau of Investigation (FBI) has provided the U.S. National Academy of Sciences (NAS) with a list of 15 questions that it wants the academy to consider in its review of the scientific evidence in the FBI's case against Bruce Ivins, the Army microbiologist implicated in the anthrax letter attacks of 2001. Besides asking whether the genomic analysis carried out to trace the source of the anthrax was valid, the questions address aspects such as the source of silicon found in the spores and whether the attacker needed specialized equipment to grind the spores into an easily dispersible powder. But even before the academy frames the scope of the study and seeks approval from its governing board, members of Congress and bioterrorism experts are voicing concerns that a purely scientific review won't counter skepticism that Ivins, working solo, was the perpetrator of the attacks. One expert calls the FBI's request “a nice little jujitsu move” to deflect attention from nonscientific questions about the investigation, such as how the FBI ruled out all the other individuals who had access to RMR-1029, the flask of anthrax under Ivins's control. Last week, those concerns prompted Representative Rush Holt (D-NJ) to introduce legislation proposing a commission—similar to the one that investigated the 11 September 2001 terrorist strikes—that would review all the evidence in the case. Since Ivins committed suicide on 29 July, FBI officials have unsealed court documents that detail part of the scientific evidence linking the anthrax in the letters to the flask under Ivins's control at the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick, Maryland. By requesting the NAS study, the FBI is essentially subjecting that evidence to peer review in lieu of a jury trial. The last question on the FBI's 15 September list is whether “testimony regarding the methods used to link the mailed anthrax to RMR 1029” would meet evidentiary standards in a court of law. Gregory Koblentz, a biodefense researcher at George Mason University in Fairfax, Virginia, says even for a scientific review, the questions posed by the FBI don't go far enough. He and Alan Pearson of the Center for Arms Control and Non-Proliferation in Washington, D.C., want the academy to ask more probing questions about the science as well as undertake a broader investigation; they are submitting their suggestions to NAS. For example, says Pearson, referring to a question on the FBI's list, it isn't pertinent to ask whether “Bacillus anthracis samples dried with a rudimentary methodology can pose an inhalation hazard resulting in pulmonary anthrax. Of course they can. The question is whether [this method] can produce anthrax like that found in the letter.” “Our aim here is to lay out the facts gathered in this investigation and be as transparent as we can,” says FBI spokesperson Paul Bresson. “That is all we can do and all we can control. As we have stated previously, we would have preferred to have brought this case to trial.” 3. ASTROPARTICLE PHYSICS # Europeans Think Big for Particle Detectors 1. Daniel Clery European physicists who study particles from outer space made a pitch this week for the ambitious and costly experiments they want to build over the next decade. “We've worked hard to get the tools; now we need to move to large-scale detectors,” says Christian Spiering of DESY, Germany's particle physics lab in Hamburg. Astroparticle physicists aim to snare the likes of cosmic rays, neutrinos, gravitational waves, and dark matter particles as they pass by or through Earth. To better capture these elusive cosmic signals, ASPERA, a network of astroparticle physicists funded by the European Union, this week released a road map for future projects, along with a pitch to funding agencies to double the current €70 million annual spending on astroparticle physics over the next 8 to 10 years—a tall order in what's expected to be a tough funding climate. Researchers have been detecting particles from space for decades, but so far the scientific breakthroughs from their sensors have been few. But this groundwork will soon pay off, says Spiering, who chairs ASPERA's road map committee. The road map, released on 29 September, divides the field into seven areas and identifies a key instrument in each. Three of those instruments rely on tested technology, and construction could begin on them soon. First, the proposed Pierre Auger Observatory North, a vast array of detectors that would look for ultrahigh-energy cosmic rays, would likely be a bigger Northern Hemisphere version of the existing Auger array in Argentina. Second, the Cerenkov Telescope Array would look for incoming high-energy gamma rays, following the detection strategy of existing telescopes such as MAGIC in the Canary Islands. And the recently completed ANTARES, a neutrino observatory on the Mediterranean seabed, is the prototype for the third, KM3NeT, which would use a cubic kilometer of seawater as its detector. For these three proposals, “we have the technology; now we have to find the money,” says ASPERA coordinator Stavros Katsanevas of France's CNRS research agency. The road map doesn't detail the detector of choice for two other subfields, spotting dark matter and measuring neutrino mass from a phenomenon called double beta decay; the outcomes of ongoing experiments using a variety of techniques will inform those decisions. ASPERA's lineup finishes with two mammoth projects: an underground neutrino observatory called LAGUNA with a detector made from a million tons of either water or liquid argon, and a next-generation gravitational-wave antenna dubbed the Einstein Telescope. Both require more design work, and results from the Large Hadron Collider and current gravitational-wave detectors could change the specifications. “By mid next decade, we can launch these ambitious projects,” says Katsanevas. Metallurgist John Wood of Imperial College London, who headed a European Union-sponsored effort to identify research infrastructure projects, is skeptical of ASPERA's call for funding increases. “In the current climate, their chances are pretty slim,” he says. “Politically, it's a very difficult time.” But Katsanevas says, “I'm not afraid of that.” The needed doubling of funding assumed that all of the road map's projects remained European-led, whereas he expects many will become collaborations with North America or Asia or both. In fact, French officials have asked the Organisation for Economic Co-operation and Development in Paris to act as a coordinating body, comparing regional road maps to find openings for collaboration. 4. NATIONAL INSTITUTES OF HEALTH # Adding a Turn to the Roadmap, Zerhouni to Step Down 1. Jocelyn Kaiser Without saying much about his next move, Elias Zerhouni announced last week that he is resigning from the U.S. National Institutes of Health (NIH). He will step down by the end of October after more than 6 years as director. During that time, he tried to break down institutional and scientific barriers at the$29 billion agency and push discoveries into medicine. Those efforts won praise from Congress and leaders in the research community. But he also had to deal with a string of ethics controversies, and it was a tough time for rank-and-file scientists, who were squeezed by 5 years of flat budgets.

Rumors have swirled since January that Zerhouni might replace Johns Hopkins University President William Brody, who is retiring at the end of this year. When reporters asked Zerhouni about this last week, he responded: “That's not been decided by me at all.” Instead, he said he plans to “take some time out” and do some writing. He chose to depart before the 4 November presidential election, he said, so that the next Administration will “focus on NIH as early and as soon as possible.”

As for why he's leaving at all, Zerhouni saw his departure as following “the natural cycle of tenures for this position,” about 6 years. A look back at the previous eight directors shows that their terms varied in length; two stayed longer than 6 years: James Shannon (13 years) and James Wyngaarden (9 years).

Zerhouni, 57, an Algerian-born radiologist who invented several new imaging techniques, was an administrator at Johns Hopkins before he took the helm of NIH in May 2002. Zerhouni's background set him apart from his predecessor, the basic biologist Harold Varmus. Many observers say Zerhouni's management experience made him the right person for a time of belt-tightening. A 5-year doubling of NIH's budget from 1998 to 2003 was coming to an end, and Varmus and some other scientific leaders were concerned about NIH's unchecked administrative growth, including the creation in 2000 of an institute focused on imaging.

