News this Week

Science  11 Jul 2008:
Vol. 321, Issue 5886, pp. 184

    Arsenic and Paddy Rice: A Neglected Cancer Risk?

    1. Richard Stone

    BEIJING—Rice is the staff of life for 3 billion people, predominantly in Asia. But does the food that sustains half of humanity also increase the risk of cancer for some? That question arises from three sets of findings—including data now in press—that report elevated arsenic levels in rice and products such as rice bran and rice crackers.

    Much of the arsenic found in these studies is in an inorganic form—the oxides arsenate and arsenite—known to sicken people exposed via drinking water. Cancer runs high in this population. “The problem is big,” says Steve McGrath, a biogeochemist at Rothamsted Research in Harpenden, U.K., who studies contaminants in crops and is familiar with the new findings. Because rice accumulates arsenic, he says, even the background level “is a problem for people who eat much rice in their diet.”

    Experts caution that there are no data linking rice and cancer. Although there's “a definite need to reduce arsenic levels in rice,” says Richard Loeppert, a crop scientist at Texas A&M University in College Station, “it's not an immediate hazard.” A lead researcher, environmental biologist Zhu Yong-Guan of the Research Center for Eco-environmental Sciences in Beijing, acknowledges that “we still don't have all the answers.” “But arsenic is arsenic,” he says.

    China agrees: It's one of a handful of countries that regulate arsenic levels in food. In 2005, the government lowered the acceptable limit in rice from 700 to 150 micrograms (μg) of inorganic arsenic per kilogram. Fish and other seafood contain an organic compound, arsenobetaine, that's largely benign at dietary levels. In a guidance document issued for shellfish consumption in 1993, the U.S. Food and Drug Administration recommended a “tolerable daily intake” of inorganic arsenic of 130 μg. But most governments, including the United States and the European Union, have not set legal limits on inorganic arsenic in food. The recent findings could provide an impetus for regulators to move faster.

    Pick your poison?

    Zhu Yong-Guan's group is attempting to reduce arsenic levels in rice at this plot in China. In five varieties (inset) sampled in Zhu's lab, levels of inorganic arsenic ranged from 63 micrograms per kilogram (μg/kg) in Chinese white rice (far right) to 421 μg/kg in French red rice (center).


    Zhu and others are not waiting; they're already exploring ways to defang rice, which contains at least 10-fold higher arsenic concentrations than wheat and other cereals. Possibilities include altering farm practices—growing paddy rice in raised beds, for instance—and engineering rice plants to shed arsenic. The task is urgent, some say, because the global food crisis is increasing rice cultivation near mines or smelters, or on land formerly used to grow cotton or other crops that are often heavily treated with arsenic-based pesticides. Paul Williams, a postdoctoral researcher working with Zhu and Andrew Meharg, an environmental chemist at the University of Aberdeen, U.K., says, “We fear that more and more marginal land contaminated with arsenic will be used for growing rice.”

    Inorganic arsenic in a single dose of about 100 milligrams can kill by shutting down energy metabolism. Its chronic, low-dose effects are more insidious and first came to light in the early 1980s in India and Bangladesh, where many people who relied on arsenic-tainted wells developed arsenicosis, an ailment marked by rough skin that is often a prelude to serious diseases such as skin or bladder cancer. Tainted wells typically contain hundreds of micrograms of arsenic per liter, well above the maximum contaminant level of 10 μg per liter set by the World Health Organization (WHO) and adopted by most countries. Regions with high natural arsenic levels have been trying to develop alternative water supplies (Science, 23 March 2007, p. 1659). “Billions of dollars are spent to decrease arsenic levels in water,” says Zhu. “Even if we solve that problem,” he says, “it still gets into rice.”

    Paddy rice takes up arsenite readily from waterlogged soil, from which the element is liberated by anaerobic microbes, McGrath and colleagues reported online last month in Environmental Science & Technology. (Other crops grown in watery environments such as lotus, water chestnut, and water spinach also tend to have high arsenic levels.) WHO's limit for arsenic in water equates to a daily intake of 10 μg in food, Zhu, Williams, and Meharg note in an article this month in Environmental Pollution. Assuming an average daily rice consumption of 200 grams—a lowball estimate in Asia—the researchers calculate that arsenic levels would have to be as low as 50 μg per kilogram to remain below the WHO limit for water. However, Zhu and his colleagues report, surveys around the world have found that arsenic levels in rice “commonly exceed” the 50-μg threshold and can reach 400 μg per kilogram.

    Last April, Meharg's group caused a sensation when it reported disturbing levels of arsenic in rice porridge sold in U.K. supermarkets for weaning infants. According to their findings in Environmental Pollution, 35% of baby rice samples they tested had arsenic levels exceeding China's permissible level (

    Two upcoming reports from the team could cause another stir. They found what Zhu calls “extremely high” levels of inorganic arsenic in rice bran, a common item in health food stores and a popular supplement for malnourished children in international aid programs. The samples of rice bran products they tested came from Japan and the United States. “Their research has shown the size of the problem and its international dimension,” says McGrath, who calls their analyses “state of the art.”

    The food industry has sought to allay concerns. For example, after news reports last autumn about arsenic in U.S. rice, a top official at NutraCea, a company based in Phoenix, Arizona, that sells rice bran and bran extracts, in a letter to customers wrote that “the levels found in U.S. rice are well within food tolerances established by the Food and Drug Administration. U.S. rice has been consumed for over a hundred years with no reported human health problems.” Williams argues that “there are no standards” in the United States for permissible maximum amounts of inorganic arsenic in food.

    Experts have floated several mitigation strategies. Arsenic levels are lower in rice from certain regions, including California and parts of India; rice from these sources could be blended with higher arsenic rice before sale. But blending “may be difficult in poor areas with little infrastructure and subsistence diets,” McGrath says. Another tack would be to tilt production toward upland rice, which is grown on dry land and absorbs far less arsenic than paddy rice. A third approach—growing paddy rice aerobically in raised beds—reduces the mobilization of soil arsenite and “can dramatically decrease arsenic transfer from soil to grain,” McGrath says. But that would require a fundamental change in farming practices in Asia.

    One attractive possibility is to tweak rice's metabolism. “Arsenic that accumulates in grain is effectively under genetic control,” say Zhu. A decade ago, a team led by Barry Rosen, a molecular biologist at Wayne State University in Detroit, Michigan, showed that a family of proteins called aquaglyceroporins transports arsenic and other metalloids across cell membranes. Building on that work, Thomas Jahn's group at the University of Copenhagen in Denmark last month unveiled in BMC Biology an aquaglyceroporin subfamily, nodulin26-like intrinsic proteins (NIPs), in plants, including rice. It may be possible, says team member Gerd Bienert, to engineer plants to express NIPs that resist taking up arsenic—although that will be tricky, as NIPs facilitate the uptake of vital nutrients such as boron or silicon. Rosen's lab hopes to target arsenic by engineering aquaglyceroporins to discriminate between metalloids.

    Another approach pursued by Rosen and Zhu is to create transgenic rice equipped with a bacterial enzyme—arsenite S-adenosyl-methyltransferase—that converts inorganic arsenic to methylated species, including a volatile compound. “We propose that rice expressing the enzyme will volatilize arsenic, producing rice grains with reduced arsenic content,” Rosen says. Field testing will begin in China soon. Rosen, Zhu, and colleagues are also using conventional breeding techniques to select for cultivars that accumulate little arsenic. To be a hit on the farm, any new varieties will have to have decent yields: A hypothetical cancer risk pales in comparison with an empty stomach.