In response, Zerhouni created a formal plan called the NIH Roadmap, a set of initiatives aimed at moving basic discoveries to the bedside, funded at first by taxing each of NIH's institutes. But just as these new programs were taking off, NIH's budget stopped growing, sending success rates for research grants crashing from about 30% to 20% this year. Some members of the community blamed Zerhouni and his Roadmap. Defenders say, however, that the plan was useful as a selling point for biomedical research in Congress.

Although Congress has recently given NIH tiny budget boosts, some say it has significantly elevated the NIH director. It passed a 2006 law capping the number of institutes and centers at 27, giving the NIH director more control over NIH's portfolio, and creating a permanent fund for Roadmap-like projects. That pot of money had risen to $496 million, as large as many of smaller institutes. Varmus says the NIH director's new powers will make the position “a lot more interesting.” At the same time, some Roadmap components remain just experiments. A program to bring industry-style molecular screening to academia is beset by skeptics. And the new Clinical and Translational Science Awards, which are forcing medical schools to integrate clinical science programs, have been criticized as inadequate. Zerhouni has been credited widely for trying to promote novel research and young investigators, including most recently for creating the “transformative” R01 award for risky projects. Although the total number of these awards so far is modest, “the important thing was that Zerhouni recognized” the need for them, says cell biologist Kei th Yamamoto of the University of California, San Francisco, who also helped plan a major overhaul of peer review. Zerhouni may have reaped more than the usual share of controversy. He defended sexual research grants to a Republican-led Congress and departed from the Bush Administration's tough line against human embryonic stem cell research. Addressing an uproar over industry consulting by NIH scientists, he banned such outside activities. President George W. Bush has not yet named an acting NIH director, but Zerhouni has recommended current NIH Deputy Director Raynard Kington for the post. An M.D. and Ph.D. in health policy and economics who studied health disparities before coming to NIH, Kington is not well-known to the extramural biomedical research community. As deputy, much of his time has been taken up with dealing with the intramural ethics controversy. The acting director will face a number of immediate challenges. One is deciding how to allocate the pain of a budget freeze through March, just approved by Congress in a continuing resolution (ScienceNOW, 29 September). Typically, NIH deals with such uncertainty by funding ongoing grants at the 80% level and funding fewer new awards until the next budget is approved. That will increase stress on investigators. In the short term, leading NIH “is going to be an even tougher job,” says Howard Garrison, public affairs director of the Federation of American Societies for Experimental Biology in Bethesda, Maryland. Also requiring quick attention is a call from Senate investigators for a review of conflict-of-interest rules for extramural researchers. Given such pressures, many NIH watchers hope a new director will be in place before next spring. 5. NOAA # U.S. Oceans Chief Leaves a Mixed Legacy in His 7-Year Wake 1. Eli Kintisch For 7 years, former Navy Vice Adm. Conrad Lautenbacher has preached his mantra of “one NOAA” as a way to unify the hydraheaded National Oceanic and Atmospheric Administration (NOAA). Congress has rewarded his management prowess with larger budgets, allowing the agency to expand its efforts on everything from tracking wildfires to monitoring tsunamis. Last week, Lautenbacher announced he is leaving, and scientists say the spry technocrat leaves a reorganized and stronger NOAA research program—as well as some big headaches for the next U.S. oceans skipper. Tucked into the Commerce Department, NOAA has responsibility for myriad activities in the air, at sea, and in space. “When I came to NOAA, I saw it as a holding company of six or seven multidisciplinary, very fine scientific enterprises,” says Lautenbacher. “[But] it was too compartmentalized.” Lautenbacher sought to break down agency stovepipes with 44 programs that cut across issues such as aquaculture, environmental modeling, and geodesy. He also combined six agency labs in Boulder, Colorado, to create the Earth System Research Laboratory (ESRL). “He's done a good job of knitting the pieces of NOAA together,” says marine geologist Rodey Batiza, a program manager at the U.S. National Science Foundation who has served as an outside reviewer for the agency. Congress apparently agreed: Legislators hiked the agency's budget from$3.1 billion to $4.2 billion during Lautenbacher's tenure, although they also pumped hundreds of millions of dollars into pet projects. The improved cooperation helped bolster tsunami monitoring efforts, says geophysicist Costas Synolakis of the University of Southern California in Los Angeles. Since the Sumatra tsunami of December 2004, NOAA's Pacific Marine Environmental Laboratory (PMEL) in Seattle, Washington, has collaborated with the National Weather Service on 33 new advanced undersea pressure gauges that have improved the service's predictive accuracy. The weather service is also installing new tsunami-modeling software developed by PMEL's scientists. By the same token, former NOAA advisory board chair Leonard Pietrafesa, a fluid physicist at North Carolina State University in Raleigh, says that ESRL has paved the way for better predictions of hurricane intensity. While Lautenbacher was making it easier for NOAA's scientists to talk to one another, the agency itself was having trouble communicating with two other federal agencies on one of its most important programs, the National Polar-Orbiting Operational Environmental Satellite System. Delays and cost over runs in the$14 billion Earth-monitoring program, which NOAA manages with NASA and the Pentagon, triggered a 2006 Pentagon review that stripped from the system five climate sensors. A report that year by the Department of Commerce inspector general faulted NOAA leadership's “poor management oversight” of the program, and the three agencies are still trying to agree on a budget for it.

Lautenbacher says he did his best to manage the “poorly conceived” program, which was created in 1994. “I don't regret how NOAA managed it,” he says. He reassures climate scientists that making precise climate data “operational” will be a priority for a “National Climate Service,” a new entity that his deputies are proposing for the next Administration.

Lautenbacher, who will step down next month, plans to move to Atlanta, Georgia, to chart his future. Deputy NOAA Administrator William Brennan will serve as acting director.

6. PLANETARY SCIENCE

# Minerals Suggest Water Once Flowed on Mars--But Where?

1. Richard A. Kerr

Scientists on the Phoenix mission to the high arctic of Mars announced this week that the rover had found some long-sought soil minerals. “These [minerals] are indicators of liquid water in the past,” Phoenix principal investigator Peter Smith of the University of Arizona (UA), Tucson, said at a bicoastal press conference on 29 September. The minerals are exactly what Phoenix was sent to look for in the high-latitude soil just centimeters above the frozen water suspected from orbital data.

The catch is that from Phoenix observations so far, team members can't say for certain when or where the water was liquid: recently, where Phoenix found the minerals, or long ago, somewhere else on the planet. The minerals might have blown in from ancient deposits formed in the atmosphere. And time is running out for Phoenix to find answers. The gathering gloom of martian winter means it has only a couple of months to live.

The discoveries come from two Phoenix instruments. The Thermal and Evolved Gas Analyzer (TEGA) recorded the release of water when it heated a soil sample to high temperature, most likely when water was driven off from clay, said TEGA lead scientist William Boynton of UA. TEGA also detected carbon dioxide being driven off at high temperature—a clear sign that calcium carbonate was breaking down, Boynton said. The Microscopy, Electrochemistry, and Conductivity Analyzer confirmed the presence of calcium carbonate, said MECA lead scientist Michael Hecht of the Jet Propulsion Laboratory in Pasadena, California. It measured a stable pH of 8.3 in a soil slurry even after Phoenix added acid, evidence that calcium carbonate was buffering the pH. MECA detected calcium ions in solution as well.

So liquid water interacted with minerals and carbon dioxide. The working hypothesis behind the mission was that not long ago—tens of thousands to a few millions of years ago—periodic climate swings might have melted the subsurface ice confirmed by Phoenix to make a habitable, if temporary, environment for microbial life in the soil a few centimeters down.

That scenario could still hold, says geochemist Nicholas Tosca of Harvard University. “Liquid water is required to form these minerals,” he says. “How much liquid water could be debated. A thin film could do it.” That would be enough for microbes too. But scientists cannot yet show that the minerals formed where Phoenix found them. They may have formed billions of years ago where massive deposits of clay are found today. Also, carbonates reported in martian dust may have formed in the atmosphere and could have been blown to the Phoenix site, although Smith sees few signs of such transport. “I'm not sure what they could do to test that,” says Tosca.

Now that Phoenix has completed its 90-day nominal mission and a 30-day extended mission, it's living on borrowed time. Martian winter is coming on, with the sun spending more and more time each day below the horizon, starving the spacecraft's solar panels. Mission managers are rushing to fill TEGA's last four sample cells before power levels fall too low for the sampling arm to operate. “We have not finished,” declares Smith. Near the top of the team's remaining to-do list will be looking for organic matter possibly lingering from past life. “If there's any there, it's not very much,” said Boynton, but “we are still looking.”

By late November, the crushing cold should shut down the lander as carbon dioxide frost begins to encase it. Water-ice snow is already beginning to fall from passing clouds.

7. CRYPTOGRAPHY

# Quantum Network Set to Send Uncrackable Secrets

Next week in Vienna, European scientists and engineers will put the bizarre and abstruse laws of quantum mechanics to a practical, everyday use. Researchers will demonstrate a network for transmitting uncrackable encoded messages in quantum-mechanical packets of light. Such quantum networks could soon link banks or government offices, some researchers say. “This is a moment when research turns into technology,” says Chip Elliott, a network engineer at BBN Technologies in Cambridge, Massachusetts, who 5 years ago led efforts to build the more primitive DARPA network. Still, he cautions, “it's too early to say whether there are customers for this.”

The product of a 4-year, €11.4 million collaboration funded by the European Union, the network will connect six sites across the city through eight existing fiber-optic links, all belonging to industrial giant Siemens. It will distribute the numerical “keys” for scrambling secret messages.

A message can be encrypted by converting it into a string of 0s and 1s and scrambling those bits by compounding them with a key, a random string of 0s and 1s. If only the sender, Alice, and the receiver, Bob, know the key, then only they can read the message. The trick is to transmit the key without its being seen by an eavesdropper, Eve. So-called quantum key distribution exploits the fact that it's impossible to measure a photon without also altering it.

For example, Alice can send Bob individual photons polarized horizontally to signify 0 or vertically to signify 1. Thanks to quantum weirdness, she can also send photons polarized both ways at the same time. If Eve tries to measure the light particles, that very act will “collapse” the two-way-at-once photons into either vertical or horizontal ones. Bob and Alice can detect that by comparing some randomly chosen bits.

A few companies make quantum systems to connect two users through a single link. The Vienna project weaves six disparate systems into an automated network. “You just make a connection to one node and can connect to any other user,” says Andreas Poppe, a physicist at the Austrian Research Centers in Vienna.

In fact, the network will not be a fully quantum network, which would let Alice pass photons to Bob across any number of nodes. That would require devices called “quantum repeaters” that are at least a few years away. In the Vienna network, each user generates a key that is stored as classical (nonquantum) 0s and 1s in the node he or she links to. Those classical bits flow from node to node as needed, quantum mechanically encrypted as they cross each link. “What our network assumes is that you can trust each of the intermediate nodes,” says Andrew Shields, a physicist with Toshiba Research Europe in Cambridge, U.K.

Nobody will be invited to try to hack the network, either. That's because hackers would likely ignore the quantum mechanics and attack the system's conventional parts, which wouldn't test the new concept, Poppe says.

Still, researchers hope the demonstration will signal the emergence of the new technology, especially for private networks. Some experts are skeptical. “I think the impact on the actual practice of cryptography is likely to be small,” says Ronald Rivest, a computer scientist at the Massachusetts Institute of Technology in Cambridge. Current techniques, which rely not on shared secret keys but on mathematical manipulations that are practically impossible to work backward, already work well, says Rivest, who predicts that the niche for the quantum systems will be small.

Network developers hope for more. “I think, on our scale of things, it will be a historic day,” says physicist Nicolas Gisin of the University of Geneva, Switzerland. The question is, will technologists and market analysts see it that way, too?

8. GLACIOLOGY

# Winds, Not Just Global Warming, Eating Away at the Ice Sheets

1. Richard A. Kerr

The surge of glaciers draining both the Greenland and West Antarctic ice sheets has alarmed scientists and the public alike. Global warming appeared to be taking an early toll on the planet's largest stores of ice while accelerating the rise of sea level. But two new studies point to random, wind-induced circulation changes in the ocean—not global warming—as the dominant cause of the recent ice losses through those glaciers. In Greenland, at least, “you're going to have trouble blaming this on global warming,” says glaciologist Richard Alley of Pennsylvania State University in State College. But he says the results underscore the threat of global warming by showing how warmth can “hit ice sheets where it hurts,” as glaciologist Robert Bindschadler of NASA's Goddard Space Flight Center in Greenbelt, Maryland, puts it.

The losses long puzzled glaciologists because the atmosphere over the glaciers didn't seem to have warmed enough to trigger them. Meltwater didn't lubricate glacial flow enough to explain the losses either (Science, 18 April, p. 301). Could the culprit be ocean waters? They can carry lots of heat to glaciers that float out onto coastal waters, but oceanographers had not been taking the ocean's temperature off the ice sheets.

So physical oceanographer David Holland of New York University and his colleagues turned to scientists of a different stripe: fisheries researchers. They had recorded bottom temperatures off southwest Greenland while surveying shrimp populations from 1991 to 2006. Holland and colleagues reported online this week in Nature Geoscience that an influx of warmer, saltier water in 1997 “coincided precisely” with the rapid thinning and subsequent acceleration of Jakobshavn Isbræ glacier, Greenland's most prolific outlet for ice. The warm water must have melted the glacier's exposed underside and weakened it, they say, leading to the breakup of the ice shelf that had been bracing the glacier against the shore and helping to hold it back. “I think it's fantastic,” says Bindschadler. They've “got this nailed in Greenland.”