    Top Ph.D. Feeder Schools Are Now Chinese

    1. Jeffrey Mervis

    The summer Olympics don't start until next month. But Chinese universities can already claim gold and silver medals in one important global competition involving institutions of higher learning.

    A new study has found that the most likely undergraduate alma mater for those who earned a Ph.D. in 2006 from a U.S. university was … Tsinghua University. Peking University, its neighbor in the Chinese capital, ranks second. Between 2004 and 2006, those two schools overtook the University of California, Berkeley, as the most fertile training ground for U.S. Ph.D.s (see graph). South Korea's Seoul National University occupies fourth place behind Berkeley, followed by Cornell University and the University of Michigan, Ann Arbor.

    Leading the pack.

    Tsinghua and Peking universities top Berkeley in having their graduates complete U.S. doctoral programs.


    “The United States is very attractive to Chinese students, and they are certainly taking advantage of the opportunity to study here,” says Judy Sui, director of data for Berkeley's graduate division. “At the same time, Chinese officials are trying hard to improve their system of higher education so that their students don't have to go abroad for graduate training.”

    The rankings were compiled by the Commission on Professionals in Science and Technology from a survey conducted by the U.S. National Science Foundation. In part, they reflect the fact that 37% of doctoral recipients from U.S. universities are not U.S. citizens. Sui says they also point to the wider choice of good careers available to U.S. students who hold a bachelor's or master's degree; foreign-born students are more likely to need a Ph.D. to find a good job, she says.

    Berkeley still retains its top ranking for the number of undergraduates who went on to earn Ph.D.s over the past 10 years (1997 to 2006). But its total of 4298 isn't that far ahead of Seoul's 3420. And Tsinghua and Peking could well surpass their Korean rival in upcoming decadal tallies.

  3. U.S. BUDGET

    2008 Supplemental Helps Fermilab By Putting Jobs Before Research

    1. Adrian Cho*
    1. With reporting by Eli Kintisch.

    The only remaining U.S. lab dedicated to particle physics won't have to impose involuntary layoffs this month after getting a last-minute infusion of government money. The reprieve, for up to 100 scientists and technicians at the Department of Energy's (DOE's) Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois, is the result of a $186 billion supplemental spending bill to fund the wars in Iraq and Afghanistan.

    The bill, signed 30 June by President George W. Bush after a compromise with the Democratic majority in Congress, contains $24 billion in domestic spending for 2008, including $62.5 million each for DOE science, NASA, and the National Science Foundation and $150 million for the National Institutes of Health (Science, 27 June, p. 1706). For the other three agencies, the extra money will mean a bit more for research. But for DOE, the focus is on preserving jobs. The agency, for example, still won't be able to make its promised contribution this year to ITER, a fusion reactor experiment being built in France. “Obviously, you can't run anything without the workforce, so the emphasis on jobs is probably correct,” says Michael Lubell, a lobbyist with the American Physical Society in Washington, D.C.

    In December, an unexpectedly small budget increase for DOE science forced officials at Fermilab, home of the Tevatron collider, to announce plans for layoffs affecting about 200 of its 1950 employees (Science, 11 January, p. 142). In February, lab officials instituted a rolling furlough that forced every employee to take 1 week every 2 months as unpaid leave. About 100 people have left since the beginning of the year, including about 50 who took voluntary layoffs last month.

    In late May, the picture brightened when an anonymous donor gave $5 million to the University of Chicago to be spent at Fermilab. That ended the furloughs. And last week, Director Pier Oddone called off the involuntary layoffs.

    The supplemental “was clearly targeted toward layoffs, and Fermilab was the poster child for layoffs,” says a congressional staffer. Specifically, legislators told DOE to use the money to eliminate all layoffs “which are a direct result of budgetary constraints” and to resolve that problem before spending any money on research.

    Some observers say the lab also benefited from a desire by Democratic leaders to help Representative Bill Foster (D-IL), a former Fermilab physicist, retain in the November elections the seat he won in a special election this spring. “Foster certainly can go back to his district and say, ‘Look what I did [for you],’” Lubell says.

    High-energy physics gets $32 million, all but a few million to be spent at Fermilab. Another $13.5 million goes to basic energy sciences, which supports x-ray sources and other “user facilities” for materials science, structural biology, and other fields. More than half goes to the Advanced Photon Source at Argonne National Laboratory in Illinois, preventing layoffs amounting to about 10% of the 500-person APS staff. Nuclear physics receives $1.5 million.

    Hug the messengers.

    Representative Bill Foster (at podium) and other dignitaries delivered good news last week to Fermilab scientists.


    The ITER program gets a $15.5 million slice of the supplemental. That's far less than the $160 million that DOE had told its six partners it would spend this year, the majority of which would have bought materials for the reactor parts the United States will build. The December spending bill contained only $11 million for ITER. DOE reprogrammed $9 million of that amount this spring to cover salaries for the U.S. ITER offices, most of which are at Oak Ridge National Laboratory (ORNL) in Tennessee. Foster calls the $15.5 million a “symbolic” gesture that keeps the United States in the game. But the money won't go for equipment, thanks to a likely delay in adoption of the 2009 budget beyond the 1 October start of the next fiscal year. “We have to hold it in reserve to avoid laying off the whole project team on October 1,” says ORNL Director Thom Mason.

    Persis Drell, director of the Stanford Linear Accelerator Center in Menlo Park, California, says she would have preferred Congress to have given DOE more leeway in how to spend the money. Its decision to cut funding for ITER and Fermilab, she says, “was the cause of the disaster in the 2008 budget, and I'm not any happier with [language] in the supplemental” that focuses on jobs. And Lubell and others warn that Fermi and other labs may have to reinstitute layoffs if DOE's science budget does not increase significantly next year.


    Defense, NSF Team Up on National Security Research

    1. Eli Kintisch

    The U.S. Department of Defense (DOD) hopes to spend $20 million this year on social science research aimed at understanding real and potential threats to national security. Part of the money will be funneled through the National Science Foundation's (NSF's) acclaimed merit-review process in an attempt to attract the best scientists—and to defuse criticism of DOD funding for such research.

    “The relationship between [the Pentagon] and the social sciences—humanities in particular—for decades has covered the spectrum from cooperative to hostile,” Defense Secretary Robert Gates said in an April speech to the Association of American Universities (AAU). His policy aide, Thomas Mahnken, says that NSF's role will help “make this program as attractive to the largest number of people as possible.”

    Inked last week, the 3-year agreement between the two agencies broadens a Pentagon initiative launched last month, called Minerva, that aims to bring academic social scientists into the defense research fold. Gates hopes that the 5-year, $100 million program, which he unveiled in his AAU speech, will build a firmer “intellectual foundation” in five areas: the ideological roots of terrorism, the changing face of Islam, the history of the Iraqi military, the vast unclassified literature on China's army, and miscellaneous other approaches to strengthening national security.

    Better directions?

    U.S. defense officials hope social scientists can help them learn more about the Chinese military, shown in this 2007 exercise in Henan Province.


    The program will have two arms of equal size. One will be managed by Defense officials and the other by NSF, with some Pentagon input on the selection of reviewers. “There are several topics of mutual interest” within the Minerva areas, says David Lightfoot, who heads NSF's social sciences directorate. “Securing the national defense was part of our charter in 1950,” he adds.

    Pentagon research official William Rees emphasizes that the money, which he hopes to award by December, is for “basic research to form the basis of knowledge” on various topics. But political scientist Howard Silver, executive director of the Consortium of Social Science Associations in Washington, D.C., thinks the infusion of NSF-caliber researchers could reap more immediate benefits. “If [the U.S. government] had done a better job of listening to the cultural and language needs in Iraq, things might have worked very differently,” says Silver.

    Will NSF's involvement provide sufficient cover for the Pentagon? Silver thinks “the proper protections” are in place, including promises that the Pentagon-supported research will be unclassified and that scientists will be able to publish without interference. Cognitive psychologist Baruch Fischhoff of Carnegie Mellon University in Pittsburgh, Pennsylvania, says academic reviewers should ensure top-notch applicants. But Brown University anthropologist Catherine Lutz fears that the Pentagon dollars will militarize her field by potentially “pulling people off” other projects that are unrelated to defense. She and many colleagues are upset by another DOD program, called Human Terrain Teams, that has partnered social scientists with U.S. troops in Iraq and Afghanistan in an effort to better understand those cultures.

    The Pentagon's involvement in the social sciences could reach beyond areas of interest to the military. The NSF-DOD memorandum allows defense officials to consider funding some proposals submitted to NSF's $38-million-per-year Human and Social Dynamics (HSD) program in risks and human behavior and decision-making. That would make NSF's dollars go farther.

    University of California, Irvine, psychologist Roxane Cohen Silver, whose current HSD grant expires next year, says she'd have no problem taking no-strings-attached Pentagon dollars, especially “if that then opened up additional funding for social sciences.” Fischhoff, who chairs the Department of Homeland Security's scientific advisory board, says that social scientists can sharpen their thinking by working with officials in defense and other “real life” fields. “They will press you on the quality of your data,” he says.


    Iraq Embarks on Demolition of Saddam-Era Nuclear Labs

    1. Richard Stone

    When Ronald Chesser arrived by military helicopter at the Al-Tuwaitha Nuclear Center south of Baghdad on 2 July, the radioecologist from Texas Tech University in Lubbock was thrilled by what he saw. Few would consider it a pretty sight: dozens of buildings riddled with radioactivity, some reduced to rubble by Coalition bombs. What filled Chesser with hope was a clutch of trailers, including one for decontamination showers, freshly installed for an urgent task: the dismantlement of a sprawling facility where physicists in the 1970s and 1980s tried in vain to build an atomic bomb for Saddam Hussein. “I thought, ‘Wow, this is really going to work,’” Chesser says.

    At a ceremony in Baghdad on 7 July, Iraqi officials launched a cleanup effort that's expected to take at least 15 years and cost millions of dollars. “This marks the beginning of closure on Saddam's nuclear weapons program,” says Carleton Phillips, a Texas Tech biologist who advised the Coalition Provisional Authority on nonproliferation issues until 2004. Saddam's nuclear program was much less advanced than the Bush Administration made it out to be in the runup to war in 2003. But no one disputes that Tuwaitha is a radioactive disaster zone that poses daunting challenges. “It's quite a high-tech project in a war-torn country,” says Mark Hannan, Tuwaitha project manager at the International Atomic Energy Agency in Vienna, which has been training Iraqi specialists in nuclear decommissioning.

    The cleanup is also a major milestone in efforts “to redirect former Iraqi weapons scientists to big projects important for rebuilding their country,” says Phillips. Others agree. “This project will also build skills that the Iraqis can then apply to other environmental problems facing Iraq,” says John Cochran, an expert on radioactive waste at Sandia National Laboratories in Albuquerque, New Mexico, who is also assisting the Iraqis.

    Down and dirty.

    Ron Chesser (left) and Iraqi colleagues checking contamination at the “Russian silos”—rad-waste storage wells—last week at Tuwaitha.


    The dismantlement of Saddam's main nuclear weapons complex comes after years of painstaking preparation. A big challenge lies in its chaotic state. Tuwaitha's two research reactors and other key buildings, including facilities for fuel fabrication and plutonium separation, were bombed in 1981 and 1991. During the Iraq war in April 2003, Tuwaitha staff fled and the center was looted. Unaware of the health risk, people hauled off scores of drums of uranium oxide extract—dumping some of the “yellowcake” on the grounds of Tuwaitha—to use the barrels for catching rain or washing clothes. By June, nuclear inspectors had accounted for virtually all the missing drums and uranium. Two years later, Chesser, Phillips, and Brenda Rodgers of Texas Tech, with Iraq's science ministry, surveyed schools in villages near Tuwaitha. “To our relief, we found they were not contaminated,” says Phillips. In a secret operation described earlier this week by the Associated Press, U.S. forces last April removed 550 tons of yellowcake from Tuwaitha. Iraq sold the uranium to a Canadian company for processing into fuel for civilian power reactors.

    To pinpoint where looters had dumped yellowcake and where bombs had dispersed radioactive materials, Phillips and Chesser, with colleagues from Iraq and Ukraine, in 2005 analyzed more than 400 soil samples, compiling a rough map of radioactivity at the 9300-hectare Tuwaitha compound. The contamination map laid the groundwork for a U.K.-funded “Train and Engage” program that the Texas Tech duo ran last month for 27 Iraqi scientists, including several former weaponeers. They met at the International Radioecology Laboratory in Slavutych, Ukraine, and in nearby Pripyat, a city drenched in fallout and abandoned when a reactor at the Chernobyl nuclear power plant exploded in 1986. “It's a reasonable analog for Tuwaitha,” says Hannan.

    At Tuwaitha, the first job will be to take apart the Active Metallurgy Testing Laboratory (LAMA). The facility was designed to extract enriched uranium from fuel rods and handle radioisotopes in hot cells: rooms with meter-thick concrete walls and robotic manipulating arms. “Supposedly, it was used only for a single experiment before Coalition forces bombed it” during the Gulf War in 1991, says Phillips, meaning it is lightly contaminated. But LAMA is huge—at 62,000 square meters, it covers an area equal to six football fields—and is strewn with rubble, necessitating a slow pace. A 50-strong team is expected to take at least a year and a half to finish the job.

    Last week, the Texas Tech-Iraq team took additional soil samples and probed so-called Russian silos: covered storage wells for radioactive waste that are 4 meters deep with largely unknown contents. They also scouted for a place to store low-level rad waste from LAMA and other buildings. Later, Iraqi authorities must establish a repository for hotter waste when more hazardous buildings are dismantled.

    The demolition job at Tuwaitha is by far the largest single project for redirecting former Iraqi nuclear personnel into civilian work. Part of the challenge has been to overcome what Phillips calls “the legacy of living in a dictatorship.” For example, he says, many of his Iraqi colleagues had been accustomed to shaping data and analyses to meet the expectations of superiors. “We hope that this project will be a huge step in restoring their credibility with the international scientific community,” Phillips says.

    Not all of Tuwaitha is destined for the scrapheap. The science ministry hopes to convert several intact, clean buildings into a science park. For a nuclear reserve with a checkered past and a radioactive present, that would be a remarkable future indeed.