Holland and colleagues traced the influx of ocean warmth back to the atmosphere over the North Atlantic. An abrupt weakening of winds due to a natural atmospheric phenomenon called the North Atlantic Oscillation drove more waters from the Irminger Sea near Iceland around the tip of Greenland, up onto the shelf, and under the ice.

A similar natural process may have been at work in recent heightened ice losses off West Antarctica, researchers reported in the 18 September Geophysical Research Letters. Glacier modelers Malte Thoma of the Alfred Wegener Institute for Polar and Marine Research in Bremerhaven, Germany, and colleagues, including Holland, had no water temperature data there, but they did have wind observations. When they plugged those numbers into an ocean-ice model, the shifting winds drew deeper, warmer offshore waters in the model up onto the continental shelf and under the ice at the same time in the mid-1990s that the real glaciers draining the West Antarctic Ice Sheet sped up. The wind shift may have been natural or caused by global warming, says co-author Adrian Jenkins of the British Antarctic Survey in Cambridge, U.K. Therefore, “whether we're going to see a continuation of [those losses] is not clear.”

The vagaries of the atmosphere may be sending some confusing signals about global warming, researchers say, but that's no reason to stop worrying about the ice. “The really important thing is,” says Alley, “when you look at [climate] projections, you have warming around Greenland.” And that warmth now has an obvious way to get at the ice.

9. RESEARCH FOUNDATIONS

# Biochemist Robert Tjian Named President of Hughes Institute

1. Jocelyn Kaiser

The Howard Hughes Medical Institute (HHMI), the largest private funder of biomedical research in the United States, has chosen a new president. He is University of California, Berkeley, biochemist Robert Tjian, a longtime Hughes investigator known as a driven researcher and devoted mentor. On 1 April, Tjian will replace Thomas Cech, who will return to research at the University of Colorado, Boulder.

The Chevy Chase, Maryland-based HHMI, which has an endowment of $17.5 billion and spent$685 million last year, supports more than 350 investigators at universities and funds education programs and scientists abroad. Tjian said “there are many reasons” why he accepted an offer from the Hughes board of trustees, which based its search on nominations. The main one, he says, is “to give back” to the institution that has funded him for 22 years. Moreover, Hughes “has a huge impact,” and “I think it's a fantastic opportunity to try to help scientific research and science education in the United States and internationally,” Tjian says.

Tjian, 59, studies the biochemistry of gene transcription. At Berkeley, he has been heavily involved in recruiting new faculty, reshaping its research and education programs, and directing its nearly decade-old health sciences initiative, which promotes interdisciplinary research. He also co-founded Tularik, a biotech company that was sold to Amgen in 2004 for $1.3 billion. HHMI board of trustees member Joseph Goldstein says this range of experiences made Tjian “exactly right” for a job that has become “more complicated” in the past few years, as Cech began new programs and oversaw the creation of HHMI's first research campus, Janelia Farm, in Loudoun County, Virginia. Tjian is “an outstanding scientist, he's an excellent mentor to students and postdoctoral fellows, he's interested in education, he has a reputation for being very organized, and he has a broad view of biology and medicine,” says Goldstein, a Nobel Prize-winning biochemist at the University of Texas Southwestern Medical Center in Dallas, who has known Tjian for more than 20 years. As Cech did during his 8 years at HHMI, Tjian plans to keep his Berkeley lab—he says he wouldn't have taken the job otherwise—but will spend no more than 1 day a week there and at Janelia Farm. He has also agreed to give up his position on the boards of several biotech companies by April. Tjian says that he has no specific new programs in mind coming in: “I need to go in there and take a look.” For now, he plans to continue HHMI's aim of funding the “right people.” He doesn't expect to tinker with Janelia Farm, which he considers an ongoing “experiment.” He expects to visit Hughes in the coming months while Cech is still there to “learn the ropes.” 10. FELLOWSHIPS # An International Plan to Hatch Scientist-Entrepreneurs 1. Richard Stone TIANJIN, CHINA—Who said science and business don't mix? Last week, more than 100 young researchers from 60 countries were special guests at the summer meeting of the World Economic Forum (WEF), held near Tianjin, China's third biggest urban area. While corporate titans anguished over the U.S. bank bailout, young scientists and entrepreneurs explored how to forge new links. To ease neophytes into the world of dealmaking, the InterAcademy Panel (IAP), a network that sponsors science-in-society programs on behalf of 100 national science academies, plans to award five$10,000 seed grants to the most compelling joint R&D proposals arising from interactions at the meeting between scientists and business leaders. “The idea is to nurture new linkages,” says IAP co-chair Howard Alper, a chemist and chair of Canada's Science, Technology and Innovation Council. “Companies need not put in a cent at the beginning.” Alper expects many academies to provide matching grants. The effort is timely, says Padmasree Warrior, chief technology officer at the California computer firm, Cisco Systems. “The lines are blurring between breakthrough, start-up, and scale-up,” she says.

Top scientists are no strangers to WEF, famed for its winter meetings in Davos, Switzerland. Klaus Schwab, WEF's founder and executive chair, says he has long sought “to integrate technology even more into WEF activities.” Last spring, Alper and fellow IAP co-chair Chen Zhu, China's health minister, persuaded Schwab to expand WEF's science program and invite young scientists. “We want to create a sustained integration of S&T [science and technology] in the forum,” says Alper.

As a result, WEF's second annual “New Champions” meeting featured workshops on managing science and frontier science, and plenary sessions on nanotechnology and life sciences. “The academics seemed to embrace the idea that they needed to engage with the business community in language that the latter could understand,” says Tom Ilube, chief executive officer of Garlik, a company based in Richmond, U.K., that specializes in protecting consumers against identify theft.

Guruprasad Madhavan cottoned on quickly. At the meeting, the S&T policy fellow at the National Academies in Washington, D.C., forged a partnership with entrepreneurs who will help him develop a low-cost medical device business model for poor villages in Tamil Nadu, his home state in southern India. With such tangible outcomes, Alper and others hope scientists have earned a permanent place at the WEF table.

11. NUTRITION SCIENCE

# The Peanut Butter Debate

1. Martin Enserink

A new type of ready-to-use food is changing the way severe malnutrition is treated. But questions remain about how far to push its introduction--and science has a hard time providing the answer.

A new type of ready-to-use food is changing the way severe malnutrition is treated. But questions remain about how far to push its introduction—and science has a hard time providing the answer

SAE SABOUA, NIGER—On a scorching hot day in this dusty, dry corner of the Sahel, mothers carrying babies and small children line up outside a couple of big tents. Some of the infants look healthy but others are shockingly thin, their arms like broomsticks. They're waiting to enter a “therapeutic feeding center” operated by the French section of Médecins Sans Frontières (MSF). Once inside, the children are measured and weighed and receive a quick health checkup. If they're found to be severely malnourished, they immediately receive a silvery sachet containing a new type of food that might just save their lives.