    Major European Cities Are Quietly Missing Antinoise Deadline

    1. John Bohannon

    PARIS—The Europeans have many words for noise—bruit, Lärm, fracasso—but few plans for reducing it. At a conference* here in France's noisy capital last week, European acoustical scientists admitted that they and most policymakers are not close to meeting an 18 July deadline to develop action plans to shush the European Union's (E.U.'s) largest cities.

    Chronic noise has increasingly been linked to sleep problems, poor education, and even serious heart disease. Yet urban noise reduction is a daunting—and expensive—task; most scientists are still struggling just to locate noise hot spots.

    The action plan deadline stems from a 2002 E.U. antinoise directive. “Europe has a bigger noise problem than the United States,” says Gaetano Licitra, an environmental acoustics consultant helping the Italian region of Tuscany muffle its noise. “Instead of spreading out in suburbs, we tend to both live and work in the same area, and our cities more often have railroads going right through the center and nearby airports.”

    Taking action.

    Berlin (above) has a plan to reduce urban noise from sources such as traffic.


    The first stage of the E.U. directive required mapping noise levels in all cities with at least 250,000 people. This is largely done with virtual models of cities that estimate people's average exposure to loud sound sources such as automobile, railroad, and airplane traffic and industry. One problem is that an urban noise map is a moving target, with infrastructure and traffic patterns constantly changing. Another is that “noise is not the same thing as loudness,” says Brigitte Schulte-Fortkamp, an environmental acoustician at the Technical University in Berlin. “Loudness is physical and can be measured in decibels with a sound meter, but noise is a psychological phenomenon.”

    People are far more tolerant of sound levels depending on the context and source, researchers noted at the meeting. Relatively loud natural sounds from birds and water, for example, can put people at ease, whereas quieter sources, such as an electrical buzz, cause stress. Surveys have also found large variation in noise tolerance among people and even between whole communities.

    So far, despite a June 2007 deadline for the noise maps, only a handful of major European cities have charted their soundscapes. Even fewer are close to proposing an antinoise action plan. “Most realize they will miss the deadline,” says Schulte-Fortkamp. “Now there is a scramble to finish” because failure to comply will result in stiff fines in a few years. An exception is Berlin. Not only has the city mapped its noise, but an action plan is already in public consultation.

    Most of the noise reduction in cities will come from changing transportation infrastructure, strictly regulating where trucks can travel, and relocating speed bumps and traffic lights, for example. One high-tech solution discussed at the meeting is to make the noise sources quieter. Nils-Åke Nilsson, an acoustic engineer based in Täby, Sweden, reported that asphalt containing grains of rubber hushed traffic significantly in sections of the Swedish city of Göteborg. Another strategy noted is insulating buildings better from outside noise. Pierre Leroy, a materials scientist at the French National Center for Scientific Research in Marseille, introduced a “smart foam” that efficiently dampens not only high-frequency sounds, such as the screech of brakes, but also the more difficult low-frequency sounds made by truck engines and underground trains. The foam could be incorporated into walls and road barriers.

    The complexity of dealing with noise is daunting, but E.U. cities are also dragging their feet, says Licitra, because “once you have an action plan, then you have to start spending real money to address the problem, and that will cost billions.”

    • *Acoustics'08, Paris, 29 June to 4 July.


    Steering Harvard Toward Collaborative Science

    1. Andrew Lawler

    Provost Steven Hyman is at the forefront of the university's dramatic push to transform the way it carries out research.

    Provost Steven Hyman is at the forefront of the university's dramatic push to transform the way it carries out research

    Lawrence Summers conceived of a new science complex during his stormy tenure as Harvard University's president, and the idea has been endorsed by his successor, historian Drew Faust. But it's Steven Hyman who will make sure that the ribbon is cut on the massive building in Allston in 2011. Fueled by espresso and a passion for collaborative research, the Harvard provost is leading the university's belated rush to catch up and surpass other U.S. universities in reorienting basic science. He's also trying to bridge the gap between research and applications and strengthen faculty ties with industry.

    Building excellence.

    Provost Steven Hyman hopes the Allston campus will transform research at Harvard.


    The 55-year-old researcher, hired by Summers in 2001 and retained by Faust, is himself an interdisciplinary mix of psychiatry and molecular biology. He wants to turn the oldest and most prestigious university in the United States into the locus of work to eliminate diseases, understand how the brain functions, and expand the possibilities of medical genomics. To succeed, he must attract new talent and persuade Harvard's famously independent fiefdoms to work in concert. The vehicle for that transformation is the multibillion-dollar campus in Allston, a working-class suburb across the Charles River from Harvard Yard, that for the first time will concentrate a host of science and engineering disciplines under a single roof. “We're trying a very different way in answer to our critics, who have seen us as irretrievably Balkanized,” says Hyman.

    Some critics have labeled the Allston campus a real-estate boondoggle, and others complain that Hyman's approach threatens to abandon Harvard's tradition of curiosity-driven research. But scientists both inside and outside the university say Hyman is making bold, long-needed changes that will allow Harvard to compete more ably with institutions such as Stanford University and the neighboring Massachusetts Institute of Technology (MIT), which have been at the forefront of connecting basic and applied sciences. They add that Hyman's political savvy, willingness to listen, and amiability—traits not associated with his former boss—give him a better shot at nudging Harvard in a new direction.

    Bio teammates.

    The first building on the Allston campus will house several programs in the life sciences.


    “He has a force of will, intelligence, and a lot of chutzpah,” says Alan Kraut, executive director of the Association for Psychological Science in Washington, D.C., who has followed Hyman's career for more than a decade. “And even when he's gruff he has a lot of humor.”

    Significantly altering an institution as complex and crusty as Harvard ranks among the toughest tasks in American academe. The university's faculty of arts and sciences, numbering nearly 500, is centered on the 372-year-old Cambridge campus. The medical school, across the river in the Longwood section of Boston, is home to 6400 faculty members and even more postdocs. Additional faculty are scattered among hospitals and institutes in the area. That geographical separation, combined with a tradition of independence, has allowed Harvard researchers to resist collaboration to a greater extent than researchers at most universities.

    “It's clear that Harvard has lagged behind other universities in making connections within its faculty,” says Yale University molecular biologist Joan Steitz, who is on Harvard's Board of Overseers. She notes that Yale, by contrast, has for decades given joint appointments between its medical school and its arts and sciences faculty. Harvard schools even now balk at that approach, adds Harvard chemist Gregory Verdine, who failed to win approval for such an appointment just 3 years ago.

    Although basic science has flourished within this system of fiefdoms, the number of discoveries moving from the lab bench to the clinic is too small, says Hyman. Statistics bear that out. Harvard averaged $21 million a year in licensing revenues between 2001 and 2007, and faculty formed 32 new companies. MIT, in contrasts, boasts of twice the yearly revenue and three times the rate of entrepreneurship.

    Hyman admits that changing that mindset will require him to reconcile differences in salary structure, sources of funding, and territorial claims among the various Harvard cultures. “I am not naïve; there will be air pockets and lumps and bumps,” he admits. But many researchers agree that if anyone can succeed, it is Hyman.

    Multiton tanker

    Throughout his career, Hyman has developed a reputation for encouraging collaboration and reforming staid institutions. Harold Varmus, while director of the National Institutes of Health, plucked Hyman from his position as a Harvard professor in 1996 to direct NIH's National Institute of Mental Health (NIMH) in Bethesda, Maryland. “Like Harvard, NIMH is a multiton tanker, but he was incredibly successful there,” says Kraut.

    At NIMH, Hyman shifted funds from long-running projects to a new generation of mental health researchers excited about breakthroughs in areas such as neurobiology. Those moves infuriated the old guard. “He was a little like a bull in a china shop,” Kraut recalls. Darrel Regier, then an NIMH scientist and now head of research at the American Psychiatric Association in Arlington, Virginia, felt Hyman's ax come down on his own epidemiological project. “But the changes were long overdue, and by and large, he did a good job,” he says.

    Hyman also knew how to navigate the treacherous political currents in Washington. “I was struck by how well Steve translated the science and made it compelling,” says one former staffer for Representative Patrick Kennedy (D-RI). “Unlike some scientists who bury their nose in the bench, he understood people.”

    The staffer recalls how Hyman helped his boss to blunt an attempt by one lawmaker to limit the way funds could be used for basic science; Kennedy patched in Hyman to a conference call with the lawmaker. “He was so good—he knew all the nuances—and backed her off a draconian position,” the former staffer recalls. “She dropped her plans for the amendment.” His successful track record in Washington has spawned rumors that he could succeed Elias Zerhouni as NIH director in either an Obama or a McCain Administration.

    Kraut and others say Hyman pushed NIMH into supporting more interdisciplinary as well as translational research, the latter a current buzzword for connecting basic science with applications. Hyman has tried to bridge that gap throughout his professional career. After graduating from Yale and studying the philosophy of science at the University of Cambridge, he received his M.D. from Harvard Medical School and also worked at Harvard College. His interest in molecular biology—a fascination unusual and potentially career damaging for a psychiatrist at the time—made him the ideal candidate to pull together a mind, brain, and behavior initiative at Harvard that would link researchers from various disciplines. The initiative, from then-president Neil Rudenstine, still thrives today. But it failed to establish deep roots. “It was very much a top-down initiative from people like me—central administrators—and its activities didn't become part of anybody's day job,” Hyman says.


    After Summers brought him back to Harvard, the two men agreed that the university needed to play a bigger role in scientific areas from neuroscience to stem cells. To do that, they proposed a new campus within walking distance of both the medical school and the Harvard campus. The massive construction project spooked residents, who were wary of overdevelopment, and researchers, who were unhappy with the prospect of relocating to a new site. Under the current blueprint, the first building will be a 93,000-square-meter facility for a new stem cell and regenerative biology department, a stem cell institute, the systems biology department, and bioengineering.

    Given the promise of stem cells—and the growth of opportunities in California, Singapore, and Israel—Hyman says it is critical that Harvard researchers pool their talents: “The way to hold the community together is to create the best intellectual critical mass that we possibly can.” Harvard's schools of public health and education will also likely be housed in Allston, but there are no firm plans to move other science and engineering sections there.

    Hyman argues that building a neutral place—“like Switzerland,” he jokes—provides Harvard with its best shot at persuading reluctant partners to collaborate. Summers envisioned Allston as the center of an East Coast Silicon Valley, and Verdine hopes someday to see a line of entrepreneurial companies eventually clustered along the area's Soldiers Field Road. “If you are organized as a community entirely of small curiosity-driven labs, you are not organized to move advances through the pipeline to application,” says Hyman. And if solving real-world problems is the goal, he adds, “you don't want to be organized as a colony of curiosity-driven researchers.”

    Such talk worries some physical and life scientists at Harvard, who requested anonymity for fear of retribution. “He's Mr. Translational Research,” says one senior faculty member about Hyman. “And he's attempting to put everyone in one boat, which does not serve the university or basic research.” Another professor emphasizes that “there has to be a balance” between research conducted for curiosity and that which has a specific goal. Both researchers say they fear that Harvard's real motive in the Allston project is largely economic: more grants and closer ties with industry. And there is big money to be had. In May, NIH awarded Harvard Medical School $117.5 million as part of a larger initiative to conduct bench-to-bedside research with help from university faculty and affiliated medical centers.

    “It is not about the money,” insists Hyman. “We have a cultural history that devalues technology transfer and connections with industry to some degree. I've set about reforming that, and to have a closer connection to industry.” The purpose, he adds, is to tie research efforts to combating diseases and mental health disorders. But closer ties to industry can backfire, too. Last month, a Senate investigation revealed that a well-known Harvard child psychiatrist and a medical school colleague did not report large sums in consulting fees from drug companies as university rules require (Science, 27 June, p. 1708).

    Some scientists remain unconvinced that Allston provides the best way for Harvard to assure preeminence in the life and physical sciences. Last fall, biologist and Nobelist James Watson dismissed the new campus as an “almost Soviet-style fantasy,” a misguided attempt to create a centrally planned mass of buildings to fix a problem that he said has more to do with long-term lack of funding for basic research. And Harvard molecular biologist John Dowling says that although Allston is “a terrific idea, at the moment we don't need it,” noting that a 46,452-square-meter building opening this fall on the main campus will unite neuroscientists and biologists. (The new facility, although welcomed by neuroscientists, comes 3 years after MIT dedicated its brain and cognitive science building.) “Beyond stem cells, it is not clear what role Allston will play,” notes Dowling.

    Yet most criticism of the new campus has waned since Summers's departure 2 years ago. It helps that Faust has promised a more collaborative and slower approach. “You have to start somewhere, and Allston is on a very, very good trajectory to serve real programmatic needs,” says Hyman.

    That positive trajectory allows Hyman time to feed a voracious intellectual appetite. Along with his administrative duties, he teaches an undergraduate course on neuroscience ethics, edits an annual review of neuroscience, and reviews for several journals on the side. In one corner of his wood-paneled office in Massachusetts Hall sits a well-used coffee machine. “I'm down to 20 espressos a day,” he says. “There's just not enough time to brew it.”


    Poles Apart

    1. Constance Holden

    The number of children and adolescents diagnosed with bipolar disorder has been rising sharply, prompting debate and research on how the illness should be characterized in young people.

    The number of children and adolescents diagnosed with bipolar disorder has been rising sharply, prompting debate and research on how the illness should be characterized in young people

    Bipolar disorder used to be considered a disease of adulthood. Most mental health professionals assumed that the first episode of mania—the defining event for the illness—rarely occur red before people reached their 20s and might not hit until middle age. It came as a surprise to some, then, when two studies published last year documented a dramatic increase over a decade in the number of children identified with the disease.


    A U.S. survey* revealed that in 2003, 1% of the population under 20 received the diagnosis—a 40-fold leap since 1994. Another study indicated that up to five times as many U.S. children and adolescents were hospitalized for bipolar illness in 2004 as in 1996. No one knows for sure “whether there is an increase in these very disturbed kids or whether they are being relabeled,” says psychiatrist Gabrielle Carlson of Stony Brook University School of Medicine on Long Island.

    Critics of psychiatry such as psychiatrist David Healy of Cardiff University in the U.K. attribute at least part of the increase to the influence of the pharmaceutical industry, which they believe leads to over-diagnosis by encouraging doctors to prescribe the latest drugs for problem children.

    The debate has been fueled by recent allegations that Harvard University psychiatrist Joseph Biederman, a leading proponent of the idea that many childhood disorders are actually bipolar illness, has received substantial support from drug companies. Biederman, who says “there were no conflict-of-interest violations” in his ties to industry, insists that the increase in diagnoses more closely reflects the real incidence of the disease. “I spend my days dealing with these populations” of troubled children at Massachusetts General Hospital (MGH) in Boston. “I can tell you it's a very desperate state of affairs.”