Open and squeeze the sachet and out pour 92 grams of a brown paste that looks like dark peanut butter. It's called Plumpy'nut, and one serving has 500 calories and plenty of proteins, vitamins, and minerals. Aid organizations like MSF say the paste, a so-called ready-to-use therapeutic food (RUTF), has revolutionized care for malnourished children. Plumpy'nut has a long shelf life, it does not need to be mixed with water—a major risk with standard treatments based on milk powder—and it is simple for mothers to give to their children at home. Perhaps best of all, children love the sweet, sticky stuff.

But the nutrition world is divided on just how far the introduction of these products should go. MSF wants to move beyond treating severe malnutrition and introduce peanut butter-like pastes to prevent that condition, which occurs in some 20 million children in Africa and South Asia every year. In one district in Niger, MSF has started giving the product to as many as 80,000 children between 6 and 36 months, in what's called “blanket distribution.” MSF likens the move to the large-scale introduction of antiretroviral drugs in Africa, which it helped pioneer.

But others ask: Where's the science to support such a plan? Few dispute the power of RUTFs in treating severely wasted children. But there's little evidence that such products work equally well in preventing malnutrition. And besides, skeptics say, adding them to the regular diet of millions of children is too complicated and too costly—MSF's program cost more than $55 per child in 2007—to keep up in the long run. “For prevention, we need other products,” says André Briend, a nutrition expert at the World Health Organization (WHO) in Geneva, Switzerland, who helped invent Plumpy'nut while working as a French government researcher. The issue has pitted those who want to see solid evidence before embarking on a major aid program against those—impatient with talk about P-values, cost-effectiveness, and sustainability—who want to act now. “Thousands of kids are dying,” says Milton Tectonidis, a former MSF nutrition expert and a vocal advocate of a massive introduction of RUTFs. “We have enough data now. Do something!” ## A new approach Part Sahara, part Sahel, Niger is one of the poorest countries in the world. More than 70% of the population is illiterate. Malnutrition is pervasive, especially during the so-called hunger gap—the 5 or 6 months before the annual harvest, when the previous year's supplies of sorghum and millet are running out. Protracted dry spells periodically lead to severe food crises, but even in good years, the essentially vegan diet doesn't always provide enough nutrition for fast-growing children younger than 3, says Susan Shepherd, a medical adviser at MSF in Geneva. Until a few years ago, the standard treatment for severe malnutrition was F100, a milk powder fortified with dozens of vitamins and minerals. F100 was developed in the 1980s by veteran nutrition scientist Michael Golden, now a professor emeritus at the University of Aberdeen, U.K. It needs to be reconstituted with clean drinking water and consumed almost immediately. Left unrefrigerated for a few hours, it turns into a bacterial soup that can cause infectious diseases. That's why F100 is administered only in special nutrition “hospitals” where children often stay as long as 4 weeks with a caretaker, usually their mother. Those are serious drawbacks. A mother who leaves home and work may put other children or the harvest at risk. Hospital capacities are limited, forcing governments and aid organizations to turn away patients. During a 2002 famine in Angola, MSF treated 8000 children in in-patient centers, Shepherd says, far short of what was needed. Crowded hospitals also help spread infectious diseases. Studies have shown that only between 25% and 45% of patients make a full recovery—and as many as one in five dies. Golden and others started looking for alternatives to F100 in the 1990s. In 1997, Briend, then at the Institute of Research for Development in Paris, teamed up with Michel Lescanne, the director of Nutriset, a food company in Normandy. Lescanne had experimented with Mars-like bars that had almost the same composition as F100; the problem was that they melted easily. Briend found his inspiration in a jar of Nutella, a hazelnut spread that his children loved; the duo developed a paste consisting of roasted, ground peanuts combined with vegetable oil, milk powder, sugar, and a mix of minerals and vitamins. Plumpy'nut, as they called it, is less than 2% water, which makes it a hostile environment for microbes. Suspended in a fatty environment, the vitamins and minerals are very stable. Plumpy'nut can last for up to 2 years without refrigeration and does not spoil even after the package is opened. Mark Manary, a nutrition scientist at Washington University in St. Louis, Missouri, was the first to test the product in clinical trials, in Malawi. Two studies published in 2004 showed that it was “really a breath of fresh air,” Manary says: Almost 80% of severely malnourished children recovered. And the home-based treatment regimen proved easy to organize on a large scale. Experiences elsewhere were similar. Steve Collins, who leads an Irish relief organization called Valid International, saw high recovery rates in Ethiopia, Malawi, and Sudan. MSF was sold on Plumpy'nut after it was able to treat as many as 60,000 children during a severe food crisis in Niger in 2005, says Shepherd—a vast improvement from the Angolan experience. In June of 2007, four United Nations agencies, including WHO and UNICEF, issued a joint statement advocating home treatment with RUTFs for severely malnourished children who don't have other illnesses. As a result, demand and production have exploded. Nutriset is the biggest producer by far, making more than 15,000 tons in 2008. Although some are dismayed by Nutriset's patents on Plumpy'nut (see sidebar, p. 38), other companies are entering the market as well. In Malawi, Manary set up a Nutriset franchise that churns out 500 tons of Plumpy'nut a year. UNICEF, the biggest RUTF buyer in the world, may purchase as many as 8000 tons in 2008 and expects global production to grow to at least 50,000 tons by 2011. Given that success, many were surprised when a series of major papers on malnutrition published in The Lancet earlier this year offered only lukewarm support for RUTFs. In a vociferous statement, MSF accused the authors of “undermining the support for this lifesaving intervention,” which led to a rift with the journal (Science, 1 February, p. 555). WHO's Briend was dismayed as well. But the authors of the series have since said that they were misunderstood and that they do in fact support the use of RUTFs to treat severe malnutrition. ## Daunting studies Although there's consensus about treatment, prevention is a very different matter. MSF and some other nongovernmental organizations are now proposing giving peanut paste as a supplement to children who are moderately malnourished or just at risk of severe malnutrition. Every case of severe malnutrition starts as a milder one, says Shepherd—so why wait until a child is emaciated? “After 2005 we said, 'Hell, let's try to expand it.'” Many alternatives haven't worked, experts agree. Severe malnutrition is the result of a downward spiral of poor-quality food, weak immunity, infections and diarrhea, loss of energy and appetite, and so on. Many approaches have been tried to stop that cycle: Children have been given an inexpensive, fortified blend of corn and soy flour, or tablets with specific micronutrients such as vitamin A or zinc. Mothers have been taught to breastfeed longer, cook better meals, or wash their hands to avoid infections. But nothing has really proven adequate. Whether peanut pastes will do better is far from certain. When MSF's program started, only two studies had looked at their ability to prevent severe malnutrition, both by Manary's team in Malawi. They found that moderately malnourished children given RUTFs gained weight faster than those who received corn-soy flour, “but it wasn't a knockout,” Manary says. MSF was not deterred: The fact that it worked so well as a therapy was reason enough to believe it would work in prevention, too, says Shepherd. In 2006, MSF gave Plumpy'nut to all moderately