    Other researchers agree that the numbers don't exaggerate the problem. “We don't go out in the street and offer meds to children,” says psychiatrist Christoph Correll of the Albert Einstein College of Medicine in New York city. “They are sent to us.”

    The stakes are high. A wrong diagnosis could consign a person to decades of inappropriate drug treatment; failure to spot the disease can lead to many years of misery—as was the case with child actress Patty Duke, who recounted at this year's annual meeting of the American Psychiatric Association (APA) in Washington, D.C., that she suffered for more than 15 years before being diagnosed with bipolar disorder at age 35. But getting the diagnosis right is difficult because there are no objective tests for bipolar disorder, and the disease in children can look very different from that in adults.

    An upward trend

    The disorder used to be known as manic depression. The change in name was sparked in part to avoid the somewhat derogatory word “manic” but also for accuracy. A person's primary tilt may be toward one or the other mood extreme—more often, depression—although mania is the tip-off. The trouble is, it's often hard to distinguish mania from a welter of other symptoms and problems, especially in children.

    Even in adults, bipolar disorder, estimated to afflict about 1% of the population, has been called “the great impersonator” because it comes in many guises and often coexists with other problems, says psychiatrist Husseini Manji of the U.S. National Institute of Mental Health (NIMH) in Bethesda, Maryland. And it's especially complicated because it's marked by two drastically different mood states: profoundly debilitating and often-suicidal depressions and intense phases of manic hyperactivity.


    With children, the disease is even more complex. They're “a moving target” when it comes to mental disorders, says Correll. Their fast-developing brains are unpredictable. They have difficulty expressing themselves, they have little or no history to guide the clinician, and it's often impossible to tell whether some behavior is pathological or just a twist in the path of normal development. What's more, children's symptoms do not simply mimic those of adults. Children are more likely to have “mixed” states that combine euphoric and destructive behavior.

    Partly for these reasons, it was not until 1995 that members of the Pediatric Psychopharmacology Unit at MGH published a paper suggesting that many children who were then being identified as hyperactive or having conduct disorders were in fact bipolar. Judging by the leap in diagnoses over the following decade, that finding resonated with pediatricians, says co-author Janet Wozniak, head of MGH's pediatric bipolar research program. It also jibes with recent studies of adult bipolar patients indicating that about 60% of them experienced the first symptoms before age 18.

    These troubled children are not just fidgety, noisy, whiny, sulky, or contrarian. They may be angry and self-destructive, prone to violent rages or dangerous impulses such as jumping out of a moving car during an argument, exhibit sexually inappropriate behavior, and risk losing touch with reality, says psychiatrist Barbara Geller of Washington University in St. Louis, Missouri. Geller adds that mania in a child may initially be hard to differentiate from childish giddiness. These children are “never serious, always acting up—they've been described by many parents as behaving as if they're little Jim Carreys,” she says. But there's an added element of grandiosity: “They'll get up and start teaching the class or tell coaches how to coach.”

    Such symptoms may seem distinctive, but mania is hard to recognize when it's mixed with a half-dozen other problems that youth is heir to. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), psychiatry's bible, contains many labels that could fit a troubled, acting-out child. Most common is attention deficit hyperactivity disorder (ADHD). Others include conduct disorder; anxiety disorders, including obsessive-compulsive disorder; and newer diagnoses such as “oppositional defiant disorder” and “intermittent explosive disorder.”

    Delayed diagnosis.

    Former child star Patty Duke, now 61, was diagnosed with bipolar disorder at the age of 35. In her late teens, she told psychiatrists at their May meeting, she experienced “eruptions of temper alternating with taking to bed for months at a time, getting up only to go to the bathroom and attempt suicide.”


    Narrow versus broad constructionists

    Clinicians roughly divide into two schools of thought over how broad a range of behaviors should be classified as bipolar, says Carlson. In an online seminar this year sponsored by the American Academy of Child and Adolescent Psychiatry (“What those in the know, know,”, Carlson described two cases that illustrate the challenge.

    One child, 13-year-old “Nicola,” is brought in by her parents because of a sudden behavior change over the previous 2 or 3 weeks. Formerly quiet, she is suddenly loud and grandiose, donning sexy clothing, talking constantly, and sleeping little. Her moods have become volatile, and she is easily driven to hysterical laughter or frustrated rages.

    The other, “Lynda,” 11, has been hyperactive since preschool, a condition that has been helped somewhat by stimulants (Ritalin). But lately it's gotten worse, and she has become unruly, explosive, aggressive, and provocative in her dress and behavior. She's developed some new habits including downloading porn on the computer and smoking marijuana. At the same time she's anxious and depressed, and she's falling behind in school.

    Are one or both of these girls bipolar? Some researchers, including a group at NIMH, take a conservative approach to the diagnosis. In the seminar, psychiatrist Ellen Leibenluft says she would diagnose Nicola as bipolar, tipped off by the sudden change in her personality. But Lynda's symptoms are not episodic, which the NIMH group believes is central to a bipolar diagnosis. To them, the problem looks like severe mood dysregulation (SMD), a category that Leibenluft's group has created to describe mood and behavior problems that persist over a number of years.

    The group at MGH, however, would diagnose both girls as bipolar. Wozniak puts more stock in Lynda's chronic irritability and explosive rages. Biederman, her boss, says such children have often been labeled as having ADHD. Yet, he says, ADHD is not fundamentally an emotional problem, and children like Lynda “are all the time in [emotional] turmoil.” It's “very clear,” says Biederman, that “these children had every symptom in DSM of mania.” It's just that they may have a lot of other things wrong as well.

    Psychiatrist Boris Birmaher of the University of Pittsburgh School of Medicine in Pennsylvania says, “I see the same [type of] kids as Biederman,” but he doesn't believe they're all bipolar. One way to assess the probability in a given case, he says, is to look at what's going on with a child's first-degree relatives. The disease is highly heritable, and studies have shown that the risk goes up 10-fold if a person has a bipolar parent.

    Carlson is also skeptical of Biederman's assessment. Bipolar children tend to grow into bipolar adults, she notes. Yet, “so far, what we know from long-term studies of ADHD and aggressive children” suggests that many of the type who might now be diagnosed as bipolar children grow up to be substance abusers, hotheads, and antisocial personalities—but not bipolar. Carlson is co-author of a forthcoming paper on a 23-year follow-up of 101 “high-risk” children into adulthood. Although all had big problems, she says, only “one-third of those with what some call a ‘bipolar phenotype’ developed adult-style bipolar disorder.”

    “Getting this [bipolar] diagnosis means putting people on meds for life,” says Manji, “so you kind of want to be sure we're treating the right thing.” Missing a diagnosis of bipolar disorder can also have serious repercussions: If a bipolar child is given medication for just ADHD, that can trigger mania, as can antidepressants. If someone is suspected of being bipolar, says Wozniak, they should be started on a mood stabilizer (lithium or an antiseizure drug) before getting medications for other conditions. And other drugs—for depression, anxiety, or ADHD—are almost always necessary. The average pediatric bipolar patient, clinicians say, is usually on three or four drugs.

    The bipolar brain

    Right now, physicians must make a diagnosis solely on behavioral symptoms: There is no test available for bipolar illness. Gene hunts have failed to come up with more than a list of possible suspects. And brain-imaging studies often produce conflicting information.

    Nonetheless, comparisons of brain functions between bipolar children and those with other diagnoses are yielding some intriguing clues that could eventually help in diagnosis. Psychiatrist Daniel Dickstein, formerly with Leibenluft's NIMH group and now at Brown University, thinks bipolar children have a deficit in the brain's “reward machinery.” Mania, he says, is a “hyperhedonic” state in which the brain is “excessively reward-sensitive.” Depression is the converse. He believes that teasing out different brain responses to a test involving rewards may help differentiate the brain mechanisms of bipolar illness from those of other psychiatric illnesses in children.

    Bipolar brain.

    Images show significantly greater activation in both the prefrontal cortex (top two panels) and primary motor cortex (bottom two) in 25 young people diagnosed with bipolar disorder than in controls matched by age, sex, and IQ. Activation in the prefrontal area also differentiated bipolar youth from those with severe mood disorder (SMD), according to research in press.


    The task Dickstein has used to probe these brain mechanisms assesses “reversal learning.” In this test, two groups of subjects are compared on a task in which they are rewarded for matching certain cards according to color, number, or shape; they have to learn by trial and error when rules are covertly changed by the experimenter. Fifty children aged 7 to 18 who exhibited classic cyclical bipolar illness—the kind readily recognizable in the DSM-IV—were compared with 44 others whom the NIMH group labeled as SMD: chronically irritable, agitated, and with ADHD-like symptoms. Both groups did worse than the controls on the tests, but the bipolar group—even though they were tested when in a normal mood—made more errors and took longer to learn the new rule (Journal of the American Academy of Child and Adolescent Psychiatry, March 2007). This indicates they have a harder time inhibiting a learned response that is no longer rewarded and replacing it with a new one that is. That, says Dickstein, suggests impaired “cognitive flexibility.”

    In as-yet-unpublished work, the NIMH group claims that brain imaging further bolsters this theory. Leibenluft reported at this year's APA meeting that the two groups could be distinguished on the basis of parietal lobe activity in response to a “change task” that requires subjects to switch gears cognitively, inhibiting one response and substituting a new one.

    Another type of task is designed to reveal poor regulation in both cognitive and emotional circuitry—as evidenced by lack of cognitive flexibility and emotional overreactivity. This is a frustrating computer game in which subjects are initially rewarded for speedily hitting the right button in a test; later they discover that no matter how fast they respond, they are told they lost because they weren't fast enough. During the test, Leibenluft and Brendan Rich compared a particular brain wave—the P3 wave, which reflects focused attention in the parietal lobe—in bipolar and SMD children compared with a group of normal controls. Both the bipolar and SMD groups reacted with more frustration than did the controls, the group reported in February 2007 in The American Journal of Psychiatry. But the brain waves of the bipolar children looked different. The amplitude of a much-studied brain wave, P3, was lower in this group, suggesting, says Leibenluft, that they weren't able to “mount the extra attentional effort” needed to overcome their emotional frustration.

    Other probes reinforce the picture of poor emotional regulation with bipolar illness. In a study also headed by Rich and published 6 June 2006 in the Proceedings of the National Academy of Sciences, Leibenluft's group compared brain images of 22 adolescents with 21 controls in reaction to images of facial expressions. There were no differences between the two groups in looking at a nonemotional facial feature: nose width. But those with the bipolar diagnosis saw more anger in the neutral faces and reported more fear when viewing them—showing correspondingly more activation in emotional brain areas, particularly the amygdala, the seat of fear.

    Some researchers suspect that bipolar disorder is linked to more far-flung perturbations in the nervous system. Dickstein, for example, thinks it may affect fine motor movements. He led a study comparing bipolar children, bipolar children who also had ADHD, and children diagnosed with just ADHD. The results, published in Biological Psychiatry in October 2005, indicated that the bipolar groups—both with and without ADHD—were slower than the ADHD group on a test that involved touching one's thumb to each of the four other digits in sequence and repeating the process four times, a chore that requires both motor and cognitive flexibility.

    Some scientists also believe that bipolar illness is linked to problems that extend beyond the nervous system to the endocrine and immune systems—as hinted by the fact that bipolar people have more than their share of other health problems, such as obesity, diabetes, hypothyroidism, migraine, and multiple sclerosis.

    Researchers believe that studying the disease in its earliest stages will be necessary to figure out what's really going on. Says Wozniak: “If it comes on in childhood, it stands to reason that starting our studies with children will yield better results. Symptoms in adults are complicated by meds and by years and years of illness. Studying them is like studying cancer only in the end stage.”

    • *C. Moreno et al., Archives of General Psychiatry, September 2007.

    • J.C. Blader and G. A. Carlson, Biological Psychiatry, 15 July 2007.


    Modernizing the Modern Synthesis

    1. Elizabeth Pennisi

    Seventy years ago, evolutionary biologists hammered out the modern synthesis to bring Darwin's ideas in line with current insights into how organisms change through time. Some say it's time for Modern Synthesis 2.0.

    Seventy years ago, evolutionary biologists hammered out the modern synthesis to bring Darwin's ideas in line with current insights into how organisms change through time. Some say it's time for Modern Synthesis 2.0


    Austria's Konrad Lorenz Institute for Evolution and Cognition Research is hosting a much-discussed evolutionary biology meeting.


    Massimo Pigliucci is no Jimi Hendrix. This soft-spoken evolutionary biologist from Stony Brook University in New York state looks nothing like that radical hard-rock musician whose dramatic guitar solos helped revolutionize rock ‘n'roll. But to Suzan Mazur, a veteran journalist who occasionally covers science, Pigliucci is the headliner this week at a small meeting she believes will be the equivalent of Woodstock for evolutionary biology. The invitation-only conference, being held in Altenberg, Austria, “promises to be far more transforming for the world” than the 1969 music festival, Mazur wrote online in March for, an independent news publication in New Zealand.

    That hyperbole has reverberated throughout the evolutionary biology community, putting Pigliucci and the 15 other participants at the forefront of a debate over whether ideas about evolution need updating. The mere mention of the “Altenberg 16,” as Mazur dubbed the group, causes some evolutionary biologists to roll their eyes. It's a joke, says Jerry Coyne of the University of Chicago in Illinois. “I don't think there's anything that needs fixing.” Mazur's attention, Pigliucci admits, “frankly caused me embarrassment.”

    Yet Pigliucci and others argue that the so-called modern synthesis, which has guided evolutionary thought and research for about 70 years, needs freshening up. A lot has happened in the past half-century. DNA's structure was revealed, genomes were sequenced, and developmental biologists turned their sights on evolutionary questions. Researchers have come to realize that heredity is not simply a matter of passing genes from parent to offspring, as the environment, chemical modification of DNA, and other factors come into play as well. Organisms vary not only in how they adapt to changing conditions but also in how they evolve.

    Evolution is much more nuanced than the founders of the modern synthesis fully appreciated, says Pigliucci. That doesn't mean that the overall theory of evolution is wrong, as some intelligent design proponents have tried to assert using Mazur's story as support, but rather that the modern synthesis needs to better incorporate modern science and the data revealed by it. More than genes pass on information from one generation to the next, for example, and development seems to help shape evolution's course. “Many things need fixing,” emphasizes one invited speaker, Eva Jablonka of Tel Aviv University in Israel. “I think that a new evolutionary synthesis is long overdue.”