malnourished children in its centers in one district, Guidan Roumdji. But simply identifying those children and supplying them with the peanut butter proved a huge logistical challenge; so in 2007, the agency decided to switch to mass distribution to all children between 6 and 36 months of age. Instead of Plumpy'nut, it used Plumpy'doz, a Nutriset product that comes in big jars. Mothers are supposed to give their children just three spoonfuls of Plumpy'doz per day; that way, children get only a quarter of the calories, but their intake of micronutrients stays about the same. Nutrition science is difficult enough in Western countries; clinical trials to evaluate a food program in a country like Niger are an even bigger challenge, says Rebecca Freeman-Grais, a researcher at Epicentre, MSF's epidemiology division. The study population is hard to reach, and communication is difficult. Randomizing children to two different regimes within a village would have met with resistance, she says, so the researchers compared entire villages to which Plumpy'nut was given with others to which it was not—but of course, no two villages are exactly the same. MSF's decision to move to blanket distribution of Plumpy'doz interrupted the trial, which was supposed to last for 18 months, and forced the researchers to choose a different design that compared the two products. Other aid organizations distributed food in the area as well, introducing more possible confounders. The data, which are now under review at The Journal of the American Medical Association, show that Plumpy'nut does lead to a substantial decrease in the incidence of severe malnutrition, says Philippe Guérin, Epicentre's medical director. But Plumpy'doz—although designed with prevention in mind—appears to be much less effective. That may be because children get fewer calories, but there may be other factors, says Guérin. A survey suggested that rather than giving a little bit every day, some mothers let their children eat it all early on. Plumpy'doz may also be more likely to be shared between the children in a household than the single-dose Plumpy'nut packages. Epicentre's conclusion was not welcome news to MSF. MSF's Shepherd says it's important that the researchers analyze their data independently—but says she does not agree with Epicentre's analysis. Tectonidis, who believes Plumpy'doz works in prevention and has no faith in the Epicentre study, went further: In September 2007, while working at the MSF office in Rome, he visited the project in Niger and obtained a copy of the study's database. He then asked Golden, who was not previously involved in the study, to analyze it. Golden's unpublished manuscript says the Plumpy'doz intervention had a “dramatic effect.” Guérin says he has not seen Golden's paper and declined to comment on it. ## Is it practical? Nutrition science aside, there are other questions. Even if Plumpy'nut or similar products work well for prevention, with their hefty price tag, are they the most cost-effective way? How long does the intervention go on, who pays for it, and doesn't it make a population dependent on foreign aid? “When you're going to tell the world what to do about hundreds of millions of children, it also has to work in practice,” Manary says. One solution may be to make peanut butters cheaper—for instance, by replacing all or part of the powdered milk, the most expensive ingredient, with soy. Perhaps that approach should be combined with very good infection control, says Manary. Many other ideas were on the agenda at a closed expert meeting at WHO headquarters this week, which participants said promised to be lively. But for the moment, the debate is moot in the Guidan Roumdji district. In a spat unrelated to the scientific debate, the government of Niger accused MSF France of violating several rules and suspended all of its activities on 29 July. Negotiations are ongoing, but for now, both the treatment programs for severely malnourished children and the Plumpy'doz distribution to more than 80,000 children have come to an abrupt halt. 12. NUTRITION SCIENCE # Patents: A Recipe for Problems? 1. Martin Enserink The booming market for so-called ready-to-use therapeutic foods such as Plumpy'nut (see main text) is placing Nutriset, a company in France that together with the French government owns the patent to Plumpy'nut and similar pastes, under scrutiny. NIAMEY, NIGER—A giant peanut roaster and grinder, a mixing and filling machine—it doesn't take all that much to produce the new ready-to-use therapeutic foods (RUTFs). A factory barely larger than a house in the quiet outskirts of Niger's capital produces some 500 tons of Plumpy'nut annually. But it can't do so on its own: The company, STA, is a franchise of Nutriset, a company in France that together with the French government owns the patent to Plumpy'nut and similar pastes. As the market for RUTFs is booming, that situation has come under scrutiny. Aid organizations say there should be no patents on key humanitarian nutrition products, and some worry that Nutriset, a small family-run business, won't be able to meet the soaring demand. “That is absolutely becoming a problem,” says Ellen 't Hoen of the Access to Medicine Campaign at Médecins Sans Frontières (MSF), one of Nutriset's main clients. Most past inventions in humanitarian nutrition, such as a widely used fortified milk powder called F100, weren't patented; nor was oral rehydration therapy, a lifesaver for diarrhea patients. But Nutriset and the French Institute of Research for Development obtained patents for Plumpy'nut that last until 2018 and are valid in Europe, North America, and about 30 African countries. Nutriset has threatened lawsuits to keep others—including Compact in Norway and MSI in Germany—from selling similar pastes. Nutriset's Adeline Lescanne says the company is rapidly boosting its own production capacity and at the same time taking the technology to the developing world, where it helps to stimulate the local economy. It has set up four franchises—in Niger, Malawi, Ethiopia, and the Dominican Republic—that have received equipment and training and now produce Plumpy'nut on a small scale. It has also signed a licensing deal that lets Valid International, an Irish charity, produce its own product under a different name. MSF and UNICEF, another big buyer, acknowledge that so far there have been no shortages nor evidence of price gouging. Nor is the patent valid in many malnutrition hot spots, including India, where Compact is building a factory and several other companies are interested as well. Still, MSF and UNICEF don't like to be dependent on one major producer for delivering what is becoming an essential product to a large chunk of Africa. MSF says Nutriset and other companies entering the RUTF market should forgo patents—or at least be generous in cutting licensing deals. It's unclear, meanwhile, whether the patent would withstand a challenge by a competitor. It covers not just Plumpy'nut but also, 't Hoen says, “pretty much any nut paste with milk powder, oil, and micronutrients.” Other companies could market a similar product and see what happens in court if sued, she says—but neither Compact nor MSI have been willing to take that risk. Michael Golden, who formulated F100, believes the pressure should not be on Nutriset but on the French government; he hopes that France's foreign minister, Bernard Kouchner, a physician who helped found MSF in 1971, will intervene. 13. PLANETARY SCIENCE # Culture Wars Over How to Find an Ancient Niche for Life on Mars 1. Richard A. Kerr Researchers seeking the next Mars rover landing site disagree about what makes for the most promising possibility: lots of water-altered minerals or familiar water-shaped terrain. Researchers seeking the next Mars rover landing site disagree about what makes for the most promising possibility: lots of water-altered minerals or familiar water-shaped terrain MONROVIA, CALIFORNIA—“This is not a contest,” the workshop's organizers kept insisting, but it sure sounded like one. At the end of 3 days of sales pitches, cross examinations, and warm debate, more than 100 planetary scientists gathered* in a hotel ballroom here cast their ballots for the most scientifically inviting spot to send the$1.9 billion Mars Science Laboratory (MSL) in early 2010.