    Daring duo.

    Massimo Pigliucci (right) and Gerd Müller want to update the modern synthesis.


    Modern tradition

    The modern synthesis essentially represents a marriage of the 19th century concept of evolution with Mendelian genetics, which was rediscovered at the beginning of the 20th century; the birth of population genetics in the 1920s added to the intellectual mix. By the 1940s, biologists had worked out a set of ideas that put natural selection and adaptation at evolution's core. Julian Huxley's 1942 book, Evolution: The modern synthesis, brought together this work for a broad audience.

    Simply put, the modern synthesis holds that organisms have a repertoire of traits that are passed down through the generations. Mutations in genes alter those traits bit by bit, and if conditions are such that those alterations make an individual more fit, then the altered trait becomes more common over time. This process is called natural selection. In some cases, the new feature can replace an old one; in other instances, natural selection also leads to speciation.

    However, several concepts have arisen since then that make the modern synthesis seem too simplistic to some, Pigliucci among them. In a 2007 Evolution paper, he called for the development of an “extended evolutionary synthesis.” His plea coincided with a similar one made that year by Gerd Müller, a theoretical biologist at the University of Vienna. Together, with support from the Konrad Lorenz Institute for Evolution and Cognition Research in Altenberg, they organized this week's conference, inviting many who share the view that the modern synthesis is incomplete. “What's happening now in evolutionary theory is as exciting and foundational as during the early days,” says David Wilson of Binghamton University in New York, another attendee.

    Beyond genes

    Insights from ecology, developmental biology, and genomics in particular are nudging evolutionary biology away from a focus on population genetics—how the distribution of genes changes across groups of individuals—and toward an understanding of the molecular underpinnings of these changes. Better family trees that give researchers greater confidence about the relatedness among organisms have helped promote a credible, comparative approach to these mechanisms, says invitee Günter Wagner, an evolutionary developmental biologist at Yale University.

    Some studies, for example, indicate that development constrains evolution. From the modern synthesis perspective, Wagner explains, “the body plan is a historical residue of evolutionary time, the afterglow of the evolutionary process” such that more closely related organisms share more features. The alternative view, he says, is that “body plans have internal inertia,” and evolution works around this stability.

    This perspective fits in well with that of Stuart Newman, another invitee to the conference. A developmental biologist at New York Medical College in Valhalla, Newman and Müller have focused on physical processes that guide how cells organize limbs, livers, hearts, and other tissues. The stickiness, elasticity, and chemical reactions within and between cells, for example, all influence where cells wind up in an organism. The duo thinks these processes helped define early multicellular life, a time when genetic systems were still quite primitive and body shapes were presumably more plastic than now.

    Their work suggests that body plans with interior spaces, segments, appendages, and multiple layers of tissue are inevitable. That's “heresy for the modern synthesis but inescapable if you incorporate physics into the picture,” says Newman. Studies of development that suggest how evolution proceeded—the so-called evo-devo approach—have yielded other insights, among them that genes and proteins are arranged in networks that have their own set of properties. “There are lots of interdependencies that allow only certain patterns of evolution to happen,” says Wagner.

    Much like networks, “regulation” is a new buzzword in biology circles; yet it's another concept virtually ignored in the modern synthesis. Scientists now grasp that gene activity, RNAs, and proteins are all under regulatory controls and that shifts in those controls likely drive evolution as much as traditional gene mutations that alter a protein's form. Harvard University's Marc Kirschner, for example, contends that organisms have long possessed “core” components—the machinery for energy metabolism, pattern formation during development, making cytoskeletons, or cell signaling—that have persisted relatively intact through time. But he proposes that genetic changes that alter when and where in the developing body these components are used have helped create modern diversity.

    Wagner thinks that by virtue of the breadth of genes they influence, transcription factors may be central to the type of evolutionary shifts Kirschner proposes. Changing the regulation of a few factors, even one, could help coordinate the systemic changes needed to make a new trait, helping to ensure that larger muscles coevolve with bigger jawbones for a more powerful bite, for example. Bottom line: “New traits contain very little that is new in the way of functional components, whereas regulatory change is crucial,” Kirschner and John Gerhart of the University of California, Berkeley, wrote in a supplement to the 15 May 2007 issue of the Proceedings of the National Academy of Sciences.

    The modern synthesis also doesn't take into account epigenetics. A small chemical modification of a DNA base—the addition of a methyl group, for example—can turn a gene off or on as easily as a mutation. Molecular biologists have long known about such epigenetic effects, but only recently have they demonstrated that methylation tags and other epigenetic marks that silence or activate genes can travel from one generation to the next. That potentially creates a “bewildering increase in the complexity of the entire inheritance system,” Pigliucci asserted in his 2007 call to arms.

    Certain environmental conditions, such as diet during gestation, can alter the epigenetic patterns of the resulting offspring, and new traits that result can last for generations, says Jablonka, who has been striving to get recognition for this mode of inheritance for years. For example, in a study conducted several years ago, pregnant mice injected with an endocrine disrupter gave birth to males with reduced fertility, whose subsequent sons, grandsons, and even great-grandsons were likewise affected. Each generation had inherited the same altered methylation pattern of DNA (Science, 3 June 2005, p. 1466). “It's beginning to be accepted that [epigenetics] may actually have something to contribute to evolution,” says Jablonka.

    She argues that because these chemical modifications change how tightly wound DNA is, they also influence other properties of a genome that are relevant to evolution. The coiling of a DNA strand, she points out, can alter the rate of mutation, the ease by which mobile elements can move around, the duplication of genes, and even how much gene exchange occurs between matching chromosomes.

    Beyond reason?

    As the Altenberg 16 seek to modernize the modern synthesis, other unconventional ideas will be on the table. One is evolvability, the inherent capacity of an organism or a population, even a species, to respond to a changing environment. Introduced about 20 years ago, the concept can help explain why certain groups of organisms readily and rapidly diversified. Consider vertebrate toes: Amphibians have a wider range in digit number than, say, reptiles, which may indicate that the former are more evolvable for that trait, Pigliucci points out. But the question remains whether natural selection favors more evolvable organisms. If the idea of evolvability wasn't radical enough, a few researchers have proposed that organisms can stock up mutations whose effects manifest themselves only when the right circumstances arise.

    Both ideas have their skeptics. “I don't believe organisms have a closet where they maintain all this genetic variation,” says Douglas Schemske, an evolutionary biologist at Michigan State University in East Lansing.

    Even among those coming to Altenberg, there's far from universal agreement. Wagner finds epigenetic inheritance hard to swallow. “I haven't been convinced,” he says. And some outside the Altenberg 16 don't see what all the fuss is about. “I'm happy” with the modern synthesis, says George Weiblen, an evolutionary biologist at the University of Minnesota, Minneapolis. Others note that some of the items on the meeting's agenda, such as the role of plasticity in looks and behavior in evolution, have fallen in and out of favor for decades. “It's like selling old wine in new bottles,” says Thomas Flatt of Brown University.

    But these criticisms don't faze Altenberg's organizers. The modern synthesis emerged from at least a decade's worth of discussions. “The crucial point of the workshop is bringing these concepts together,” says Müller. And no one truly expects a scientific Woodstock. “Woodstock was an immensely popular event celebrating a new musical mainstream,” says Newman. “I imagine this will be more like a jam session circa 1962.”

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