“Everyone wants to maximize the science,” says planetary geologist James Rice of Arizona State University in Tempe. In deciding how to do that, most attendees aligned themselves with one of two parties. Spectroscopists, who find martian minerals from orbit by their distinctive spectral colors, tended to favor sites that beam strong spectral signatures of rock altered by water. Geologists, by contrast, preferred sites whose geological forms speak most eloquently of past water pooling on the surface.

Water is key because, as the official mission fact sheet puts it, NASA intends MSL to assess “whether the landing area ever had or still has environmental conditions favorable to microbial life.” With that theme in mind, a lineup of paleontologists, geochemists, and geologists opened the workshop by explaining the most promising circumstances on ancient Earth for preserving evidence of habitability and traces of past life, such as river deltas that trap and preserve fossils and organic matter.

Then the wrangling began. Leading spectroscopists had proposed two of the seven landing sites still in the running (Science, 9 November 2007, p. 908) because the sites simply screamed “water!” to them. Jean-Pierre Bibring of the University of Paris, Orsay, is principal investigator of the OMEGA spectrometer onboard the Mars Express orbiter. To follow the water, he has argued, you should follow the clays. That's because clays form only after rock comes into prolonged contact with lots of water under mild conditions favorable for life. Microbes could draw energy and nutrients from the weathering rock, while the resulting clay would be ideal for preserving organic matter.

Bibring advocated landing on the highlands above Mawrth Vallis, a site blazing with the spectral colors of water-related minerals. Clays make up more than 50% of the surface there, Bibring reported—more abundant than anywhere else on Mars. The diversity of minerals—a half-dozen different clays plus a couple of other hydrated minerals—speaks of a changing environment as a layer cake of rock was altered. For similar reasons, John Mustard of Brown University and colleagues argued for landing in Nili Fossae, a great crack in the martian crust from which MSL could drive into a side canyon where many of the half-dozen aqueous minerals of the region outcrop.

Geologists weren't sold on either Mawrth or Nili. The spectroscopists “argue that there's such [spectral] diversity, there must be something of interest there,” says Horton Newsom of the University of New Mexico in Albuquerque, “but there's no geological evidence. It's essential to have both—a geological story with the spectra to back it up.”

In the case of Mawrth, was the source of the clays sediment that washed into a lake? Was it volcanic ash that fell from the sky? Was it crustal rock altered by hot springs? “How is a story going to come out of this?” demanded geologist Linda Kah of the University of Tennessee, Knoxville. Figuring it out once the rover got there, as Bibring suggested, was too risky an option for geologists still smarting from having landed the Spirit rover on an apparent lakebed that turned out to be a barren lava plain.

To avoid disappointment next time, many geologists favored landing in 67-kilometer-wide Eberswalde Crater. “It's the natural place to go,” says Rice, who led the pitch for the crater site. “It's the best delta on Mars,” meaning a river must have flowed into a lake in Eberswalde, dropping its load of sediment on entering the still water. Several different clays appear in the beautifully layered delta deposits exposed by wind erosion. Eberswalde “would make it a lot of fun,” said Kah. Other favorites of geologists were Holden Crater, another likely crater lake with layered, clay-bearing deposits but no true delta, and Gale Crater, whose 5-kilometer-high mound of layered deposits boasts a variety of water-related minerals, although the origin of the mound is uncertain.

Proponents of Nili and Mawrth took the geologists' point about the advantages of studying clays laid down in quiet standing water. “Holden is a very interesting site,” says Mustard, but there are shortcomings. Gale Mound lacks a single strong geological story, he notes, and Eberswalde could prove to be a “one-trick pony” if organic matter doesn't turn up there.

After 2.5 days of consideration, more than 100 attendees voted on how mineralogically and geologically diverse each site is, how good a geologic story each is telling, how good the prospects for habitability are, and how good the chances for preservation are. Two sites that had neither a strong geological story nor good spectral diversity—Miyamoto Crater and southern Meridiani—came in dead last. Nili and Mawrth did considerably better but still trailed the three craters with layered deposits, Eberswalde leading them all.

The outcome didn't surprise Mustard. Nili, at least, “kind of scares people,” he says. “It's hard to fit into a geological scenario.” But it's not over for Nili or Mawrth. Mission managers together with a landing-site steering committee will decide within a month or so which three sites will receive further study. Engineering considerations—such as too much cold at far-southern Holden and Eberswalde—might clear the way for a brightly colored site. Then another open workshop next spring will recommend a single site.

• *Third MSL Landing Site Workshop, 15-17 September, sponsored by the NASA-appointed Mars Landing Site Steering Committee and the MSL Project.

14. EDWARD BUCKLER PROFILE

# Romping Through Maize Diversity

1. Elizabeth Pennisi

A computer whiz turned geneticist borrows tactics from Wal-Mart and cattle breeders to manage what may be the world's largest genetic analysis.

A computer whiz turned geneticist borrows tactics from Wal-Mart and cattle breeders to manage what may be the world's largest genetic analysis

ITHACA, NEW YORK—On a steamy July morning, Edward Buckler and a crew of technicians, graduate students, postdocs, and a visiting professor from Mexico have fanned out among the 2-meter stalks in a large field of corn here. Bar-code readers in hand, they snip, stretch, or poke individual plants in order to track dozens of traits important to the crop's growth and vitality. Each week, they record the height of every stalk; in early summer, they counted leaves, assessed surface “hairiness,” and took small samples of tissue to freeze-dry and send to Germany.

Welcome to the Nested Association Mapping (NAM) project, arguably the world's largest controlled genetic study. It encompasses more than 1000 genetic markers in each of 5000 lines of maize in an effort to elucidate the relationship between genes and physical traits in plants. “It's basically the maize analog of the human HapMap Project, but it is much more powerful and cost-effective,” says population geneticist Magnus Nordborg of the University of Southern California in Los Angeles.

Buckler, the 38-year-old plant geneticist running the show, doesn't believe in thinking small. If he gets his way, plane flights will one day monitor tens of thousands of plants daily. “I'd like to know what goes on every hour of every day,” says Buckler, a U.S. Department of Agriculture (USDA) researcher based at Cornell University here.

Buckler has capitalized on his combination of computer and biology expertise to develop methods to find genes faster. He and his colleagues have also used existing maize variants to boost the vitamin A content of corn. “Ed seems equally at home in the field pollinating maize as in the lab or developing software or doing theory,” says plant geneticist J. Antoni Rafalski of E. I. du Pont de Nemours & Co. (Inc.) in Wilmington, Delaware. Adds James Holland of USDA at North Carolina State University (NCSU) in Raleigh, “He has single-handedly influenced the plant genetics community to a remarkable extent.”

The goal of the massive NAM study is twopronged. Maize is the number-one crop produced around the world, and NAM will help breeders to exploit its natural variation to improve yields and nutritional value. In addition, Buckler expects to answer a fundamental question: Do a few genes underlie each complex trait, or is there a bewildering array, with each having a minor influence? The answer will not only help plant breeders, but it may also aid biomedical researchers trying to understand the genetics of diabetes, heart disease, and other disorders. “I expect we will learn a lot about quantitative genetics from the maize work, and this will, of course, help us to understand human variation as well,” says Nordborg.

So far, its looks like more than a few genes control most traits. That realization will complicate attempts to pin down the genetic basis of disease. But with maize, even a 1% improvement in yield translates into millions more tons of food for people and animals, so genes of small effect can make a significant difference. Thanks in large part to Buckler's efforts, “people have changed their thinking, and companies are much more focused on natural diversity” as opposed to adding new genes to improve crops, says USDA plant geneticist Michael McMullen of the University of Missouri, Columbia.

## Genetics by second nature

Growing up in Arlington, Virginia, Buckler had unlimited access to a personal computer, on which he designed his own games. To him, genetics is basically life's equivalent of computer programming. “There are not many rules: You get to recombine and to mutate, but you can make incredibly complex things.” Buckler laughs, giving his boyish smile: “And it's more rewarding to do genetics than programming.”

After high school, he left for the University of Virginia, Charlottesville. He studied early American cultures and became both fascinated with the domestication of maize and appalled at how inefficient agriculture was. “I decided that if I wanted to do something worthwhile, plant genetics was the way to go,” he says. With a Ph.D. from the University of Missouri, Columbia, and postdoc experience in statistical genetics at NCSU, Buckler joined USDA in 1998 to work on the Maize Diversity Project, part of the Plant Genome Initiative (Science, 23 October 1998, p. 652). Now poised for its second renewal, the project has morphed over time from an emphasis on genome evolution to a massive effort to conquer the genetics of complex traits, with NAM as a key component.

As the Maize Diversity Project matured, Buckler and his colleagues came up with a more efficient way to find genes that influence traits. Researchers typically take two approaches to this task. In one, linkage analysis, they use families—which in corn means plants that can be traced back to the same set of parents. The other approach, association studies, relies on unrelated individuals, be they corn seedlings or people. “What we've been doing is blending the lines between the two” approaches, Buckler explains.

In association studies, researchers often look for gene variants that co-occur with a trait, such as golden rather than yellow kernels. But many of the variants they find are false positives, for example, having no effect on kernel color at all. The number of such false positives can be influenced by kinship among individuals and by evolutionary history. For example, when two populations are isolated from each other, their genomes can diverge in such a way that a particular variant might seem to be associated with kernel color, even though it isn't. “That's really a complicated and difficult problem,” says John Doebley, a plant geneticist at the University of Wisconsin, Madison. Likewise, when two individual plants are closely related, their kinship can skew any associations detected.

With Jianming Yu, now at Kansas State University in Manhattan, Buckler has found ways to incorporate both history and kinship into his analyses, eliminating many false associations. For example, to take account of how closely individual plants are related, Yu, Buckler, and their colleagues used genetic markers to assess kinship, then borrowed mathematical tricks used by cattle breeders to analyze giant pedigree matrices. The resulting “unified mixed model” method greatly reduced the number of false positives, they reported in the February 2006 issue of Nature Genetics. Buckler estimates, for example, that about 9 million DNA variants, or SNPS, would show up as linked to flowering time using the old approach. The new method narrows that to only a few thousand.

The method has also yielded natural gene variants that enrich maize in vitamin A. Buckler, Torbert Rocheford of the University of Illinois, Urbana-Champaign, and their colleagues measured the amount of the vitamin in hundreds of lines of corn that vary in kernel color—the more orange, the more vitamin A. Using association studies, they pinned down the gene variants responsible for producing more vitamin A precursors (Science, 18 January, p. 330). Without this method, “we would have had a lot more junk to deal with,” says Buckler. Now researchers with HarvestPlus for Africa and elsewhere are using Buckler's genetic markers to breed those variants into maize varieties, thus boosting vitamin A without introducing foreign genes.

## Bigger is better

Once Buckler started doing association studies, he hungered to make them more powerful. For NAM, he and his colleagues picked 25 unrelated “parent” lines of maize, including popcorn, sweet corn, tropical and temperate varieties, plus long-used commercial strains, representing the full range of diversity in this species. Buckler, Cornell colleague Stephen Kresovich, Holland, and, later, McMullen bred each line with the much-studied (and now draft-sequenced) B73 maize. From each “parent,” they created a “family” of 200 new lines, for a total of 5000 lines. Thus this single study includes “families” available for linkage analysis, as well as a large, diverse population of 5000 lines for association studies. The next biggest genetic study involves mice, uses just eight strains, and has the ultimate goal of creating 1000 new strains (Science, 25 July 2003, p. 456).

NAM also presented an enormous data-crunching challenge. At the time, “it was not obvious to me how gene-phenotype association information could be jointly analyzed across the 25 cross-populations,” Holland recalls. “Ed conceived of the analysis that would efficiently achieve that.” Nor was Buckler daunted by the challenge of generating thousands of new maize lines and recording how individual plants grew. His response to his colleagues' concerns: Borrow methods from an operation that daily tracks tens of thousands of items—Wal-Mart. He outfitted his team with the same portable bar-code scanners that Wal-Mart uses for taking inventory and had them tag each plant.

Now that the hard work is done, anyone can grow out the seeds of the NAM lines or traipse through the project's fields to measure variation in their favorite trait, such as starch content. Then, using the project's analytical tools, they can home in on the genes affecting that trait.

Buckler calls the NAM project a “field of dreams,” and, as in the movie of the same name, it's attracting attention and copycats. Dozens of private and academic researchers have ordered NAM seeds from USDA to start their own fields. Cornell's Rebecca Nelson and graduate student Jesse Poland are assessing the genetic basis of disease resistance in a NAM field next to Buckler's. Says Poland: “It's an incredible resource.”

Yet even in the dream fields, pinning down genes will not be easy. “Association mapping is not without its problems,” says Rafalski. Human geneticists have millions of markers to help navigate the human genome, and they still struggle to find gene variants connected to disease; maize researchers have only about 1100 markers. And picking out which associated variants are the most promising is always a challenge, he adds.

However, Buckler is still thinking big. He has \$1 million from the U.S. National Science Foundation to partially sequence each parent NAM maize strain, which will yield many more markers. He has also set his sights beyond cornfields: He wants to apply genomics to USDA's vast archive of germ plasm—seeds and other tissues from all plants. Breeders can order any of some 600,000 crop varieties from USDA, but it's often hard to know which varieties will improve a crop the most. To begin to find out, Buckler is starting with the grape germ plasm on file, assessing 10,000 SNPs and, to a limited extent, their association to relevant traits. He's hopeful money will come through next year to assess the SNPs in the entire USDA collection. “That Ed is an idea person is as much of an understatement as you can say,” says McMullen. “He's always proposing new ideas, and even before we can do the experiment, [the project] will be bigger.”